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  1. Telomerase and Tel1p Preferentially Associate with Short Telomeres in S. cerevisiae

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    Sabourin, Michelle; Tuzon, Creighton T.; Zakian, Virginia A.

    2009-01-01

    SUMMARY In diverse organisms, telomerase preferentially elongates short telomeres. We generated a single short telomere in otherwise wild-type (WT) S. cerevisiae cells. The binding of the positive regulators Ku and Cdc13p was similar at short and WT-length telomeres. The negative regulators Rif1p and Rif2p were present at the short telomere, although Rif2p levels were reduced. Two telomerase holoenzyme components, Est1p and Est2p, were preferentially enriched at short telomeres in late S/G2 phase, the time of telomerase action. Tel1p, the yeast ATM-like checkpoint kinase, was highly enriched at short telomeres from early S through G2 phase and even into the next cell cycle. Nonetheless, induction of a single short telomere did not elicit a cell-cycle arrest. Tel1p binding was dependent on Xrs2p and required for preferential binding of telomerase to short telomeres. These data suggest that Tel1p targets telomerase to the DNA ends most in need of extension. PMID:17656141

  2. Telomerers rolle i cancer

    DEFF Research Database (Denmark)

    Bendix, Laila; Kølvraa, Steen

    2010-01-01

    Telomeres are a double-edged sword when it comes to cancer. On one hand, telomeres limit the cells' ability to divide and thereby restrict the uninhibited growth seen in cancer. On the other hand, short telomeres can initiate the chromosome instability that characterizes cancer. Diseases...... with the combination of short telomeres and high cancer risk are seen, but until now the use of telomeres as predictors of cancer has, in general, been unsuccessful. Telomeres and telomerase play an important role in further cancer development. Researchers are trying to exploit this in the development of new cancer...

  3. The distribution pattern of critically short telomeres in human osteoarthritic knees

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    Harbo, Maria; Bendix, Laila; Bay-Jensen, Anne Christine

    2012-01-01

    ABSTRACT: INTRODUCTION: Telomere shortening is associated with a number of common age-related diseases. A role of telomere shortening in osteoarthritis (OA) has been suggested, mainly based on the assessment of mean telomere length in ex vivo expanded chondrocytes. We addressed this role directly...... in vivo by using a newly developed assay, which measures specifically the load of ultra-short single telomeres (below 1,500 base pairs), that is, the telomere subpopulation believed to promote cellular senescence. METHODS: Samples were obtained from human OA knees at two distances from the central lesion...... site. Each sample was split into three: one was used for quantification of ultra-short single telomeres through the Universal single telomere length assay (STELA), one for histological Mankin grading of OA, and one for mean telomere length measurement through quantitative fluorescence in situ...

  4. Regulation of homologous recombination at telomeres in budding yeast

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    Eckert-Boulet, Nadine; Lisby, Michael

    2010-01-01

    Homologous recombination is suppressed at normal length telomere sequences. In contrast, telomere recombination is allowed when telomeres erode in the absence of telomerase activity or as a consequence of nucleolytic degradation or incomplete replication. Here, we review the mechanisms that contr...... that contribute to regulating mitotic homologous recombination at telomeres and the role of these mechanisms in signalling short telomeres in the budding yeast Saccharomyces cerevisiae....

  5. Disrupted lymphocyte homeostasis in hepatitis‐associated acquired aplastic anemia is associated with short telomeres

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    Babushok, Daria V.; Grignon, Anne‐Laure; Li, Yimei; Atienza, Jamie; Xie, Hongbo M.; Lam, Ho‐Sun; Hartung, Helge; Bessler, Monica

    2016-01-01

    Hepatitis‐associated aplastic anemia (HAA) is a variant of acquired aplastic anemia (AA) in which immune‐mediated bone marrow failure (BMF) develops following an acute episode of seronegative hepatitis. Dyskeratosis congenita (DC) is an inherited BMF syndrome characterized by the presence of short telomeres, mucocutaneous abnormalities, and cancer predisposition. While both conditions may cause BMF and hepatic impairment, therapeutic approaches are distinct, making it imperative to establish the correct diagnosis. In clinical practice, lymphocyte telomere lengths (TL) are used as a first‐line screen to rule out inherited telomeropathies before initiating treatment for AA. To evaluate the reliability of TL in the HAA population, we performed a retrospective analysis of TL in 10 consecutively enrolled HAA patients compared to 19 patients with idiopathic AA (IAA). HAA patients had significantly shorter telomeres than IAA patients (P = 0.009), including four patients with TL at or below the 1st percentile for age‐matched controls. HAA patients had no clinical features of DC and did not carry disease‐causing mutations in known genes associated with inherited telomere disorders. Instead, short TLs were significantly correlated with severe lymphopenia and skewed lymphocyte subsets, features characteristic of HAA. Our results indicate the importance of caution in the interpretation of TL measurements in HAA, because, in this patient population, short telomeres have limited specificity. Am. J. Hematol. 91:243–247, 2016. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc. PMID:26615915

  6. Telomeres: Implications for Cancer Development

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    Aina Bernal

    2018-01-01

    Full Text Available Telomeres facilitate the protection of natural ends of chromosomes from constitutive exposure to the DNA damage response (DDR. This is most likely achieved by a lariat structure that hides the linear telomeric DNA through protein-protein and protein-DNA interactions. The telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in unmasked telomeres. Then, the subsequent activation of the DDR will define the fate of cells according to the functionality of cell cycle checkpoints. Dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptotic pathways, but they can also promote tumour initiation. Studies in telomere dynamics and karyotype analysis underpin telomere crisis as a key event driving genomic instability. Significant attainment of telomerase or alternative lengthening of telomeres (ALT-pathway to maintain telomere length may be permissive and required for clonal evolution of genomically-unstable cells during progression to malignancy. We summarise current knowledge of the role of telomeres in the maintenance of chromosomal stability and carcinogenesis.

  7. Drosophila atm/telomere fusion is required for telomeric localization of HP1 and telomere position effect.

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    Oikemus, Sarah R; McGinnis, Nadine; Queiroz-Machado, Joana; Tukachinsky, Hanna; Takada, Saeko; Sunkel, Claudio E; Brodsky, Michael H

    2004-08-01

    Terminal deletions of Drosophila chromosomes can be stably protected from end-to-end fusion despite the absence of all telomere-associated sequences. The sequence-independent protection of these telomeres suggests that recognition of chromosome ends might contribute to the epigenetic protection of telomeres. In mammals, Ataxia Telangiectasia Mutated (ATM) is activated by DNA damage and acts through an unknown, telomerase-independent mechanism to regulate telomere length and protection. We demonstrate that the Drosophila homolog of ATM is encoded by the telomere fusion (tefu) gene. In the absence of ATM, telomere fusions occur even though telomere-specific Het-A sequences are still present. High levels of spontaneous apoptosis are observed in ATM-deficient tissues, indicating that telomere dysfunction induces apoptosis in Drosophila. Suppression of this apoptosis by p53 mutations suggests that loss of ATM activates apoptosis through a DNA damage-response mechanism. Loss of ATM reduces the levels of heterochromatin protein 1 (HP1) at telomeres and suppresses telomere position effect. We propose that recognition of chromosome ends by ATM prevents telomere fusion and apoptosis by recruiting chromatin-modifying complexes to telomeres.

  8. Human MLH1 suppresses the insertion of telomeric sequences at intra-chromosomal sites in telomerase-expressing cells

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    Jia, Pingping; Chastain, Megan; Zou, Ying; Her, Chengtao

    2017-01-01

    Abstract Aberrant formation of interstitial telomeric sequences (ITSs) promotes genome instabilities. However, it is unclear how aberrant ITS formation is suppressed in human cells. Here, we report that MLH1, a key protein involved in mismatch repair (MMR), suppresses telomeric sequence insertion (TSI) at intra-chromosomal regions. The frequency of TSI can be elevated by double-strand break (DSB) inducer and abolished by ATM/ATR inhibition. Suppression of TSI requires MLH1 recruitment to DSBs, indicating that MLH1's role in DSB response/repair is important for suppressing TSI. Moreover, TSI requires telomerase activity but is independent of the functional status of p53 and Rb. Lastly, we show that TSI is associated with chromosome instabilities including chromosome loss, micronuclei formation and chromosome breakage that are further elevated by replication stress. Our studies uncover a novel link between MLH1, telomerase, telomere and genome stability. PMID:28180301

  9. Rif1 acts through Protein Phosphatase 1 but independent of replication timing to suppress telomere extension in budding yeast.

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    Kedziora, Sylwia; Gali, Vamsi K; Wilson, Rosemary H C; Clark, Kate R M; Nieduszynski, Conrad A; Hiraga, Shin-Ichiro; Donaldson, Anne D

    2018-05-04

    The Rif1 protein negatively regulates telomeric TG repeat length in the budding yeast Saccharomyces cerevisiae, but how it prevents telomere over-extension is unknown. Rif1 was recently shown to control DNA replication by acting as a Protein Phosphatase 1 (PP1)-targeting subunit. Therefore, we investigated whether Rif1 controls telomere length by targeting PP1 activity. We find that a Rif1 mutant defective for PP1 interaction causes a long-telomere phenotype, similar to that of rif1Δ cells. Tethering PP1 at a specific telomere partially substitutes for Rif1 in limiting TG repeat length, confirming the importance of PP1 in telomere length control. Ablating Rif1-PP1 interaction is known to cause precocious activation of telomere-proximal replication origins and aberrantly early telomere replication. However, we find that Rif1 still limits telomere length even if late replication is forced through deletion of nearby replication origins, indicating that Rif1 can control telomere length independent of replication timing. Moreover we find that, even at a de novo telomere created after DNA synthesis during a mitotic block, Rif1-PP1 interaction is required to suppress telomere lengthening and prevent inappropriate recruitment of Tel1 kinase. Overall, our results show that Rif1 controls telomere length by recruiting PP1 to directly suppress telomerase-mediated TG repeat lengthening.

  10. The relationship between ultra-short telomeres, aging of articular cartilage and the development of human hip osteoarthritis

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    Harbo, M; Delaisse, J M; Kjaersgaard-Andersen, P

    2013-01-01

    Ultra-short telomeres caused by stress-induced telomere shortening are suggested to induce chondrocyte senescence in human osteoarthritic knees. Here we have further investigated the role of ultra-short telomeres in the development of osteoarthritis (OA) and in aging of articular cartilage in human...

  11. The Long and Short of It: The Role of Telomeres in Fetal Origins of Adult Disease

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    Stephanie E. Hallows

    2012-01-01

    Full Text Available Placental insufficiency, maternal malnutrition, and other causes of intrauterine growth restriction (IUGR can significantly affect short-term growth and long-term health. Following IUGR, there is an increased risk for cardiovascular disease and Type 2 Diabetes. The etiology of these diseases is beginning to be elucidated, and premature aging or cellular senescence through increased oxidative stress and DNA damage to telomeric ends may be initiators of these disease processes. This paper will explore the areas where telomere and telomerase biology can have significant effects on various tissues in the body in IUGR outcomes.

  12. Short telomere length, lung function and chronic obstructive pulmonary disease in 46,396 individuals

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    Rode, Line; Bojesen, Stig Egil; Weischer, Maren

    2013-01-01

    A previous case-control study of 100 individuals found that short telomere length was associated with a 28-fold increased risk of chronic obstructive pulmonary disease (COPD).......A previous case-control study of 100 individuals found that short telomere length was associated with a 28-fold increased risk of chronic obstructive pulmonary disease (COPD)....

  13. Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability.

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    Le Guen, Tangui; Jullien, Laurent; Touzot, Fabien; Schertzer, Michael; Gaillard, Laetitia; Perderiset, Mylène; Carpentier, Wassila; Nitschke, Patrick; Picard, Capucine; Couillault, Gérard; Soulier, Jean; Fischer, Alain; Callebaut, Isabelle; Jabado, Nada; Londono-Vallejo, Arturo; de Villartay, Jean-Pierre; Revy, Patrick

    2013-08-15

    Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrow failure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomere dysfunction and these diseases. By combining whole-genome linkage analysis and exome sequencing, we identified compound heterozygous RTEL1 (regulator of telomere elongation helicase 1) mutations in three patients with HHS from two unrelated families. RTEL1 is a DNA helicase that participates in DNA replication, DNA repair and telomere integrity. We show that, in addition to short telomeres, RTEL1-deficient cells from patients exhibit hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges and telomeric aberrations. Collectively, these results identify RTEL1 as a novel HHS-causing gene and highlight its role as a genomic caretaker in humans.

  14. Telomere length and depression

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    Wium-Andersen, Marie Kim; Ørsted, David Dynnes; Rode, Line

    2017-01-01

    BACKGROUND: Depression has been cross-sectionally associated with short telomeres as a measure of biological age. However, the direction and nature of the association is currently unclear. AIMS: We examined whether short telomere length is associated with depression cross-sectionally as well...... as prospectively and genetically. METHOD: Telomere length and three polymorphisms, TERT, TERC and OBFC1, were measured in 67 306 individuals aged 20-100 years from the Danish general population and associated with register-based attendance at hospital for depression and purchase of antidepressant medication....... RESULTS: Attendance at hospital for depression was associated with short telomere length cross-sectionally, but not prospectively. Further, purchase of antidepressant medication was not associated with short telomere length cross-sectionally or prospectively. Mean follow-up was 7.6 years (range 0...

  15. Escape from Telomere-Driven Crisis Is DNA Ligase III Dependent

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    Rhiannon E. Jones

    2014-08-01

    Full Text Available Short dysfunctional telomeres are capable of fusion, generating dicentric chromosomes and initiating breakage-fusion-bridge cycles. Cells that escape the ensuing cellular crisis exhibit large-scale genomic rearrangements that drive clonal evolution and malignant progression. We demonstrate that there is an absolute requirement for fully functional DNA ligase III (LIG3, but not ligase IV (LIG4, to facilitate the escape from a telomere-driven crisis. LIG3- and LIG4-dependent alternative (A and classical (C nonhomologous end-joining (NHEJ pathways were capable of mediating the fusion of short dysfunctional telomeres, both displaying characteristic patterns of microhomology and deletion. Cells that failed to escape crisis exhibited increased proportions of C-NHEJ-mediated interchromosomal fusions, whereas those that escaped displayed increased proportions of intrachromosomal fusions. We propose that the balance between inter- and intrachromosomal telomere fusions dictates the ability of human cells to escape crisis and is influenced by the relative activities of A- and C-NHEJ at short dysfunctional telomeres.

  16. Telomeric repeat-containing RNA/G-quadruplex-forming sequences cause genome-wide alteration of gene expression in human cancer cells in vivo.

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    Hirashima, Kyotaro; Seimiya, Hiroyuki

    2015-02-27

    Telomere erosion causes cell mortality, suggesting that longer telomeres enable more cell divisions. In telomerase-positive human cancer cells, however, telomeres are often kept shorter than those of surrounding normal tissues. Recently, we showed that cancer cell telomere elongation represses innate immune genes and promotes their differentiation in vivo. This implies that short telomeres contribute to cancer malignancy, but it is unclear how such genetic repression is caused by elongated telomeres. Here, we report that telomeric repeat-containing RNA (TERRA) induces a genome-wide alteration of gene expression in telomere-elongated cancer cells. Using three different cell lines, we found that telomere elongation up-regulates TERRA signal and down-regulates innate immune genes such as STAT1, ISG15 and OAS3 in vivo. Ectopic TERRA oligonucleotides repressed these genes even in cells with short telomeres under three-dimensional culture conditions. This appeared to occur from the action of G-quadruplexes (G4) in TERRA, because control oligonucleotides had no effect and a nontelomeric G4-forming oligonucleotide phenocopied the TERRA oligonucleotide. Telomere elongation and G4-forming oligonucleotides showed similar gene expression signatures. Most of the commonly suppressed genes were involved in the innate immune system and were up-regulated in various cancers. We propose that TERRA G4 counteracts cancer malignancy by suppressing innate immune genes. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  17. RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity.

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    Vannier, Jean-Baptiste; Pavicic-Kaltenbrunner, Visnja; Petalcorin, Mark I R; Ding, Hao; Boulton, Simon J

    2012-05-11

    T loops and telomeric G-quadruplex (G4) DNA structures pose a potential threat to genome stability and must be dismantled to permit efficient telomere replication. Here we implicate the helicase RTEL1 in the removal of telomeric DNA secondary structures, which is essential for preventing telomere fragility and loss. In the absence of RTEL1, T loops are inappropriately resolved by the SLX4 nuclease complex, resulting in loss of the telomere as a circle. Depleting SLX4 or blocking DNA replication abolished telomere circles (TCs) and rescued telomere loss in RTEL1(-/-) cells but failed to suppress telomere fragility. Conversely, stabilization of telomeric G4-DNA or loss of BLM dramatically enhanced telomere fragility in RTEL1-deficient cells but had no impact on TC formation or telomere loss. We propose that RTEL1 performs two distinct functions at telomeres: it disassembles T loops and also counteracts telomeric G4-DNA structures, which together ensure the dynamics and stability of the telomere. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Telomere length analysis.

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    Canela, Andrés; Klatt, Peter; Blasco, María A

    2007-01-01

    Most somatic cells of long-lived species undergo telomere shortening throughout life. Critically short telomeres trigger loss of cell viability in tissues, which has been related to alteration of tissue function and loss of regenerative capabilities in aging and aging-related diseases. Hence, telomere length is an important biomarker for aging and can be used in the prognosis of aging diseases. These facts highlight the importance of developing methods for telomere length determination that can be employed to evaluate telomere length during the human aging process. Telomere length quantification methods have improved greatly in accuracy and sensitivity since the development of the conventional telomeric Southern blot. Here, we describe the different methodologies recently developed for telomere length quantification, as well as their potential applications for human aging studies.

  19. Telomere dysfunction and chromosome instability

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    Murnane, John P., E-mail: jmurnane@radonc.ucsf.edu [Department of Radiation Oncology, University of California San Francisco, 2340 Sutter Street, San Francisco, CA 94143-1331 (United States)

    2012-02-01

    The ends of chromosomes are composed of a short repeat sequence and associated proteins that together form a cap, called a telomere, that keeps the ends from appearing as double-strand breaks (DSBs) and prevents chromosome fusion. The loss of telomeric repeat sequences or deficiencies in telomeric proteins can result in chromosome fusion and lead to chromosome instability. The similarity between chromosome rearrangements resulting from telomere loss and those found in cancer cells implicates telomere loss as an important mechanism for the chromosome instability contributing to human cancer. Telomere loss in cancer cells can occur through gradual shortening due to insufficient telomerase, the protein that maintains telomeres. However, cancer cells often have a high rate of spontaneous telomere loss despite the expression of telomerase, which has been proposed to result from a combination of oncogene-mediated replication stress and a deficiency in DSB repair in telomeric regions. Chromosome fusion in mammalian cells primarily involves nonhomologous end joining (NHEJ), which is the major form of DSB repair. Chromosome fusion initiates chromosome instability involving breakage-fusion-bridge (B/F/B) cycles, in which dicentric chromosomes form bridges and break as the cell attempts to divide, repeating the process in subsequent cell cycles. Fusion between sister chromatids results in large inverted repeats on the end of the chromosome, which amplify further following additional B/F/B cycles. B/F/B cycles continue until the chromosome acquires a new telomere, most often by translocation of the end of another chromosome. The instability is not confined to a chromosome that loses its telomere, because the instability is transferred to the chromosome donating a translocation. Moreover, the amplified regions are unstable and form extrachromosomal DNA that can reintegrate at new locations. Knowledge concerning the factors promoting telomere loss and its consequences is

  20. Short telomeres in hatchling snakes: erythrocyte telomere dynamics and longevity in tropical pythons.

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    Beata Ujvari

    Full Text Available BACKGROUND: Telomere length (TL has been found to be associated with life span in birds and humans. However, other studies have demonstrated that TL does not affect survival among old humans. Furthermore, replicative senescence has been shown to be induced by changes in the protected status of the telomeres rather than the loss of TL. In the present study we explore whether age- and sex-specific telomere dynamics affect life span in a long-lived snake, the water python (Liasis fuscus. METHODOLOGY/PRINCIPAL FINDINGS: Erythrocyte TL was measured using the Telo TAGGG TL Assay Kit (Roche. In contrast to other vertebrates, TL of hatchling pythons was significantly shorter than that of older snakes. However, during their first year of life hatchling TL increased substantially. While TL of older snakes decreased with age, we did not observe any correlation between TL and age in cross-sectional sampling. In older snakes, female TL was longer than that of males. When using recapture as a proxy for survival, our results do not support that longer telomeres resulted in an increased water python survival/longevity. CONCLUSIONS/SIGNIFICANCE: In fish high telomerase activity has been observed in somatic cells exhibiting high proliferation rates. Hatchling pythons show similar high somatic cell proliferation rates. Thus, the increase in TL of this group may have been caused by increased telomerase activity. In older humans female TL is longer than that of males. This has been suggested to be caused by high estrogen levels that stimulate increased telomerase activity. Thus, high estrogen levels may also have caused the longer telomeres in female pythons. The lack of correlation between TL and age among old snakes and the fact that longer telomeres did not appear to affect python survival do not support that erythrocyte telomere dynamics has a major impact on water python longevity.

  1. Short telomeres in hatchling snakes: erythrocyte telomere dynamics and longevity in tropical pythons.

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    Ujvari, Beata; Madsen, Thomas

    2009-10-16

    Telomere length (TL) has been found to be associated with life span in birds and humans. However, other studies have demonstrated that TL does not affect survival among old humans. Furthermore, replicative senescence has been shown to be induced by changes in the protected status of the telomeres rather than the loss of TL. In the present study we explore whether age- and sex-specific telomere dynamics affect life span in a long-lived snake, the water python (Liasis fuscus). Erythrocyte TL was measured using the Telo TAGGG TL Assay Kit (Roche). In contrast to other vertebrates, TL of hatchling pythons was significantly shorter than that of older snakes. However, during their first year of life hatchling TL increased substantially. While TL of older snakes decreased with age, we did not observe any correlation between TL and age in cross-sectional sampling. In older snakes, female TL was longer than that of males. When using recapture as a proxy for survival, our results do not support that longer telomeres resulted in an increased water python survival/longevity. In fish high telomerase activity has been observed in somatic cells exhibiting high proliferation rates. Hatchling pythons show similar high somatic cell proliferation rates. Thus, the increase in TL of this group may have been caused by increased telomerase activity. In older humans female TL is longer than that of males. This has been suggested to be caused by high estrogen levels that stimulate increased telomerase activity. Thus, high estrogen levels may also have caused the longer telomeres in female pythons. The lack of correlation between TL and age among old snakes and the fact that longer telomeres did not appear to affect python survival do not support that erythrocyte telomere dynamics has a major impact on water python longevity.

  2. Mre11 and Blm-Dependent Formation of ALT-Like Telomeres in Ku-Deficient Ustilago maydis.

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    Eun Young Yu

    2015-10-01

    Full Text Available A subset of human cancer cells uses a specialized, aberrant recombination pathway known as ALT to maintain telomeres, which in these cells are characterized by complex aberrations including length heterogeneity, high levels of unpaired C-strand, and accumulation of extra-chromosomal telomere repeats (ECTR. These phenotypes have not been recapitulated in any standard budding or fission yeast mutant. We found that eliminating Ku70 or Ku80 in the yeast-like fungus Ustilago maydis results initially in all the characteristic telomere aberrations of ALT cancer cells, including C-circles, a highly specific marker of ALT. Subsequently the ku mutants experience permanent G2 cell cycle arrest, accompanied by loss of telomere repeats from chromosome ends and even more drastic accumulation of very short ECTRs (vsECTRs. The deletion of atr1 or chk1 rescued the lethality of the ku mutant, and "trapped" the telomere aberrations in the early ALT-like stage. Telomere abnormalities are telomerase-independent, but dramatically suppressed by deletion of mre11 or blm, suggesting major roles for these factors in the induction of the ALT pathway. In contrast, removal of other DNA damage response and repair factors such as Rad51 has disparate effects on the ALT phenotypes, suggesting that these factors process ALT intermediates or products. Notably, the antagonism of Ku and Mre11 in the induction of ALT is reminiscent of their roles in DSB resection, in which Blm is also known to play a key role. We suggest that an aberrant resection reaction may constitute an early trigger for ALT telomeres, and that the outcomes of ALT are distinct from DSB because of the unique telomere nucleoprotein structure.

  3. Therapeutic effect of androgen therapy in a mouse model of aplastic anemia produced by short telomeres.

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    Bär, Christian; Huber, Nicolas; Beier, Fabian; Blasco, Maria A

    2015-10-01

    Aplastic anemia is a rare but life-threatening disorder characterized by cytopenia in at least two of the three blood lineages. A frequent feature of patients with aplastic anemia is that they have shorter telomeres than those of age-matched controls. Testosterone has been used for over half a century in the treatment of aplastic anemia. However, although remissions are frequent following hormone therapy, the molecular mechanism underlying the response to treatment has remained unknown. Here we explored the possibility that the recently described regulation of telomerase activity by sex hormones may be the mechanism responsible. To this end, we used a mouse model of aplastic anemia induced by short telomeres in the bone marrow compartment. We found that testosterone therapy results in telomerase up-regulation, improved blood counts, and a significant extension of life-span of these mice. Importantly, longitudinal follow-up studies revealed longer telomeres in peripheral blood in mice subjected to hormone treatment. Our results demonstrate that testosterone-mediated telomerase activation can attenuate or reverse aplastic anemia disease progression associated with the presence of short telomeres. Copyright© Ferrata Storti Foundation.

  4. Do Telomeres Adapt to Physiological Stress? Exploring the Effect of Exercise on Telomere Length and Telomere-Related Proteins

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    Andrew T. Ludlow

    2013-01-01

    Full Text Available Aging is associated with a tissue degeneration phenotype marked by a loss of tissue regenerative capacity. Regenerative capacity is dictated by environmental and genetic factors that govern the balance between damage and repair. The age-associated changes in the ability of tissues to replace lost or damaged cells is partly the cause of many age-related diseases such as Alzheimer's disease, cardiovascular disease, type II diabetes, and sarcopenia. A well-established marker of the aging process is the length of the protective cap at the ends of chromosomes, called telomeres. Telomeres shorten with each cell division and with increasing chronological age and short telomeres have been associated with a range of age-related diseases. Several studies have shown that chronic exposure to exercise (i.e., exercise training is associated with telomere length maintenance; however, recent evidence points out several controversial issues concerning tissue-specific telomere length responses. The goals of the review are to familiarize the reader with the current telomere dogma, review the literature exploring the interactions of exercise with telomere phenotypes, discuss the mechanistic research relating telomere dynamics to exercise stimuli, and finally propose future directions for work related to telomeres and physiological stress.

  5. Telomere Length Reprogramming in Embryos and Stem Cells

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    Keri Kalmbach

    2014-01-01

    Full Text Available Telomeres protect and cap linear chromosome ends, yet these genomic buffers erode over an organism’s lifespan. Short telomeres have been associated with many age-related conditions in humans, and genetic mutations resulting in short telomeres in humans manifest as syndromes of precocious aging. In women, telomere length limits a fertilized egg’s capacity to develop into a healthy embryo. Thus, telomere length must be reset with each subsequent generation. Although telomerase is purportedly responsible for restoring telomere DNA, recent studies have elucidated the role of alternative telomeres lengthening mechanisms in the reprogramming of early embryos and stem cells, which we review here.

  6. Reliability and short-term intra-individual variability of telomere length measurement using monochrome multiplexing quantitative PCR.

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    Sangmi Kim

    Full Text Available Studies examining the association between telomere length and cancer risk have often relied on measurement of telomere length from a single blood draw using a real-time PCR technique. We examined the reliability of telomere length measurement using sequential samples collected over a 9-month period.Relative telomere length in peripheral blood was estimated using a single tube monochrome multiplex quantitative PCR assay in blood DNA samples from 27 non-pregnant adult women (aged 35 to 74 years collected in 7 visits over a 9-month period. A linear mixed model was used to estimate the components of variance for telomere length measurements attributed to variation among women and variation between time points within women. Mean telomere length measurement at any single visit was not significantly different from the average of 7 visits. Plates had a significant systematic influence on telomere length measurements, although measurements between different plates were highly correlated. After controlling for plate effects, 64% of the remaining variance was estimated to be accounted for by variance due to subject. Variance explained by time of visit within a subject was minor, contributing 5% of the remaining variance.Our data demonstrate good short-term reliability of telomere length measurement using blood from a single draw. However, the existence of technical variability, particularly plate effects, reinforces the need for technical replicates and balancing of case and control samples across plates.

  7. Short telomeres: from dyskeratosis congenita to sporadic aplastic anemia and malignancy.

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    Gramatges, Maria M; Bertuch, Alison A

    2013-12-01

    Telomeres are DNA-protein structures that form a protective cap on chromosome ends. As such, they prevent the natural ends of linear chromosomes from being subjected to DNA repair activities that would result in telomere fusion, degradation, or recombination. Both the DNA and protein components of the telomere are required for this essential function, because insufficient telomeric DNA length, loss of the terminal telomeric DNA structure, or deficiency of key telomere-associated factors may elicit a DNA damage response and result in cellular senescence or apoptosis. In the setting of failed checkpoint mechanisms, such DNA-protein defects can also lead to genomic instability through telomere fusions or recombination. Thus, as shown in both model systems and in humans, defects in telomere biology are implicated in cellular and organismal aging as well as in tumorigenesis. Bone marrow failure and malignancy are 2 life-threatening disease manifestations in the inherited telomere biology disorder dyskeratosis congenita. We provide an overview of basic telomere structure and maintenance. We outline the telomere biology defects observed in dyskeratosis congenita, focusing on recent discoveries in this field. Last, we review the evidence of how telomere biology may impact sporadic aplastic anemia and the risk for various cancers. Copyright © 2013 Mosby, Inc. All rights reserved.

  8. Mitosis, double strand break repair, and telomeres: a view from the end: how telomeres and the DNA damage response cooperate during mitosis to maintain genome stability.

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    Cesare, Anthony J

    2014-11-01

    Double strand break (DSB) repair is suppressed during mitosis because RNF8 and downstream DNA damage response (DDR) factors, including 53BP1, do not localize to mitotic chromatin. Discovery of the mitotic kinase-dependent mechanism that inhibits DSB repair during cell division was recently reported. It was shown that restoring mitotic DSB repair was detrimental, resulting in repair dependent genome instability and covalent telomere fusions. The telomere DDR that occurs naturally during cellular aging and in cancer is known to be refractory to G2/M checkpoint activation. Such DDR-positive telomeres, and those that occur as part of the telomere-dependent prolonged mitotic arrest checkpoint, normally pass through mitosis without covalent ligation, but result in cell growth arrest in G1 phase. The discovery that suppressing DSB repair during mitosis may function primarily to protect DDR-positive telomeres from fusing during cell division reinforces the unique cooperation between telomeres and the DDR to mediate tumor suppression. © 2014 The Author. Bioessays published by WILEY Periodicals, Inc.

  9. Telomere Length and the Cancer-Atherosclerosis Trade-Off.

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    Rivka C Stone

    2016-07-01

    Full Text Available Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. In this communication, we discuss (a the genetics of human telomere length, a highly heritable complex trait that is influenced by genetic ancestry, sex, and paternal age at conception, (b how cancer might have played a role in the evolution of telomere biology across mammals, (c evidence that in modern humans telomere length is a determinant (rather than only a biomarker of cancer and atherosclerosis, and (d the potential influence of relatively recent evolutionary forces in fashioning the variation in telomere length across and within populations, and their likely lasting impact on major diseases in humans. Finally, we propose venues for future research on human telomere genetics in the context of its potential role in shaping the modern human lifespan.

  10. 3D nuclear organization of telomeres in the Hodgkin cell lines U-HO1 and U-HO1-PTPN1: PTPN1 expression prevents the formation of very short telomeres including "t-stumps"

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    Lemieux Bruno

    2010-12-01

    Full Text Available Abstract Background In cancer cells the three-dimensional (3D telomere organization of interphase nuclei into a telomeric disk is heavily distorted and aggregates are found. In Hodgkin's lymphoma quantitative FISH (3D Q-FISH reveals a major impact of nuclear telomere dynamics during the transition form mononuclear Hodgkin (H to diagnostic multinuclear Reed-Sternberg (RS cells. In vitro and in vivo formation of RS-cells is associated with the increase of very short telomeres including "t-stumps", telomere loss, telomeric aggregate formation and the generation of "ghost nuclei". Results Here we analyze the 3D telomere dynamics by Q-FISH in the novel Hodgkin cell line U-HO1 and its non-receptor protein-tyrosine phosphatase N1 (PTPN1 stable transfectant U-HO1-PTPN1, derived from a primary refractory Hodgkin's lymphoma. Both cell lines show equally high telomerase activity but U-HO1-PTPN differs from U-HO1 by a three times longer doubling time, low STAT5A expression, accumulation of RS-cells (p As expected, multinuclear U-HO1-RS-cells and multinuclear U-HO1-PTPN1-RS-cells differ from their mononuclear H-precursors by their nuclear volume (p Conclusion Abundant RS-cells without additional very short telomeres including "t-stumps", high rate of apoptosis, but low STAT5A expression, are hallmarks of the U-HO1-PTPN1 cell line. These characteristics are independent of telomerase activity. Thus, PTPN1 induced dephosphorylation of STAT5 with consecutive lack of Akt/PKB activation and cellular arrest in G2, promoting induction of apoptosis, appears as a possible pathogenetic mechanism deserving further experimental investigation.

  11. The MLH1 ATPase domain is needed for suppressing aberrant formation of interstitial telomeric sequences.

    Science.gov (United States)

    Jia, Pingping; Chai, Weihang

    2018-05-01

    Genome instability gives rise to cancer. MLH1, commonly known for its important role in mismatch repair (MMR), DNA damage signaling and double-strand break (DSB) repair, safeguards genome stability. Recently we have reported a novel role of MLH1 in preventing aberrant formation of interstitial telomeric sequences (ITSs) at intra-chromosomal regions. Deficiency in MLH1, in particular its N-terminus, leads to an increase of ITSs. Here, we identify that the ATPase activity in the MLH1 N-terminal domain is important for suppressing the formation of ITSs. The ATPase activity is also needed for recruiting MLH1 to DSBs. Moreover, defective ATPase activity of MLH1 causes an increase in micronuclei formation. Our results highlight the crucial role of MLH1's ATPase domain in preventing the aberrant formation of telomeric sequences at the intra-chromosomal regions and preserving genome stability. Copyright © 2018 Elsevier B.V. All rights reserved.

  12. Short fetal leukocyte telomere length and preterm prelabor rupture of the membranes.

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    Ramkumar Menon

    Full Text Available BACKGROUND: Rupture of the fetal membranes is a common harbinger of imminent labor and delivery. Telomere shortening is a surrogate for oxidative stress (OS and senescence. Fetal leukocyte and placental membrane DNA telomere lengths were evaluated to determine their association with preterm prelabor rupture of the membranes (pPROM or spontaneous preterm births with intact membranes (PTB, compared to term birth. METHODS: Telomere lengths were quantified in cord blood leukocytes (n = 133 from three major groups: 1 pPROM (n = 28, 2 PTB (n = 69 and 3 uncomplicated full term births (controls, n = 35, using real-time quantitative PCR. Placental membrane specimens (n = 18 were used to correlate fetal leukocyte and placental telomere lengths. Telomere length differences among the groups were analyzed by ANOVA. Pearson correlation coefficients determined relationships between leukocyte and placental membrane telomere lengths. RESULTS: In pregnancies with intact membranes, fetal leukocyte telomere length was inversely proportional to gestational age. The mean telomere length decreased as gestation progressed, with the shortest at term. pPROM had telomere lengths (9962 ± 3124 bp that were significantly shorter than gestational age-matched PTB (11546 ± 4348 bp, p = 0.04, but comparable to term births (9011 ± 2497 bp, p = 0.31. Secondary analyses revealed no effects of race (African American vs. Caucasian or intraamniotic infection on telomere length. A strong Pearson's correlation was noted between fetal leukocyte and placental membrane telomere lengths (ρ = 0.77; p<0.01. CONCLUSIONS: Fetal leukocyte telomere length is reduced in pPROM compared to PTB but is similar to term births. pPROM represents a placental membrane disease likely mediated by OS-induced senescence.

  13. Within the genome, long telomeres are more informative than short telomeres with respect to fitness components in a long-lived seabird

    NARCIS (Netherlands)

    Bauch, Christina; Becker, Peter H.; Verhulst, Simon

    Telomeres, DNA-protein structures at chromosome ends, shorten with age, and telomere length has been linked to age-related diseases and survival. In vitro studies revealed that the shortest telomeres trigger cell senescence, but whether the shortest telomeres are also the best biomarker of ageing is

  14. Leukocyte telomere dynamics in the elderly

    DEFF Research Database (Denmark)

    Steenstrup, Troels; Hjelmborg, Jacob V B; Mortensen, Laust H

    2013-01-01

    Limited data suggest that leukocytes of the elderly display ultra-short telomeres. It was reported that in some elderly persons leukocyte telomere length (LTL) shows age-dependent elongation. Using cross-sectional and longitudinal models, we characterized LTL dynamics in participants...

  15. Extreme telomere length dimorphism in the Tasmanian devil and related marsupials suggests parental control of telomere length.

    Directory of Open Access Journals (Sweden)

    Hannah S Bender

    Full Text Available Telomeres, specialised structures that protect chromosome ends, play a critical role in preserving chromosome integrity. Telomere dynamics in the Tasmanian devil (Sarcophilus harrisii are of particular interest in light of the emergence of devil facial tumour disease (DFTD, a transmissible malignancy that causes rapid mortality and threatens the species with extinction. We used fluorescent in situ hybridisation to investigate telomere length in DFTD cells, in healthy Tasmanian devils and in four closely related marsupial species. Here we report that animals in the Order Dasyuromorphia have chromosomes characterised by striking telomere length dimorphism between homologues. Findings in sex chromosomes suggest that telomere length dimorphism may be regulated by events in the parental germlines. Long telomeres on the Y chromosome imply that telomere lengthening occurs during spermatogenesis, whereas telomere diminution occurs during oogenesis. Although found in several somatic cell tissue types, telomere length dimorphism was not found in DFTD cancer cells, which are characterised by uniformly short telomeres. This is, to our knowledge, the first report of naturally occurring telomere length dimorphism in any species and suggests a novel strategy of telomere length control. Comparative studies in five distantly related marsupials and a monotreme indicate that telomere dimorphism evolved at least 50 million years ago.

  16. Association of Donor and Recipient Telomere Length with Clinical Outcomes following Lung Transplantation.

    Science.gov (United States)

    Courtwright, Andrew M; Fried, Sabrina; Villalba, Julian A; Moniodis, Anna; Guleria, Indira; Wood, Isabelle; Milford, Edgar; Mallidi, Hari H; Hunninghake, Gary M; Raby, Benjamin A; Agarwal, Suneet; Camp, Philip C; Rosas, Ivan O; Goldberg, Hilary J; El-Chemaly, Souheil

    2016-01-01

    Patients with short telomere syndromes and pulmonary fibrosis have increased complications after lung transplant. However, the more general impact of donor and recipient telomere length in lung transplant has not been well characterized. This was an observational cohort study of patients who received lung transplant at a single center between January 1st 2012 and January 31st 2015. Relative donor lymphocyte telomere length was measured and classified into long (third tertile) and short (other tertiles). Relative recipient lung telomere length was measured and classified into short (first tertile) and long (other tertiles). Outcome data included survival, need for modification of immunosuppression, liver or kidney injury, cytomegalovirus reactivation, and acute rejection. Recipient lung tissue telomere lengths were measured for 54 of the 79 patients (68.3%) who underwent transplant during the study period. Donor lymphocyte telomeres were measured for 45 (83.3%) of these recipients. Neither long donor telomere length (hazard ratio [HR] = 0.58, 95% confidence interval [CI], 0.12-2.85, p = 0.50) nor short recipient telomere length (HR = 1.01, 95% CI = 0.50-2.05, p = 0.96) were associated with adjusted survival following lung transplant. Recipients with short telomeres were less likely to have acute cellular rejection (23.5% vs. 58.8%, p = 0.02) but were not more likely to have other organ dysfunction. In this small cohort, neither long donor lymphocyte telomeres nor short recipient lung tissue telomeres were associated with adjusted survival after lung transplantation. Larger studies are needed to confirm these findings.

  17. The roles of WRN and BLM RecQ helicases in the Alternative Lengthening of Telomeres.

    Science.gov (United States)

    Mendez-Bermudez, Aaron; Hidalgo-Bravo, Alberto; Cotton, Victoria E; Gravani, Athanasia; Jeyapalan, Jennie N; Royle, Nicola J

    2012-11-01

    Approximately 10% of all cancers, but a higher proportion of sarcomas, use the recombination-based alternative lengthening of telomeres (ALT) to maintain telomeres. Two RecQ helicase genes, BLM and WRN, play important roles in homologous recombination repair and they have been implicated in telomeric recombination activity, but their precise roles in ALT are unclear. Using analysis of sequence variation present in human telomeres, we found that a WRN- ALT+ cell line lacks the class of complex telomere mutations attributed to inter-telomeric recombination in other ALT+ cell lines. This suggests that WRN facilitates inter-telomeric recombination when there are sequence differences between the donor and recipient molecules or that sister-telomere interactions are suppressed in the presence of WRN and this promotes inter-telomeric recombination. Depleting BLM in the WRN- ALT+ cell line increased the mutation frequency at telomeres and at the MS32 minisatellite, which is a marker of ALT. The absence of complex telomere mutations persisted in BLM-depleted clones, and there was a clear increase in sequence homogenization across the telomere and MS32 repeat arrays. These data indicate that BLM suppresses unequal sister chromatid interactions that result in excessive homogenization at MS32 and at telomeres in ALT+ cells.

  18. Prostate stromal cell telomere shortening is associated with risk of prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial.

    Science.gov (United States)

    Heaphy, Christopher M; Gaonkar, Gaurav; Peskoe, Sarah B; Joshu, Corinne E; De Marzo, Angelo M; Lucia, M Scott; Goodman, Phyllis J; Lippman, Scott M; Thompson, Ian M; Platz, Elizabeth A; Meeker, Alan K

    2015-08-01

    Telomeres are repetitive nucleoproteins that help maintain chromosomal stability by inhibiting exonucleolytic degradation, prohibiting inappropriate homologous recombination, and preventing chromosomal fusions by suppressing double-strand break signals. We recently observed that men treated for clinically localized prostate cancer with shorter telomeres in their cancer-associated stromal cells, in combination with greater variation in cancer cell telomere lengths, were significantly more likely to progress to distant metastases, and die from their disease. Here, we hypothesized that shorter stromal cell telomere length would be associated with prostate cancer risk at time of biopsy. Telomere-specific fluorescence in situ hybridization (FISH) analysis was performed in normal-appearing stromal, basal epithelial, and luminal epithelial cells in biopsies from men randomized to the placebo arm of the Prostate Cancer Prevention Trial. Prostate cancer cases (N = 32) were either detected on a biopsy performed for cause or at the end of the study per trial protocol, and controls (N = 50), defined as negative for cancer on an end-of-study biopsy performed per trial protocol (e.g., irrespective of indication), were sampled. Logistic regression was used to estimate the association between mean telomere length of the particular cell populations, cell-to-cell telomere length variability, and risk of prostate cancer. Men with short stromal cell telomere lengths (below median) had 2.66 (95% CI 1.04-3.06; P = 0.04) times the odds of prostate cancer compared with men who had longer lengths (at or above median). Conversely, we did not observe statistically significant associations for short telomere lengths in normal-appearing basal (OR = 2.15, 95% CI 0.86-5.39; P= 0 .10) or luminal (OR = 1.15, 95% CI 0.47-2.80; P = 0.77) cells. These findings suggest that telomere shortening in normal stromal cells is associated with prostate cancer risk. It is essential

  19. Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs

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    Jiao Yang

    2016-05-01

    Full Text Available Ten-eleven translocation (Tet family proteins convert 5-methylcytosine to 5-hydroxymethylcytosine. We show that mouse embryonic stem cells (ESCs depleted of Tet1 and/or Tet2 by RNAi exhibit short telomeres and chromosomal instability, concomitant with reduced telomere recombination. Tet1 and Tet2 double-knockout ESCs also display short telomeres but to a lesser extent. Notably, Tet1/2/3 triple-knockout ESCs show heterogeneous telomere lengths and increased frequency of telomere loss and chromosomal fusion. Mechanistically, Tets depletion or deficiency increases Dnmt3b and decreases 5hmC levels, resulting in elevated methylation levels at sub-telomeres. Consistently, knockdown of Dnmt3b or addition of 2i (MAPK and GSK3β inhibitors, which also inhibits Dnmt3b, reduces telomere shortening, partially rescuing Tet1/2 deficiency. Interestingly, Tet1/2 double or Tet1/2/3 triple knockout in ESCs consistently upregulates Zscan4, which may counteract telomere shortening. Together, Tet enzymes play important roles in telomere maintenance and chromosomal stability of ESCs by modulating sub-telomeric methylation levels.

  20. Telomeres and the natural lifespan limit in humans

    DEFF Research Database (Denmark)

    Steenstrup, Troels; Kark, Jeremy D; Verhulst, Simon

    2017-01-01

    An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal...... natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends...

  1. Alternative Lengthening of Telomeres: Recurrent Cytogenetic Aberrations and Chromosome Stability under Extreme Telomere Dysfunction

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    Despoina Sakellariou

    2013-11-01

    Full Text Available Human tumors using the alternative lengthening of telomeres (ALT exert high rates of telomere dysfunction. Numerical chromosomal aberrations are very frequent, and structural rearrangements are widely scattered among the genome. This challenging context allows the study of telomere dysfunction-driven chromosomal instability in neoplasia (CIN in a massive scale. We used molecular cytogenetics to achieve detailed karyotyping in 10 human ALT neoplastic cell lines.We identified 518 clonal recombinant chromosomes affected by 649 structural rearrangements. While all human chromosomes were involved in random or clonal, terminal, or pericentromeric rearrangements and were capable to undergo telomere healing at broken ends, a differential recombinatorial propensity of specific genomic regions was noted.We show that ALT cells undergo epigenetic modifications rendering polycentric chromosomes functionally monocentric, and because of increased terminal recombinogenicity, they generate clonal recombinant chromosomes with interstitial telomeric repeats. Losses of chromosomes 13, X, and 22, gains of 2, 3, 5, and 20, and translocation/deletion events involving several common chromosomal fragile sites (CFSs were recurrent. Long-term reconstitution of telomerase activity in ALT cells reduced significantly the rates of random ongoing telomeric and pericentromeric CIN. However, the contribution of CFS in overall CIN remained unaffected, suggesting that in ALT cells whole-genome replication stress is not suppressed by telomerase activation. Our results provide novel insights into ALT-driven CIN, unveiling in parallel specific genomic sites that may harbor genes critical for ALT cancerous cell growth.

  2. Telomere in Aging and Age-Related Diseases

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    Anna Meiliana

    2017-12-01

    Full Text Available BACKGROUND: The number of elderly population in the world keep increasing. In their advanced ages, many elderly face years of disability because of multiple chronic diseases, frailty, making them lost their independence. Consequently, this could have impacts on social and economic stability. A huge challenge has been sent for biomedical researchers to compress or at least eliminate this period of disability and increase the health span. CONTENT: Over the past decades, many studies of telomere biology have demonstrated that telomeres and telomere-associated proteins are implicated in human diseases. Accelerated telomere erosion was clearly correlated with a pack of metabolic and inflammatory diseases. Critically short telomeres or the unprotected end, are likely to form telomeric fusion, generating genomic instability, the cornerstone for carcinogenesis. Enlightening how telomeres involved in the mechanisms underlying the diseases’ pathogenesis was expected to uncover new molecular targets for any important diagnosis or therapeutic implications. SUMMARY: Telomere shortening was foreseen as an imporant mechanism to supress tumor by limiting cellular proliferative capacity by regulating senescence check point activation. Many human diseases and carcinogenesis are causally related to defective telomeres, asserting the importance of telomeres sustainment. Thus, telomere length assessment might serve as an important tool for clinical prognostic, diagnostic, monitoring and management. KEYWORDS: telomerase, cellular senescence, aging, cancer

  3. DNA Amplification by Breakage/Fusion/Bridge Cycles Initiated by Spontaneous Telomere Loss in a Human Cancer Cell Line

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    Anthony W.l. Lo

    2002-01-01

    Full Text Available The development of genomic instability is an important step in generatingthe multiple genetic changes required for cancer. One consequence of genomic instability is the overexpression of oncogenes due to gene amplification. One mechanism for gene amplification is the breakagelfusionlbridge (B/F/Bcyclethatinvolvesthe repeated fusion and breakage of chromosomes following the loss of a telomere. B/F/B cycles have been associated with low-copy gene amplification in human cancer cells, and have been proposed to be an initiating event in high-copy gene amplification. We have found that spontaneous telomere loss on a marker chromosome 16 in a human tumor cell line results in sister chromatid fusion and prolonged periods of chromosome instability. The high rate of anaphase bridges involving chromosome 16 demonstrates that this instability results from B/F/B cycles. The amplification of subtelomeric DNA on the marker chromosome provides conclusive evidence that B/F/B cycles initiated by spontaneous telomere loss are a mechanism for gene amplification in human cancer cells.

  4. Telomere dynamics in human mesenchymal stem cells after exposure to acute oxidative stress

    DEFF Research Database (Denmark)

    Harbo, M.; Koelvraa, S.; Serakinci, N.

    2012-01-01

    mesenchymal stem cells, either primary or hTERT immortalized, were exposed to sub-lethal doses of hydrogen peroxide, and the short term effect on telomere dynamics was monitored by Universal STELA and TRF measurements. Both telomere measures were then correlated with the percentage of senescent cells......A gradual shortening of telomeres due to replication can be measured using the standard telomere restriction fragments (TRF) assay and other methods by measuring the mean length of all the telomeres in a cell. In contrast, stress-induced telomere shortening, which is believed to be just...... estimated by senescence-associated beta-galactosidase staining. The exposure to acute oxidative stress resulted in an increased number of ultra-short telomeres, which correlated strongly with the percentage of senescent cells, whereas a correlation between mean telomere length and the percentage...

  5. The human CTC1/STN1/TEN1 complex regulates telomere maintenance in ALT cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Chenhui; Jia, Pingping; Chastain, Megan; Shiva, Olga; Chai, Weihang, E-mail: wchai@wsu.edu

    2017-06-15

    Maintaining functional telomeres is important for long-term proliferation of cells. About 15% of cancer cells are telomerase-negative and activate the alternative-lengthening of telomeres (ALT) pathway to maintain their telomeres. Recent studies have shown that the human CTC1/STN1/TEN1 complex (CST) plays a multi-faceted role in telomere maintenance in telomerase-expressing cancer cells. However, the role of CST in telomere maintenance in ALT cells is unclear. Here, we report that human CST forms a functional complex localizing in the ALT-associated PML bodies (APBs) in ALT cells throughout the cell cycle. Suppression of CST induces telomere instabilities including telomere fragility and elevates telomeric DNA recombination, leading to telomere dysfunction. In addition, CST deficiency significantly diminishes the abundance of extrachromosomal circular telomere DNA known as C-circles and t-circles. Suppression of CST also results in multinucleation in ALT cells and impairs cell proliferation. Our findings imply that the CST complex plays an important role in regulating telomere maintenance in ALT cells. - Highlights: • CST localizes at telomeres and ALT-associated PML bodies in ALT cells throughout the cell cycle. • CST is important for promoting telomeric DNA replication in ALT cells. • CST deficiency decreases ECTR formation and increases T-SCE. • CST deficiency impairs ALT cell proliferation and results in multinucleation.

  6. Mice with Pulmonary Fibrosis Driven by Telomere Dysfunction

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    Juan M. Povedano

    2015-07-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a degenerative disease of the lungs with an average survival post-diagnosis of 2–3 years. New therapeutic targets and treatments are necessary. Mutations in components of the telomere-maintenance enzyme telomerase or in proteins important for telomere protection are found in both familial and sporadic IPF cases. However, the lack of mouse models that faithfully recapitulate the human disease has hampered new advances. Here, we generate two independent mouse models that develop IPF owing to either critically short telomeres (telomerase-deficient mice or severe telomere dysfunction in the absence of telomere shortening (mice with Trf1 deletion in type II alveolar cells. We show that both mouse models develop pulmonary fibrosis through induction of telomere damage, thus providing proof of principle of the causal role of DNA damage stemming from dysfunctional telomeres in IPF development and identifying telomeres as promising targets for new treatments.

  7. Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients

    DEFF Research Database (Denmark)

    Mansouri, Larry; Grabowski, Pawel; Degerman, Sofie

    2013-01-01

    Most previous studies on telomere length (TL) in chronic lymphocytic leukemia (CLL) are based on referral cohorts including a high proportion of aggressive cases. Here, the impact of TL was analyzed in a population-based cohort of newly diagnosed CLL (n = 265) and in relation to other prognostic ...... markers. Short telomeres were particularly associated with high-risk genetic markers, such as NOTCH1, SF3B1, or TP53 aberrations, and predicted a short time to treatment (TTT) and overall survival (OS) (both P...

  8. Dietary restriction ameliorates haematopoietic ageing independent of telomerase, whilst lack of telomerase and short telomeres exacerbates the ageing phenotype.

    Science.gov (United States)

    Al-Ajmi, Nouf; Saretzki, Gabriele; Miles, Colin; Spyridopoulos, Ioakim

    2014-10-01

    Ageing is associated with an overall decline in the functional capacity of tissues and stem cells, including haematopoietic stem and progenitor cells (HSPCs), as well as telomere dysfunction. Dietary restriction (DR) is a recognised anti-ageing intervention that extends lifespan and improves health in several organisms. To investigate the role of telomeres and telomerase in haematopoietic ageing, we compared the HSPC profile and clonogenic capacity of bone marrow cells from wild type with telomerase-deficient mice and the effect of DR on these parameters. Compared with young mice, aged wild type mice demonstrated a significant accumulation of HSPCs (1.3% vs 0.2%, P=0.002) and elevated numbers of granulocyte/macrophage colony forming units (CFU-GM, 26.4 vs 17.3, P=0.0037) consistent with myeloid "skewing" of haematopoiesis. DR was able to restrict the increase in HSPC number as well as the myeloid "skewing" in aged wild type mice. In order to analyse the influence of short telomeres on the ageing phenotype we examined mice lacking the RNA template for telomerase, TERC(-/-). Telomere shortening resulted in a similar bone marrow phenotype to that seen in aged mice, with significantly increased HSPC numbers and an increased formation of all myeloid colony types but at a younger age than wild type mice. However, an additional increase in erythroid colonies (BFU-E) was also evident. Mice lacking telomerase reverse transcriptase without shortened telomeres, TERT(-/-), also presented with augmented haematopoietic ageing which was ameliorated by DR, demonstrating that the effect of DR was not dependent on the presence of telomerase in HSPCs. We conclude that whilst shortened telomeres mimic some aspects of haematopoietic ageing, both shortened telomeres and the lack of telomerase produce specific phenotypes, some of which can be prevented by dietary restriction. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. The role of telomeres in Etoposide induced tumor cell death.

    Science.gov (United States)

    Jeyapalan, Jessie; Leake, Alan; Ahmed, Shaheda; Saretzki, Gabriele; Tilby, Michael; von Zglinicki, Thomas

    2004-09-01

    Etoposide, a topoisomerase II poison is used in the treatment of a number of solid tumors. Contradictory data exist on the role of the telomere/telomerase complex in etoposide induced apoptosis. Therefore we examined the effects of etoposide treatment in the neuroblastoma cell line SHSY5Y, with very short telomeres and the acute lymphoblastic T cell line 1301, which displays extremely long telomeres. Both short-term and continuous exposure to the drug were examined. Etoposide induced widespread DNA damage followed by DNA damage foci formation and ultimately growth arrest and apoptosis in a concentration-dependent manner. However, length of telomeres and of single stranded telomeric G rich overhangs did not change significantly under the treatments in any cell line. There was no significant induction of single-strand breaks in the G-rich strand of telomeres. Telomerase activity was transiently upregulated under low concentrations of etoposide, while high concentrations resulted in decreased telomerase activity only after onset of apoptosis. Telomerase overexpression protected against etoposide induced apoptosis in fibroblasts. The data suggest that telomeres are not major signal transducers towards growth arrest or apoptosis after etoposide treatment. However, upregulation of telomerase might be part of an attempted adaptative response, which protects cells by a mechanism that might be independent of telomere length maintenance.

  10. Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita.

    Science.gov (United States)

    Ballew, Bari J; Yeager, Meredith; Jacobs, Kevin; Giri, Neelam; Boland, Joseph; Burdett, Laurie; Alter, Blanche P; Savage, Sharon A

    2013-04-01

    Dyskeratosis congenita (DC) is an inherited bone marrow failure and cancer predisposition syndrome caused by aberrant telomere biology. The classic triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia is diagnostic of DC, but substantial clinical heterogeneity exists; the clinically severe variant Hoyeraal Hreidarsson syndrome (HH) also includes cerebellar hypoplasia, severe immunodeficiency, enteropathy, and intrauterine growth retardation. Germline mutations in telomere biology genes account for approximately one-half of known DC families. Using exome sequencing, we identified mutations in RTEL1, a helicase with critical telomeric functions, in two families with HH. In the first family, two siblings with HH and very short telomeres inherited a premature stop codon from their mother who has short telomeres. The proband from the second family has HH and inherited a premature stop codon in RTEL1 from his father and a missense mutation from his mother, who also has short telomeres. In addition, inheritance of only the missense mutation led to very short telomeres in the proband's brother. Targeted sequencing identified a different RTEL1 missense mutation in one additional DC proband who has bone marrow failure and short telomeres. Both missense mutations affect the helicase domain of RTEL1, and three in silico prediction algorithms suggest that they are likely deleterious. The nonsense mutations both cause truncation of the RTEL1 protein, resulting in loss of the PIP box; this may abrogate an important protein-protein interaction. These findings implicate a new telomere biology gene, RTEL1, in the etiology of DC.

  11. TRF2 Recruits RTEL1 to Telomeres in S Phase to Promote T-Loop Unwinding

    OpenAIRE

    Sarek, Grzegorz; Vannier, Jean-Baptiste; Panier, Stephanie; Petrini, John?H.J.; Boulton, Simon?J.

    2015-01-01

    Summary The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres. An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear. Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required to?prevent catastrophic t-loop processing by structure-specific nucleases. We show that ...

  12. Telomeres and viruses: common themes of genome maintenance

    Science.gov (United States)

    Deng, Zhong; Wang, Zhuo; Lieberman, Paul M.

    2012-01-01

    Genome maintenance mechanisms actively suppress genetic instability associated with cancer and aging. Some viruses provoke genetic instability by subverting the host’s control of genome maintenance. Viruses have their own specialized strategies for genome maintenance, which can mimic and modify host cell processes. Here, we review some of the common features of genome maintenance utilized by viruses and host chromosomes, with a particular focus on terminal repeat (TR) elements. The TRs of cellular chromosomes, better known as telomeres, have well-established roles in cellular chromosome stability. Cellular telomeres are themselves maintained by viral-like mechanisms, including self-propagation by reverse transcription, recombination, and retrotransposition. Viral TR elements, like cellular telomeres, are essential for viral genome stability and propagation. We review the structure and function of viral repeat elements and discuss how they may share telomere-like structures and genome protection functions. We consider how viral infections modulate telomere regulatory factors for viral repurposing and can alter normal host telomere structure and chromosome stability. Understanding the common strategies of viral and cellular genome maintenance may provide new insights into viral–host interactions and the mechanisms driving genetic instability in cancer. PMID:23293769

  13. Isolation of Chromatin from Dysfunctional Telomeres Reveals an Important Role for Ring1b in NHEJ-Mediated Chromosome Fusions

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    Cristina Bartocci

    2014-05-01

    Full Text Available When telomeres become critically short, DNA damage response factors are recruited at chromosome ends, initiating a cellular response to DNA damage. We performed proteomic isolation of chromatin fragments (PICh in order to define changes in chromatin composition that occur upon onset of acute telomere dysfunction triggered by depletion of the telomere-associated factor TRF2. This unbiased purification of telomere-associated proteins in functional or dysfunctional conditions revealed the dynamic changes in chromatin composition that take place at telomeres upon DNA damage induction. On the basis of our results, we describe a critical role for the polycomb group protein Ring1b in nonhomologous end-joining (NHEJ-mediated end-to-end chromosome fusions. We show that cells with reduced levels of Ring1b have a reduced ability to repair uncapped telomeric chromatin. Our data represent an unbiased isolation of chromatin undergoing DNA damage and are a valuable resource to map the changes in chromatin composition in response to DNA damage activation.

  14. Role of arterial telomere dysfunction in hypertension: relative contributions of telomere shortening and telomere uncapping.

    Science.gov (United States)

    Morgan, R Garrett; Ives, Stephen J; Walker, Ashley E; Cawthon, Richard M; Andtbacka, Robert H I; Noyes, Dirk; Lesniewski, Lisa A; Richardson, Russell S; Donato, Anthony J

    2014-06-01

    Telomere shortening in arteries could lead to telomere uncapping and cellular senescence, which in turn could promote the development of hypertension. To assess the novel role of arterial telomere dysfunction in hypertension, we compared mean telomere length (qPCR), telomere uncapping (serine 139 phosphorylated histone γ-H2A.X (γ-H2) localized to telomeres: ChIP), and tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence (P53 bound to P21 gene promoter: ChIP) in arteries from 55 age-matched hypertensive and nonhypertensive individuals. Arterial mean telomere length was not different in hypertensive patients compared with nonhypertensive individuals (P = 0.29). Arterial telomere uncapping and P53/P21-induced senescence were two-fold greater in hypertensive patients compared with nonhypertensive individuals (P = 0.04 and P = 0.02, respectively). Arterial mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence (r = -0.02, P = 0.44 and r = 0.01, P = 0.50, respectively), but telomere uncapping was a highly influential covariate for the hypertension group difference in P53/P21-induced senescence (r = 0.62, P hypertension status (P = 0.03), whereas mean telomere length was not (P = 0.68). Collectively, these findings demonstrate that arterial telomere uncapping and P53/P21-induced senescence are linked to hypertension independently of mean telomere length, and telomere uncapping influences hypertension status more than mean telomere length.

  15. Drosophila cell cycle under arrest: uncapped telomeres plead guilty.

    Science.gov (United States)

    Cenci, Giovanni

    2009-04-01

    Telomeres are specialized structures that protect chromosome ends from degradation and fusion events. In most organisms, telomeres consist of short, repetitive G-rich sequences added to chromosome ends by a reverse transcriptase with an internal RNA template, called telomerase. Specific DNA-binding protein complexes associate with telomeric sequences preventing chromosome ends from being recognized as DNA double strand breaks (DSBs). Telomeres that lose their cap activate the DNA damage response (DDR) likewise DSBs and, if inappropriately repaired, generate telomeric fusions, which eventually lead to genome instability. In Drosophila there is not telomerase, and telomere length is maintained by transposition of three specialized retroelements. However, fly telomeres are protected by multi protein complexes like their yeast and vertebrate counterparts; these complexes bind chromosome ends in a sequence-independent fashion and are required to prevent checkpoint activation and end-to-end fusion. Uncapped Drosophila telomeres elicit a DDR just as dysfunctional human telomeres. Most interestingly, uncapped Drosophila telomeres also activate the spindle assembly checkpoint (SAC) by recruiting the SAC kinase BubR1. BubR1 accumulations at chromosome ends trigger the SAC that inhibits the metaphase-to-anaphase transition. These findings, reviewed here, highlight an intriguing and unsuspected connection between telomeres and cell cycle regulation, providing a clue to understand human telomere function.

  16. Young parents produce offspring with short telomeres: A study in a long-lived bird, the Black-browed Albatross (Thalassarche melanophrys)

    Science.gov (United States)

    Barbraud, Christophe; Chastel, Olivier; Delord, Karine; Ruault, Stéphanie; Weimerskirch, Henri; Angelier, Frédéric

    2018-01-01

    In wild vertebrates, young parents are less likely to successfully rear offspring relative to older ones because of lower parental skills (‘the constraint hypothesis’), lower parental investment (‘the restraint hypothesis’) or because of a progressive disappearance of lower-quality individuals at young ages (‘the selection hypothesis’). Because it is practically difficult to follow an offspring during its entire life, most studies have only focused on the ability of individuals to breed or produce young, while neglecting the ability of such young to subsequently survive and reproduce. Several proxies of individual quality can be useful to assess the ability of young to survive and recruit into the population. Among them, telomere length measurement appears especially promising because telomere length has been linked to longevity and fitness in captive and wild animals. By sampling 51 chicks reared by known-aged parents, we specifically tested whether parental age was correlated to offspring telomere length and body condition in a long-lived bird species, the Black-browed Albatross (Thalassarche melanophrys). Young Black-browed albatrosses produced chicks with shorter telomere relative to those raised by older ones. Short offspring telomeres could result from poor developmental conditions or heritability of telomere length. Moreover, young parents also had chicks of lower body condition when compared with older parents, although this effect was significant in female offspring only. Overall, our study demonstrates that parental age is correlated to two proxies of offspring fitness (body condition and telomere length), suggesting therefore that older individuals provide better parental cares to their offspring because of increased parental investment (restraint hypothesis), better foraging/parental skills (constraint hypothesis) or because only high-quality individuals reach older ages (selection hypothesis). PMID:29561856

  17. Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe.

    Science.gov (United States)

    Margalef, Pol; Kotsantis, Panagiotis; Borel, Valerie; Bellelli, Roberto; Panier, Stephanie; Boulton, Simon J

    2018-01-25

    Telomere maintenance critically depends on the distinct activities of telomerase, which adds telomeric repeats to solve the end replication problem, and RTEL1, which dismantles DNA secondary structures at telomeres to facilitate replisome progression. Here, we establish that reversed replication forks are a pathological substrate for telomerase and the source of telomere catastrophe in Rtel1 -/- cells. Inhibiting telomerase recruitment to telomeres, but not its activity, or blocking replication fork reversal through PARP1 inhibition or depleting UBC13 or ZRANB3 prevents the rapid accumulation of dysfunctional telomeres in RTEL1-deficient cells. In this context, we establish that telomerase binding to reversed replication forks inhibits telomere replication, which can be mimicked by preventing replication fork restart through depletion of RECQ1 or PARG. Our results lead us to propose that telomerase inappropriately binds to and inhibits restart of reversed replication forks within telomeres, which compromises replication and leads to critically short telomeres. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. The telomere length dynamic and methods of its assessment.

    Science.gov (United States)

    Lin, Kah-Wai; Yan, Ju

    2005-01-01

    Human telomeres are composed of long repeating sequences of TTAGGG, associated with a variety of telomere-binding proteins. Its function as an end-protector of chromosomes prevents the chromosome from end-to-end fusion, recombination and degradation. Telomerase acts as reverse transcriptase in the elongation of telomeres, which prevent the loss of telomeres due to the end replication problems. However, telomerase activity is detected at low level in somatic cells and high level in embryonic stem cells and tumor cells. It confers immortality to embryonic stem cells and tumor cells. In most tumor cells, telomeres are extremely short and stable. Telomere length is an important indicator of the telomerase activity in tumor cells and it may be used in the prognosis of malignancy. Thus, the assessment of telomeres length is of great experimental and clinical significance. This review describes the role of telomere and telomerase in cancer pathogenesis and the dynamics of the telomeres length in different cell types. The various methods of measurement of telomeres length, i.e. southern blot, hybridization protection assay, fluorescence in situ hybridization, primed in situ, quantitative PCR and single telomere length analysis are discussed. The principle and comparative evaluation of these methods are reviewed. The detection of G-strand overhang by telomeric-oligonucleotide ligation assay, primer extension/nick translation assay and electron microscopy are briefly discussed.

  19. Telomeres and replicative senescence: Is it only length that counts?

    Science.gov (United States)

    von Zglinicki, T

    2001-07-26

    Telomeres are well established as a major 'replicometer', counting the population doublings in primary human cell cultures and ultimately triggering replicative senescence. However, neither is the pace of this biological clock inert, nor is there a fixed threshold telomere length acting as the universal trigger of replicative senescence. The available data suggest that opening of the telomeric loop and unscheduled exposure of the single-stranded G-rich telomeric overhang might act like a semaphore to signal senescent cell cycle arrest. Short telomere length, telomeric single-strand breaks, low levels of loop-stabilizing proteins, or other factors may trigger this opening of the loop. Thus, both telomere shortening and the ultimate signalling into senescence are able to integrate different environmental and genetic factors, especially oxidative stress-mediated damage, which might otherwise become a thread to genomic stability.

  20. The long and the short of telomeres in bone marrow recipient SCID patients.

    Science.gov (United States)

    Sarzotti-Kelsoe, Marcella; Daniell, Xiaoju G; Whitesides, John F; Buckley, Rebecca H

    2011-04-01

    Telomeres are noncoding DNA regions at the end of the chromosomes that are crucial for genome stability. Since telomere length decreases with cell division, they can be used as a signature of cell proliferation history. T-cell reconstitution in severe combined immunodeficiency (SCID) subjects, recipients of T-cell-depleted, allogeneic-related bone marrow cells, is due to the development and maturation of donor T-cell precursors in the infant's vestigial thymus and to homeostatic proliferation of mature T cells in the peripheral organs. Since T-cell function, thymic output, and T-cell clonal diversity are maintained long term in these patients, we investigated whether donor T-cell engraftment resulted in increased telomere shortening. Our study of seven SCID patients, following successful bone marrow transplantation, demonstrates that the patients' peripheral T cells did not exhibit greater than normal telomere shortening.

  1. Maternal telomere length inheritance in the king penguin.

    Science.gov (United States)

    Reichert, S; Rojas, E R; Zahn, S; Robin, J-P; Criscuolo, F; Massemin, S

    2015-01-01

    Telomeres are emerging as a biomarker for ageing and survival, and are likely important in shaping life-history trade-offs. In particular, telomere length with which one starts in life has been linked to lifelong survival, suggesting that early telomere dynamics are somehow related to life-history trajectories. This result highlights the importance of determining the extent to which telomere length is inherited, as a crucial factor determining early life telomere length. Given the scarcity of species for which telomere length inheritance has been studied, it is pressing to assess the generality of telomere length inheritance patterns. Further, information on how this pattern changes over the course of growth in individuals living under natural conditions should provide some insight on the extent to which environmental constraints also shape telomere dynamics. To fill this gap partly, we followed telomere inheritance in a population of king penguins (Aptenodytes patagonicus). We tested for paternal and maternal influence on chick initial telomere length (10 days old after hatching), and how these relationships changed with chick age (at 70, 200 and 300 days old). Based on a correlative approach, offspring telomere length was positively associated with maternal telomere length early in life (at 10 days old). However, this relationship was not significant at older ages. These data suggest that telomere length in birds is maternally inherited. Nonetheless, the influence of environmental conditions during growth remained an important factor shaping telomere length, as the maternal link disappeared with chicks' age.

  2. Patients with gout have short telomeres compared with healthy participants: association of telomere length with flare frequency and cardiovascular disease in gout.

    Science.gov (United States)

    Vazirpanah, N; Kienhorst, L B E; Van Lochem, E; Wichers, C; Rossato, M; Shiels, P G; Dalbeth, N; Stamp, L K; Merriman, T R; Janssen, M; Radstake, T R D J; Broen, J Ca

    2017-07-01

    Chronic inflammation associates with increased senescence, which is a strong predictor for cardiovascular disease. We hypothesised that inflammation accelerates senescence and thereby enhances the risk of cardiovascular disease in gout. We assessed replicative senescence by quantifying telomere length (TL) in a discovery cohort of 145 Dutch patients with gout and 273 healthy individuals and validated our results in 474 patients with gout and 293 healthy participants from New Zealand. Subsequently, we investigated the effect of cardiovascular disease on TL of all participants. Also, we measured TL of CD4 + and CD8 + T lymphocytes, B lymphocytes, monocytes, natural killer cells and plasmacytoid dendritic cells. Additionally, we assessed the potential temporal difference in TL and telomerase activity. TL in PBMCs of healthy donors decreased over time, reflecting normal ageing. Patients with gout demonstrated shorter telomeres (p=0.001, R 2 =0.01873). In fact, the extent of telomere erosion in patients with gout was higher at any age compared with healthy counterparts at any age (pgout with cardiovascular disease had the shortest telomeres and TL was an independent risk factor for cardiovascular disease in patients with gout (p=0.001). TL was inversely associated with the number of gouty flares (p=0.005). Patients with gout have shorter telomeres than healthy participants, reflecting increased cellular senescence. Telomere shortening was associated with the number of flares and with cardiovascular disease in people with gout. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  3. Telomere Shortening Unrelated to Smoking, Body Weight, Physical Activity, and Alcohol Intake

    DEFF Research Database (Denmark)

    Weischer, Maren; Bojesen, Stig E; Nordestgaard, Børge G

    2014-01-01

    Cross-sectional studies have associated short telomere length with smoking, body weight, physical activity, and possibly alcohol intake; however, whether these associations are due to confounding is unknown. We tested these hypotheses in 4,576 individuals from the general population cross......-year inter-observational tobacco consumption, body weight, physical activity, or alcohol intake. Prospectively during a further 10 years follow-up after the second examination, quartiles of telomere length change did not associate with risk of all-cause mortality, cancer, chronic obstructive pulmonary...... disease, diabetes mellitus, ischemic cerebrovascular disease, or ischemic heart disease. In conclusion, smoking, increased body weight, and physical inactivity were associated with short telomere length cross-sectionally, but not with telomere length change during 10 years observation, and alcohol intake...

  4. RTEL1 contributes to DNA replication and repair and telomere maintenance.

    Science.gov (United States)

    Uringa, Evert-Jan; Lisaingo, Kathleen; Pickett, Hilda A; Brind'Amour, Julie; Rohde, Jan-Hendrik; Zelensky, Alex; Essers, Jeroen; Lansdorp, Peter M

    2012-07-01

    Telomere maintenance and DNA repair are important processes that protect the genome against instability. mRtel1, an essential helicase, is a dominant factor setting telomere length in mice. In addition, mRtel1 is involved in DNA double-strand break repair. The role of mRtel1 in telomere maintenance and genome stability is poorly understood. Therefore we used mRtel1-deficient mouse embryonic stem cells to examine the function of mRtel1 in replication, DNA repair, recombination, and telomere maintenance. mRtel1-deficient mouse embryonic stem cells showed sensitivity to a range of DNA-damaging agents, highlighting its role in replication and genome maintenance. Deletion of mRtel1 increased the frequency of sister chromatid exchange events and suppressed gene replacement, demonstrating the involvement of the protein in homologous recombination. mRtel1 localized transiently at telomeres and is needed for efficient telomere replication. Of interest, in the absence of mRtel1, telomeres in embryonic stem cells appeared relatively stable in length, suggesting that mRtel1 is required to allow extension by telomerase. We propose that mRtel1 is a key protein for DNA replication, recombination, and repair and efficient elongation of telomeres by telomerase.

  5. High-throughput telomere length quantification by FISH and its application to human population studies.

    Science.gov (United States)

    Canela, Andrés; Vera, Elsa; Klatt, Peter; Blasco, María A

    2007-03-27

    A major limitation of studies of the relevance of telomere length to cancer and age-related diseases in human populations and to the development of telomere-based therapies has been the lack of suitable high-throughput (HT) assays to measure telomere length. We have developed an automated HT quantitative telomere FISH platform, HT quantitative FISH (Q-FISH), which allows the quantification of telomere length as well as percentage of short telomeres in large human sample sets. We show here that this technique provides the accuracy and sensitivity to uncover associations between telomere length and human disease.

  6. RTEL1 is a replisome-associated helicase that promotes telomere and genome-wide replication.

    Science.gov (United States)

    Vannier, Jean-Baptiste; Sandhu, Sumit; Petalcorin, Mark I R; Wu, Xiaoli; Nabi, Zinnatun; Ding, Hao; Boulton, Simon J

    2013-10-11

    Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles telomere loops (T loops) and suppresses telomere fragility to maintain the integrity of chromosome ends. We established that RTEL1 also associates with the replisome through binding to proliferating cell nuclear antigen (PCNA). Mouse cells disrupted for the RTEL1-PCNA interaction (PIP mutant) exhibited accelerated senescence, replication fork instability, reduced replication fork extension rates, and increased origin usage. Although T-loop disassembly at telomeres was unaffected in the mutant cells, telomere replication was compromised, leading to fragile sites at telomeres. RTEL1-PIP mutant mice were viable, but loss of the RTEL1-PCNA interaction accelerated the onset of tumorigenesis in p53-deficient mice. We propose that RTEL1 plays a critical role in both telomere and genome-wide replication, which is crucial for genetic stability and tumor avoidance.

  7. A different approach to telomere analysis with ddPRINS in chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Palanduz, Sukru; Serakinci, Nedime; Cefle, Kivanc

    2006-01-01

    in patients with B-cell CLL in a comparison with the control group by using ddPRINS technique. Twenty patients with CLL and four healthy donors as a control group were included. We found short telomeres and no detectable telomeric repeats at the sites of chromosome fusion. We hypothesise that the telomeric...

  8. Shortened telomeres in serous tubal intraepithelial carcinoma: an early event in ovarian high-grade serous carcinogenesis.

    Science.gov (United States)

    Kuhn, Elisabetta; Meeker, Alan; Wang, Tian-Li; Sehdev, Ann Smith; Kurman, Robert J; Shih, Ie-Ming

    2010-06-01

    Short telomeres are one of the main genetic manifestations in human cancer, as they have been shown to play an important role in inducing chromosomal instability and in contributing to tumor progression. The purpose of this study was to determine if changes in telomere length occur in serous tubal intraepithelial carcinoma (STIC), the putative precursor of "ovarian" high-grade serous carcinoma (HGSC). Twenty-two STICs from 15 patients with concurrent but discrete HGSCs were analyzed for telomere length on formalin-fixed, paraffin-embedded sections by conducting p53 immunofluorescence to assist in identifying STICs and telomere-specific FISH. Telomere length (short, long, or no change) in STICs was compared with HGSCs using normal fallopian tube epithelium and stromal cells as controls. We found that STICs had the shortest telomeres, as 18 (82%) of 22 STICs had short telomeres, whereas only 2 (9%) showed no change and 2 (9%) had long telomeres compared with the normal-looking tubal epithelium. In contrast, among 12 paired HGSCs and STICs, 6 HGSCs showed an increase in telomere length, one showed a decrease in length and 5 did not show any change when compared with their matched STICs, although, such as STICs, the majority of HGSCs had shorter telomeres than the associated normal tubal epithelial cells. These differences in telomere length between normal tubal epithelial cells and STICs, and between STICs and HGSCs were statisticaly significant (PSTICs provides further support to the proposal that STICs are precursors of HGSC and opens new areas of research in elucidating the early events of ovarian high-grade serous carcinogenesis.

  9. Vanishing honey bees: Is the dying of adult worker bees a consequence of short telomeres and premature aging?

    Science.gov (United States)

    Stindl, Reinhard; Stindl, Wolfgang

    2010-10-01

    Einstein is often quoted to have said that without the bee, mankind would have but 4years to live. It is highly unlikely that he made this comment, which was even mentioned in a Lancet article on honey bees. However, the current vanishing of the bees can have serious consequences for human health, because 35% of the human diet is thought to benefit from pollination. Colony collapse disorder (CCD) in honey bees is characterized by the rapid decline of the adult bee population, leaving the brood and the queen poorly or completely unattended, with no dead bodies in or around the hive. A large study found no evidence that the presence or amount of any individual pesticide or infectious agent occurred more frequently or abundantly in CCD-affected colonies. The growing consensus is that honey bees are suffering from comprised immune systems, which allow various infectious pathogens to invade. The question remains, what causes immunosuppression in many colonies of Apis mellifera in North America and Europe? Telomeres are protective DNA structures located at eukaryotic chromosome tips that shorten in the somatic tissues of animals with age. Lifelong tissue regeneration takes place in Apis mellifera, and worker bees have been shown to senesce. In humans, a vast amount of literature has accumulated on exhausted telomere reserves causing impaired tissue regeneration and age-associated diseases, specifically cancer and immunosuppression. Therefore, we propose a new causative mechanism for the vanishing of the bees: critically short telomeres in long-lived winter bees. We term this the telomere premature aging syndrome. Copyright 2010 Elsevier Ltd. All rights reserved.

  10. Shorter leukocyte telomere length is associated with higher risk of infections

    DEFF Research Database (Denmark)

    Helby, Jens; Nordestgaard, Børge G; Benfield, Thomas

    2017-01-01

    In the general population, older age is associated with short leukocyte telomere length and with high risk of infections. In a recent study of allogeneic hematopoietic cell transplantation for severe aplastic anemia, long donor leukocyte telomere length was associated with improved survival...

  11. Peripheral blood leukocyte telomere length and mortality among 64,637 individuals from the general population

    DEFF Research Database (Denmark)

    Rode, Line; Nordestgaard, Børge G; Bojesen, Stig E

    2015-01-01

    BACKGROUND: Short telomeres in peripheral blood leukocytes are associated with older age and age-related diseases. We tested the hypotheses that short telomeres are associated with both increased cancer mortality and all-cause mortality. METHODS: Individuals (n = 64637) were recruited from 1991...

  12. Segregating YKU80 and TLC1 alleles underlying natural variation in telomere properties in wild yeast.

    Directory of Open Access Journals (Sweden)

    Gianni Liti

    2009-09-01

    Full Text Available In yeast, as in humans, telomere length varies among individuals and is controlled by multiple loci. In a quest to define the extent of variation in telomere length, we screened 112 wild-type Saccharomyces sensu stricto isolates. We found extensive telomere length variation in S. paradoxus isolates. This phenotype correlated with their geographic origin: European strains were observed to have extremely short telomeres (400 bp. Insertions of a URA3 gene near telomeres allowed accurate analysis of individual telomere lengths and telomere position effect (TPE. Crossing the American and European strains resulted in F1 spores with a continuum of telomere lengths consistent with what would be predicted if many quantitative trait loci (QTLs were involved in length maintenance. Variation in TPE is similarly quantitative but only weakly correlated with telomere length. Genotyping F1 segregants indicated several QTLs associated with telomere length and silencing variation. These QTLs include likely candidate genes but also map to regions where there are no known genes involved in telomeric properties. We detected transgressive segregation for both phenotypes. We validated by reciprocal hemizygosity that YKU80 and TLC1 are telomere-length QTLs in the two S. paradoxus subpopulations. Furthermore, we propose that sequence divergence within the Ku heterodimer generates negative epistasis within one of the allelic combinations (American-YKU70 and European-YKU80 resulting in very short telomeres.

  13. Segregating YKU80 and TLC1 alleles underlying natural variation in telomere properties in wild yeast.

    Science.gov (United States)

    Liti, Gianni; Haricharan, Svasti; Cubillos, Francisco A; Tierney, Anna L; Sharp, Sarah; Bertuch, Alison A; Parts, Leopold; Bailes, Elizabeth; Louis, Edward J

    2009-09-01

    In yeast, as in humans, telomere length varies among individuals and is controlled by multiple loci. In a quest to define the extent of variation in telomere length, we screened 112 wild-type Saccharomyces sensu stricto isolates. We found extensive telomere length variation in S. paradoxus isolates. This phenotype correlated with their geographic origin: European strains were observed to have extremely short telomeres (400 bp). Insertions of a URA3 gene near telomeres allowed accurate analysis of individual telomere lengths and telomere position effect (TPE). Crossing the American and European strains resulted in F1 spores with a continuum of telomere lengths consistent with what would be predicted if many quantitative trait loci (QTLs) were involved in length maintenance. Variation in TPE is similarly quantitative but only weakly correlated with telomere length. Genotyping F1 segregants indicated several QTLs associated with telomere length and silencing variation. These QTLs include likely candidate genes but also map to regions where there are no known genes involved in telomeric properties. We detected transgressive segregation for both phenotypes. We validated by reciprocal hemizygosity that YKU80 and TLC1 are telomere-length QTLs in the two S. paradoxus subpopulations. Furthermore, we propose that sequence divergence within the Ku heterodimer generates negative epistasis within one of the allelic combinations (American-YKU70 and European-YKU80) resulting in very short telomeres.

  14. Mutant Mice Lacking the p53 C-Terminal Domain Model Telomere Syndromes

    Directory of Open Access Journals (Sweden)

    Iva Simeonova

    2013-06-01

    Full Text Available Mutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53Δ31, a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres. Indeed, p53Δ31/Δ31 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Heterozygous p53+/Δ31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms. Importantly, several genes involved in telomere metabolism were downregulated in p53Δ31/Δ31 cells, including Dyskerin, Rtel1, and Tinf2, which are mutated in dyskeratosis congenita, and Terf1, which is implicated in aplastic anemia. Together, these data reveal that a truncating mutation can activate p53 and that p53 plays a major role in the regulation of telomere metabolism.

  15. Radiation initiated telomerization of ethylene with formamide and dimethylformamide

    International Nuclear Information System (INIS)

    Dederichs, B.; Saus, A.

    1977-01-01

    The radiation initiated telomerization of ethylene with formic acid amide and dimethylformamide under pressure was studied in detail. With formamide, homologous odd numbered linear alkane carbonic acid amides are obtained as the main products. Dimethylformamide gives homologous N,N-dimethyl alkane carbonic acid amides and N-methyl-N-alkyl-formic acid amides with a molar ratio of 1:1. The distribution of the homologous amides corresponds to a geometrical progression. The yield of telomers is proportional to the absorbed dose. The influence of the dose rate is given by the following equation: G = K x Isup(a-1). The exponent a was found to be 0.6. The reaction is pressure and temperature dependent. With increasing pressure the distribution of telomers is shifted to longer chain acid amides. Increasing temperature favours the yield of acid amides. The results are discussed from the radiation chemical point of view. (author)

  16. A product of the bicistronic Drosophila melanogaster gene CG31241, which also encodes a trimethylguanosine synthase, plays a role in telomere protection.

    Science.gov (United States)

    Komonyi, Orban; Schauer, Tamas; Papai, Gabor; Deak, Peter; Boros, Imre M

    2009-03-15

    Although telomere formation occurs through a different mechanism in Drosophila compared with other organisms, telomere associations result from mutations in homologous genes, indicating the involvement of similar pathways in chromosome end protection. We report here that mutations of the Drosophila melanogaster gene CG31241 lead to high frequency chromosome end fusions. CG31241 is a bicistronic gene that encodes trimethylguanosine synthase (TGS1), which forms the m3G caps of noncoding small RNAs, and a novel protein, DTL. We show that although TGS1 has no role in telomere protection, DTL is localized at specific sites, including the ends of polytene chromosomes, and its loss results in telomere associations. Mutations of ATM- and Rad3-related (ATR) kinase suppress telomere fusions in the absence of DTL. Thus, genetic interactions place DTL in an ATR-related pathway in telomere protection. In contrast to ATR kinase, mutations of ATM (ataxia telangiectasia mutated) kinase, which acts in a partially overlapping pathway of telomere protection, do not suppress formation of telomere associations in the absence of DTL. Thus, uncovering the role of DTL will help to dissect the evolutionary conserved pathway(s) controlling ATM-ATR-related telomere protection.

  17. The power of exercise: buffering the effect of chronic stress on telomere length.

    Directory of Open Access Journals (Sweden)

    Eli Puterman

    2010-05-01

    Full Text Available Chronic psychological stress is associated with detrimental effects on physical health, and may operate in part through accelerated cell aging, as indexed by shorter telomeres at the ends of chromosomes. However, not all people under stress have distinctly short telomeres, and we examined whether exercise can serve a stress-buffering function. We predicted that chronic stress would be related to short telomere length (TL in sedentary individuals, whereas in those who exercise, stress would not have measurable effects on telomere shortening.63 healthy post-menopausal women underwent a fasting morning blood draw for whole blood TL analysis by a quantitative polymerase chain reaction method. Participants completed the Perceived Stress Scale (Cohen et al., 1983, and for three successive days reported daily minutes of vigorous activity. Participants were categorized into two groups-sedentary and active (those getting Centers for Disease Control-recommended daily amount of activity. The likelihood of having short versus long telomeres was calculated as a function of stress and exercise group, covarying age, BMI and education. Logistic regression analyses revealed a significant moderating effect of exercise. As predicted, among non-exercisers a one unit increase in the Perceived Stress Scale was related to a 15-fold increase in the odds of having short telomeres (p<.05, whereas in exercisers, perceived stress appears to be unrelated to TL (B = -.59, SE = .78, p = .45.Vigorous physical activity appears to protect those experiencing high stress by buffering its relationship with TL. We propose pathways through which physical activity acts to buffer stress effects.

  18. Telomerer og telomerase

    DEFF Research Database (Denmark)

    Bendix, Laila; Kølvraa, Steen

    2010-01-01

    In 2009 the Nobel Prize in Medicine was awarded to EH Blackburn, CW Greider and JW Szostak for their work on "How chromosomes are protected by telomeres and the enzyme telomerase". Telomeres are specialized DNA structures localized at the end of linear chromosomes. Telomeres are known as the biol......In 2009 the Nobel Prize in Medicine was awarded to EH Blackburn, CW Greider and JW Szostak for their work on "How chromosomes are protected by telomeres and the enzyme telomerase". Telomeres are specialized DNA structures localized at the end of linear chromosomes. Telomeres are known...

  19. Drosophila atm/telomere fusion is required for telomeric localization of HP1 and telomere position effect

    OpenAIRE

    Oikemus, Sarah R.; McGinnis, Nadine; Queiroz-Machado, Joana; Tukachinsky, Hanna; Takada, Saeko; Sunkel, Claudio E.; Brodsky, Michael H.

    2004-01-01

    Terminal deletions of Drosophila chromosomes can be stably protected from end-to-end fusion despite the absence of all telomere-associated sequences. The sequence-independent protection of these telomeres suggests that recognition of chromosome ends might contribute to the epigenetic protection of telomeres. In mammals, Ataxia Telangiectasia Mutated (ATM) is activated by DNA damage and acts through an unknown, telomerase-independent mechanism to regulate telomere length and protection. We dem...

  20. Lead Exposure Induces Telomere Instability in Human Cells.

    Directory of Open Access Journals (Sweden)

    Géraldine Pottier

    Full Text Available Lead (Pb is an important environmental contaminant due to its widespread use over many centuries. While it affects primarily every organ system of the body, the most pernicious effects of Pb are on the central nervous system leading to cognitive and behavioral modification. Despite decades of research, the mechanisms responsible for Pb toxicity remain poorly understood. Recent work has suggested that Pb exposure may have consequences on chromosomal integrity as it was shown that Pb exposure leads to the generation of γH2Ax foci, a well-established biomarker for DNA double stranded break (DSB formation. As the chromosomal localization of γH2Ax foci plays an important role in determining the molecular mechanism responsible for their formation, we examined the localization of Pb-induced foci with respect to telomeres. Indeed, short or dysfunctional telomeres (uncapped or damaged telomeres may be recognized as DSB by the DNA repair machinery, leading to "telomere-Induced Foci" (TIFs. In the current study, we show that while Pb exposure did not increase intra-chromosomal foci, it significantly induced TIFs, leading in some cases, to chromosomal abnormalities including telomere loss. The evidence suggests that these chromosomal abnormalities are likely due to perturbation of telomere replication, in particular on the lagging DNA strand. We propose a mechanism by which Pb exposure leads to the loss of telomere maintenance. As numerous studies have demonstrated a role for telomere maintenance in brain development and tissue homeostasis, our results suggest a possible mechanism for lead-induced neurotoxicity.

  1. Pulmonary phenotypes associated with genetic variation in telomere-related genes.

    Science.gov (United States)

    Hoffman, Thijs W; van Moorsel, Coline H M; Borie, Raphael; Crestani, Bruno

    2018-05-01

    Genomic mutations in telomere-related genes have been recognized as a cause of familial forms of idiopathic pulmonary fibrosis (IPF). However, it has become increasingly clear that telomere syndromes and telomere shortening are associated with various types of pulmonary disease. Additionally, it was found that also single nucleotide polymorphisms (SNPs) in telomere-related genes are risk factors for the development of pulmonary disease. This review focuses on recent updates on pulmonary phenotypes associated with genetic variation in telomere-related genes. Genomic mutations in seven telomere-related genes cause pulmonary disease. Pulmonary phenotypes associated with these mutations range from many forms of pulmonary fibrosis to emphysema and pulmonary vascular disease. Telomere-related mutations account for up to 10% of sporadic IPF, 25% of familial IPF, 10% of connective-tissue disease-associated interstitial lung disease, and 1% of COPD. Mixed disease forms have also been found. Furthermore, SNPs in TERT, TERC, OBFC1, and RTEL1, as well as short telomere length, have been associated with several pulmonary diseases. Treatment of pulmonary disease caused by telomere-related gene variation is currently based on disease diagnosis and not on the underlying cause. Pulmonary phenotypes found in carriers of telomere-related gene mutations and SNPs are primarily pulmonary fibrosis, sometimes emphysema and rarely pulmonary vascular disease. Genotype-phenotype relations are weak, suggesting that environmental factors and genetic background of patients determine disease phenotypes to a large degree. A disease model is presented wherever genomic variation in telomere-related genes cause specific pulmonary disease phenotypes whenever triggered by environmental exposure, comorbidity, or unknown factors.

  2. Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia.

    Science.gov (United States)

    Bär, Christian; Povedano, Juan Manuel; Serrano, Rosa; Benitez-Buelga, Carlos; Popkes, Miriam; Formentini, Ivan; Bobadilla, Maria; Bosch, Fatima; Blasco, Maria A

    2016-04-07

    Aplastic anemia is a fatal bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia. The disease can be hereditary or acquired and develops at any stage of life. A subgroup of the inherited form is caused by replicative impairment of hematopoietic stem and progenitor cells due to very short telomeres as a result of mutations in telomerase and other telomere components. Abnormal telomere shortening is also described in cases of acquired aplastic anemia, most likely secondary to increased turnover of bone marrow stem and progenitor cells. Here, we test the therapeutic efficacy of telomerase activation by using adeno-associated virus (AAV)9 gene therapy vectors carrying the telomerase Tert gene in 2 independent mouse models of aplastic anemia due to short telomeres (Trf1- and Tert-deficient mice). We find that a high dose of AAV9-Tert targets the bone marrow compartment, including hematopoietic stem cells. AAV9-Tert treatment after telomere attrition in bone marrow cells rescues aplastic anemia and mouse survival compared with mice treated with the empty vector. Improved survival is associated with a significant increase in telomere length in peripheral blood and bone marrow cells, as well as improved blood counts. These findings indicate that telomerase gene therapy represents a novel therapeutic strategy to treat aplastic anemia provoked or associated with short telomeres. © 2016 by The American Society of Hematology.

  3. Placental telomere shortening in stillbirth: a sign of premature senescence?

    Science.gov (United States)

    Ferrari, Francesca; Facchinetti, Fabio; Saade, George; Menon, Ramkumar

    2016-01-01

    The objective of this study is to investigate placental telomere shortening in unexplained stillbirths (SBs) as an indication of premature senescence. Placentas were collected from 42 unexplained SB (>22 weeks), 43 term and 15 preterm live births, at the Policlinico Hospital of Modena (Italy). DNA extracted from placentae was studied for telomere length by real time PCR. Standard curves were generated for telomere lengths from single copy gene amplifications using a reference DNA. The telomere length for each sample was derived based on the ratio of telomere length between the sample and single copy gene standard (T/S ratio). The mean ratio of placental telomere in term live births was 5.181 ± 3.841. A twofold decrease in telomere length was seen in SBs (over all 2.455 ± 1.239; p PTBs) (6.382 ± 5.525; p < 0.01), whereas SBs telomere length were similar to those of preterm premature rupture of membranes (pPROM) (3.296 ± 3.599; p = ns). Substantial reduction in telomere length in SBs is indicative of placental senescence. These data provide mechanistic insights that premature aging may lead to placental dysfunction as an initiator of fetal demise in unexplained SBs.

  4. Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome.

    Science.gov (United States)

    Deng, Zhong; Glousker, Galina; Molczan, Aliah; Fox, Alan J; Lamm, Noa; Dheekollu, Jayaraju; Weizman, Orr-El; Schertzer, Michael; Wang, Zhuo; Vladimirova, Olga; Schug, Jonathan; Aker, Memet; Londoño-Vallejo, Arturo; Kaestner, Klaus H; Lieberman, Paul M; Tzfati, Yehuda

    2013-09-03

    Telomeres repress the DNA damage response at the natural chromosome ends to prevent cell-cycle arrest and maintain genome stability. Telomeres are elongated by telomerase in a tightly regulated manner to ensure a sufficient number of cell divisions throughout life, yet prevent unlimited cell division and cancer development. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and a broad range of pathologies, including bone marrow failure, immunodeficiency, and developmental defects. HHS-causing mutations have previously been found in telomerase and the shelterin component telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2 (TIN2). We identified by whole-genome exome sequencing compound heterozygous mutations in four siblings affected with HHS, in the gene encoding the regulator of telomere elongation helicase 1 (RTEL1). Rtel1 was identified in mouse by its genetic association with telomere length. However, its mechanism of action and whether it regulates telomere length in human remained unknown. Lymphoblastoid cell lines obtained from a patient and from the healthy parents carrying heterozygous RTEL1 mutations displayed telomere shortening, fragility and fusion, and growth defects in culture. Ectopic expression of WT RTEL1 suppressed the telomere shortening and growth defect, confirming the causal role of the RTEL1 mutations in HHS and demonstrating the essential function of human RTEL1 in telomere protection and elongation. Finally, we show that human RTEL1 interacts with the shelterin protein TRF1, providing a potential recruitment mechanism of RTEL1 to telomeres.

  5. Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal–Hreidarsson syndrome

    Science.gov (United States)

    Deng, Zhong; Glousker, Galina; Molczan, Aliah; Fox, Alan J.; Lamm, Noa; Dheekollu, Jayaraju; Weizman, Orr-El; Schertzer, Michael; Wang, Zhuo; Vladimirova, Olga; Schug, Jonathan; Aker, Memet; Londoño-Vallejo, Arturo; Kaestner, Klaus H.; Lieberman, Paul M.; Tzfati, Yehuda

    2013-01-01

    Telomeres repress the DNA damage response at the natural chromosome ends to prevent cell-cycle arrest and maintain genome stability. Telomeres are elongated by telomerase in a tightly regulated manner to ensure a sufficient number of cell divisions throughout life, yet prevent unlimited cell division and cancer development. Hoyeraal–Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and a broad range of pathologies, including bone marrow failure, immunodeficiency, and developmental defects. HHS-causing mutations have previously been found in telomerase and the shelterin component telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2 (TIN2). We identified by whole-genome exome sequencing compound heterozygous mutations in four siblings affected with HHS, in the gene encoding the regulator of telomere elongation helicase 1 (RTEL1). Rtel1 was identified in mouse by its genetic association with telomere length. However, its mechanism of action and whether it regulates telomere length in human remained unknown. Lymphoblastoid cell lines obtained from a patient and from the healthy parents carrying heterozygous RTEL1 mutations displayed telomere shortening, fragility and fusion, and growth defects in culture. Ectopic expression of WT RTEL1 suppressed the telomere shortening and growth defect, confirming the causal role of the RTEL1 mutations in HHS and demonstrating the essential function of human RTEL1 in telomere protection and elongation. Finally, we show that human RTEL1 interacts with the shelterin protein TRF1, providing a potential recruitment mechanism of RTEL1 to telomeres. PMID:23959892

  6. The association of telomere length and genetic variation in telomere biology genes.

    Science.gov (United States)

    Mirabello, Lisa; Yu, Kai; Kraft, Peter; De Vivo, Immaculata; Hunter, David J; Prescott, Jennifer; Wong, Jason Y Y; Chatterjee, Nilanjan; Hayes, Richard B; Savage, Sharon A

    2010-09-01

    Telomeres cap chromosome ends and are critical for genomic stability. Many telomere-associated proteins are important for telomere length maintenance. Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in genes encoding telomere-associated proteins (RTEL1 and TERT-CLPTM1) as markers of cancer risk. We conducted an association study of telomere length and 743 SNPs in 43 telomere biology genes. Telomere length in peripheral blood DNA was determined by Q-PCR in 3,646 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Nurses' Health Study. We investigated associations by SNP, gene, and pathway (functional group). We found no associations between telomere length and SNPs in TERT-CLPTM1L or RTEL1. Telomere length was not significantly associated with specific functional groups. Thirteen SNPs from four genes (MEN1, MRE11A, RECQL5, and TNKS) were significantly associated with telomere length. The strongest findings were in MEN1 (gene-based P=0.006), menin, which associates with the telomerase promoter and may negatively regulate telomerase. This large association study did not find strong associations with telomere length. The combination of limited diversity and evolutionary conservation suggest that these genes may be under selective pressure. More work is needed to explore the role of genetic variants in telomere length regulation. Published 2010 Wiley-Liss, Inc.

  7. Zen meditation, Length of Telomeres, and the Role of Experiential Avoidance and Compassion.

    Science.gov (United States)

    Alda, Marta; Puebla-Guedea, Marta; Rodero, Baltasar; Demarzo, Marcelo; Montero-Marin, Jesus; Roca, Miquel; Garcia-Campayo, Javier

    Mindfulness refers to an awareness that emerges by intentionally focusing on the present experience in a nonjudgmental or evaluative manner. Evidence regarding its efficacy has been increasing exponentially, and recent research suggests that the practice of meditation is associated with longer leukocyte telomere length. However, the psychological mechanisms underlying this potential relationship are unknown. We examined the telomere lengths of a group of 20 Zen meditation experts and another 20 healthy matched comparison participants who had not previously meditated. We also measured multiple psychological variables related to meditation practice. Genomic DNA was extracted for telomere measurement using a Life Length proprietary program. High-throughput quantitative fluorescence in situ hybridization (HT-Q-FISH) was used to measure the telomere length distribution and the median telomere length (MTL). The meditators group had a longer MTL ( p  = 0.005) and a lower percentage of short telomeres in individual cells ( p  = 0.007) than those in the comparison group. To determine which of the psychological variables contributed more to telomere maintenance, two regression analyses were conducted. In the first model, which applied to the MTL, the following three factors were significant: age, absence of experiential avoidance, and Common Humanity subscale of the Self Compassion Scale. Similarly, in the model that examined the percentage of short telomeres, the same factors were significant: age, absence of experiential avoidance, and Common Humanity subscale of the Self Compassion Scale. Although limited by a small sample size, these results suggest that the absence of experiential avoidance of negative emotions and thoughts is integral to the connection between meditation and telomeres.

  8. TRF2 recruits RTEL1 to telomeres in S phase to promote t-loop unwinding.

    Science.gov (United States)

    Sarek, Grzegorz; Vannier, Jean-Baptiste; Panier, Stephanie; Petrini, John H J; Boulton, Simon J

    2015-02-19

    The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres. An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear. Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required to prevent catastrophic t-loop processing by structure-specific nucleases. We show that the TRF2-RTEL1 interaction is mediated by a metal-coordinating C4C4 motif in RTEL1, which is compromised by the Hoyeraal-Hreidarsson syndrome (HHS) mutation, RTEL1(R1264H). Conversely, we define a TRF2(I124D) substitution mutation within the TRFH domain of TRF2, which eliminates RTEL1 binding and phenocopies the RTEL1(R1264H) mutation, giving rise to aberrant t-loop excision, telomere length heterogeneity, and loss of the telomere as a circle. These results implicate TRF2 in the recruitment of RTEL1 to facilitate t-loop disassembly at telomeres in S phase. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  9. The long and the short of telomeres in bone marrow recipient SCID patients

    OpenAIRE

    Sarzotti-Kelsoe, Marcella; Daniell, Xiaoju G.; Whitesides, John F.; Buckley, Rebecca H.

    2011-01-01

    Telomeres are noncoding DNA regions at the end of the chromosomes that are crucial for genome stability. Since telomere length decreases with cell division, they can be used as a signature of cell proliferation history. T-cell reconstitution in severe combined immunodeficiency (SCID) subjects, recipients of T-cell-depleted, allogeneic-related bone marrow cells, is due to the development and maturation of donor T-cell precursors in the infant’s vestigial thymus and to homeostatic proliferation...

  10. Characterization of oxidative guanine damage and repair in mammalian telomeres.

    Directory of Open Access Journals (Sweden)

    Zhilong Wang

    2010-05-01

    Full Text Available 8-oxo-7,8-dihydroguanine (8-oxoG and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG are among the most common oxidative DNA lesions and are substrates for 8-oxoguanine DNA glycosylase (OGG1-initiated DNA base excision repair (BER. Mammalian telomeres consist of triple guanine repeats and are subject to oxidative guanine damage. Here, we investigated the impact of oxidative guanine damage and its repair by OGG1 on telomere integrity in mice. The mouse cells were analyzed for telomere integrity by telomere quantitative fluorescence in situ hybridization (telomere-FISH, by chromosome orientation-FISH (CO-FISH, and by indirect immunofluorescence in combination with telomere-FISH and for oxidative base lesions by Fpg-incision/Southern blot assay. In comparison to the wild type, telomere lengthening was observed in Ogg1 null (Ogg1(-/- mouse tissues and primary embryonic fibroblasts (MEFs cultivated in hypoxia condition (3% oxygen, whereas telomere shortening was detected in Ogg1(-/- mouse hematopoietic cells and primary MEFs cultivated in normoxia condition (20% oxygen or in the presence of an oxidant. In addition, telomere length abnormalities were accompanied by altered telomere sister chromatid exchanges, increased telomere single- and double-strand breaks, and preferential telomere lagging- or G-strand losses in Ogg1(-/- mouse cells. Oxidative guanine lesions were increased in telomeres in Ogg1(-/- mice with aging and primary MEFs cultivated in 20% oxygen. Furthermore, oxidative guanine lesions persisted at high level in Ogg1(-/- MEFs after acute exposure to hydrogen peroxide, while they rapidly returned to basal level in wild-type MEFs. These findings indicate that oxidative guanine damage can arise in telomeres where it affects length homeostasis, recombination, DNA replication, and DNA breakage repair. Our studies demonstrate that BER pathway is required in repairing oxidative guanine damage in telomeres and maintaining telomere integrity

  11. Expression of Telomere-Associated Proteins is Interdependent to Stabilize Native Telomere Structure and Telomere Dysfunction by G-Quadruplex Ligand Causes TERRA Upregulation.

    Science.gov (United States)

    Sadhukhan, Ratan; Chowdhury, Priyanka; Ghosh, Sourav; Ghosh, Utpal

    2018-06-01

    Telomere DNA can form specialized nucleoprotein structure with telomere-associated proteins to hide free DNA ends or G-quadruplex structures under certain conditions especially in presence of G-quadruplex ligand. Telomere DNA is transcribed to form non-coding telomere repeat-containing RNA (TERRA) whose biogenesis and function is poorly understood. Our aim was to find the role of telomere-associated proteins and telomere structures in TERRA transcription. We silenced four [two shelterin (TRF1, TRF2) and two non-shelterin (PARP-1, SLX4)] telomere-associated genes using siRNA and verified depletion in protein level. Knocking down of one gene modulated expression of other telomere-associated genes and increased TERRA from 10q, 15q, XpYp and XqYq chromosomes in A549 cells. Telomere was destabilized or damaged by G-quadruplex ligand pyridostatin (PDS) and bleomycin. Telomere dysfunction-induced foci (TIFs) were observed for each case of depletion of proteins, treatment with PDS or bleomycin. TERRA level was elevated by PDS and bleomycin treatment alone or in combination with depletion of telomere-associated proteins.

  12. The effect of regular strength training on telomere length in human skeletal muscle

    DEFF Research Database (Denmark)

    Kadi, F.; Ponsot, Elodie; Piehl-Aulin, Karin

    2008-01-01

    PURPOSE: The length of DNA telomeres is an important parameter of the proliferative potential of tissues. A recent study has reported abnormally short telomeres in skeletal muscle of athletes with exercise-associated fatigue. This important report raises the question of whether long-term practice...... of sports might have deleterious effects on muscle telomeres. Therefore, we aimed to compare telomere length of a group of power lifters (PL; N = 7) who trained for 8 +/- 3 yr against that of a group of healthy, active subjects (C; N = 7) with no history of strength training. METHODS: Muscle biopsies were...

  13. Telomere dysfunction and chromosome structure modulate the contribution of individual chromosomes in abnormal nuclear morphologies

    Energy Technology Data Exchange (ETDEWEB)

    Pampalona, J.; Soler, D.; Genesca, A. [Department of Cell Biology, Physiology and Immunology, Universitat Autonoma de Barcelona, Bellaterra E-08193 (Spain); Tusell, L., E-mail: laura.tusell@uab.es [Department of Cell Biology, Physiology and Immunology, Universitat Autonoma de Barcelona, Bellaterra E-08193 (Spain)

    2010-01-05

    The cytokinesis-block micronucleus assay has emerged as a biomarker of chromosome damage relevant to cancer. Although it was initially developed to measure micronuclei, it is also useful for measuring nucleoplasmic bridges and nuclear buds. Abnormal nuclear morphologies are frequently observed in malignant tissues and short-term tumour cell cultures. Changes in chromosome structure and number resulting from chromosome instability are important factors in oncogenesis. Telomeres have become key players in the initiation of chromosome instability related to carcinogenesis by means of breakage-fusion-bridge cycles. To better understand the connection between telomere dysfunction and the appearance of abnormal nuclear morphologies, we have characterised the presence of micronuclei, nucleoplasmic bridges and nuclear buds in human mammary primary epithelial cells. These cells can proliferate beyond the Hayflick limit by spontaneously losing expression of the p16{sup INK4a} protein. Progressive telomere shortening leads to the loss of the capping function, and the appearance of end-to-end chromosome fusions that can enter into breakage-fusion-bridge cycles generating massive chromosomal instability. In human mammary epithelial cells, different types of abnormal nuclear morphologies were observed, however only nucleoplasmatic bridges and buds increased significantly with population doublings. Fluorescent in situ hybridisation using centromeric and painting specific probes for chromosomes with eroded telomeres has revealed that these chromosomes are preferentially included in the different types of abnormal nuclear morphologies observed, thus reflecting their common origin. Accordingly, real-time imaging of cell divisions enabled us to determine that anaphase bridge resolution was mainly through chromatin breakage and the formation of symmetric buds in daughter nuclei. Few micronuclei emerged in this cell system thus validating the scoring of nucleoplasmic bridges and

  14. Telomere dysfunction and chromosome structure modulate the contribution of individual chromosomes in abnormal nuclear morphologies

    International Nuclear Information System (INIS)

    Pampalona, J.; Soler, D.; Genesca, A.; Tusell, L.

    2010-01-01

    The cytokinesis-block micronucleus assay has emerged as a biomarker of chromosome damage relevant to cancer. Although it was initially developed to measure micronuclei, it is also useful for measuring nucleoplasmic bridges and nuclear buds. Abnormal nuclear morphologies are frequently observed in malignant tissues and short-term tumour cell cultures. Changes in chromosome structure and number resulting from chromosome instability are important factors in oncogenesis. Telomeres have become key players in the initiation of chromosome instability related to carcinogenesis by means of breakage-fusion-bridge cycles. To better understand the connection between telomere dysfunction and the appearance of abnormal nuclear morphologies, we have characterised the presence of micronuclei, nucleoplasmic bridges and nuclear buds in human mammary primary epithelial cells. These cells can proliferate beyond the Hayflick limit by spontaneously losing expression of the p16 INK4a protein. Progressive telomere shortening leads to the loss of the capping function, and the appearance of end-to-end chromosome fusions that can enter into breakage-fusion-bridge cycles generating massive chromosomal instability. In human mammary epithelial cells, different types of abnormal nuclear morphologies were observed, however only nucleoplasmatic bridges and buds increased significantly with population doublings. Fluorescent in situ hybridisation using centromeric and painting specific probes for chromosomes with eroded telomeres has revealed that these chromosomes are preferentially included in the different types of abnormal nuclear morphologies observed, thus reflecting their common origin. Accordingly, real-time imaging of cell divisions enabled us to determine that anaphase bridge resolution was mainly through chromatin breakage and the formation of symmetric buds in daughter nuclei. Few micronuclei emerged in this cell system thus validating the scoring of nucleoplasmic bridges and nuclear

  15. Telomere dysfunction and chromosome structure modulate the contribution of individual chromosomes in abnormal nuclear morphologies.

    Science.gov (United States)

    Pampalona, J; Soler, D; Genescà, A; Tusell, L

    2010-01-05

    The cytokinesis-block micronucleus assay has emerged as a biomarker of chromosome damage relevant to cancer. Although it was initially developed to measure micronuclei, it is also useful for measuring nucleoplasmic bridges and nuclear buds. Abnormal nuclear morphologies are frequently observed in malignant tissues and short-term tumour cell cultures. Changes in chromosome structure and number resulting from chromosome instability are important factors in oncogenesis. Telomeres have become key players in the initiation of chromosome instability related to carcinogenesis by means of breakage-fusion-bridge cycles. To better understand the connection between telomere dysfunction and the appearance of abnormal nuclear morphologies, we have characterised the presence of micronuclei, nucleoplasmic bridges and nuclear buds in human mammary primary epithelial cells. These cells can proliferate beyond the Hayflick limit by spontaneously losing expression of the p16(INK4a) protein. Progressive telomere shortening leads to the loss of the capping function, and the appearance of end-to-end chromosome fusions that can enter into breakage-fusion-bridge cycles generating massive chromosomal instability. In human mammary epithelial cells, different types of abnormal nuclear morphologies were observed, however only nucleoplasmatic bridges and buds increased significantly with population doublings. Fluorescent in situ hybridisation using centromeric and painting specific probes for chromosomes with eroded telomeres has revealed that these chromosomes are preferentially included in the different types of abnormal nuclear morphologies observed, thus reflecting their common origin. Accordingly, real-time imaging of cell divisions enabled us to determine that anaphase bridge resolution was mainly through chromatin breakage and the formation of symmetric buds in daughter nuclei. Few micronuclei emerged in this cell system thus validating the scoring of nucleoplasmic bridges and nuclear

  16. Tired telomeres: Poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women.

    Science.gov (United States)

    Prather, Aric A; Gurfein, Blake; Moran, Patricia; Daubenmier, Jennifer; Acree, Michael; Bacchetti, Peter; Sinclair, Elizabeth; Lin, Jue; Blackburn, Elizabeth; Hecht, Frederick M; Epel, Elissa S

    2015-07-01

    Poor sleep quality and short sleep duration are associated with increased incidence and progression of a number of chronic health conditions observed at greater frequency among the obese and those experiencing high levels of stress. Accelerated cellular aging, as indexed by telomere attrition in immune cells, is a plausible pathway linking sleep and disease risk. Prior studies linking sleep and telomere length are mixed. One factor may be reliance on leukocytes, which are composed of varied immune cell types, as the sole measure of telomere length. To better clarify these associations, we investigated the relationships of global sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), and diary-reported sleep duration with telomere length in different immune cell subsets, including granulocytes, peripheral blood mononuclear cells (PBMCs), CD8+ and CD4+ T lymphocytes, and B lymphocytes in a sample of 87 obese men and women (BMI mean=35.4, SD=3.6; 81.6% women; 62.8% Caucasian). Multiple linear regression analyses were performed adjusting for age, gender, race, education, BMI, sleep apnea risk, and perceived stress. Poorer PSQI global sleep quality was associated with statistically significantly shorter telomere length in lymphocytes but not granulocytes and in particular CD8+ T cells (b=-56.8 base pairs per one point increase in PSQI, SE=20.4, p=0.007) and CD4+ T cells (b=-37.2, SE=15.9, p=0.022). Among separate aspects of global sleep quality, low perceived sleep quality and decrements in daytime function were most related to shorter telomeres. In addition, perceived stress moderated the sleep-CD8+ telomere association. Poorer global sleep quality predicted shorter telomere length in CD8+ T cells among those with high perceived stress but not in low stress participants. These findings provide preliminary evidence that poorer global sleep quality is related to telomere length in several immune cell types, which may serve as a pathway linking sleep and

  17. Telomere dynamics and homeostasis in a transmissible cancer.

    Science.gov (United States)

    Ujvari, Beata; Pearse, Anne-Maree; Taylor, Robyn; Pyecroft, Stephen; Flanagan, Cassandra; Gombert, Sara; Papenfuss, Anthony T; Madsen, Thomas; Belov, Katherine

    2012-01-01

    Devil Facial Tumour Disease (DFTD) is a unique clonal cancer that threatens the world's largest carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii) with extinction. This transmissible cancer is passed between individual devils by cell implantation during social interactions. The tumour arose in a Schwann cell of a single devil over 15 years ago and since then has expanded clonally, without showing signs of replicative senescence; in stark contrast to a somatic cell that displays a finite capacity for replication, known as the "Hayflick limit". In the present study we investigate the role of telomere length, measured as Telomere Copy Number (TCN), and telomerase and shelterin gene expression, as well as telomerase activity in maintaining hyperproliferation of Devil Facial Tumour (DFT) cells. Our results show that DFT cells have short telomeres. DFTD TCN does not differ between geographic regions or between strains. However, TCN has increased over time. Unlimited cell proliferation is likely to have been achieved through the observed up-regulation of the catalytic subunit of telomerase (TERT) and concomitant activation of telomerase. Up-regulation of the central component of shelterin, the TRF1-intercating nuclear factor 2 (TINF2) provides DFT a mechanism for telomere length homeostasis. The higher expression of both TERT and TINF2 may also protect DFT cells from genomic instability and enhance tumour proliferation. DFT cells appear to monitor and regulate the length of individual telomeres: i.e. shorter telomeres are elongated by up-regulation of telomerase-related genes; longer telomeres are protected from further elongation by members of the shelterin complex, which may explain the lack of spatial and strain variation in DFT telomere copy number. The observed longitudinal increase in gene expression in DFT tissue samples and telomerase activity in DFT cell lines might indicate a selection for more stable tumours with higher proliferative potential.

  18. Telomere dynamics and homeostasis in a transmissible cancer.

    Directory of Open Access Journals (Sweden)

    Beata Ujvari

    Full Text Available Devil Facial Tumour Disease (DFTD is a unique clonal cancer that threatens the world's largest carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii with extinction. This transmissible cancer is passed between individual devils by cell implantation during social interactions. The tumour arose in a Schwann cell of a single devil over 15 years ago and since then has expanded clonally, without showing signs of replicative senescence; in stark contrast to a somatic cell that displays a finite capacity for replication, known as the "Hayflick limit".In the present study we investigate the role of telomere length, measured as Telomere Copy Number (TCN, and telomerase and shelterin gene expression, as well as telomerase activity in maintaining hyperproliferation of Devil Facial Tumour (DFT cells. Our results show that DFT cells have short telomeres. DFTD TCN does not differ between geographic regions or between strains. However, TCN has increased over time. Unlimited cell proliferation is likely to have been achieved through the observed up-regulation of the catalytic subunit of telomerase (TERT and concomitant activation of telomerase. Up-regulation of the central component of shelterin, the TRF1-intercating nuclear factor 2 (TINF2 provides DFT a mechanism for telomere length homeostasis. The higher expression of both TERT and TINF2 may also protect DFT cells from genomic instability and enhance tumour proliferation.DFT cells appear to monitor and regulate the length of individual telomeres: i.e. shorter telomeres are elongated by up-regulation of telomerase-related genes; longer telomeres are protected from further elongation by members of the shelterin complex, which may explain the lack of spatial and strain variation in DFT telomere copy number. The observed longitudinal increase in gene expression in DFT tissue samples and telomerase activity in DFT cell lines might indicate a selection for more stable tumours with higher proliferative

  19. Chromatid interchanges at intrachromosomal telomeric DNA sequences

    International Nuclear Information System (INIS)

    Fernandez, J.L.; Vazquez-Gundin, F.; Bilbao, A.; Gosalvez, J.; Goyanes, V.

    1997-01-01

    Chinese hamster Don cells were exposed to X-rays, mitomycin C and teniposide (VM-26) to induce chromatid exchanges (quadriradials and triradials). After fluorescence in situ hybridization (FISH) of telomere sequences it was found that interstitial telomere-like DNA sequence arrays presented around five times more breakage-rearrangements than the genome overall. This high recombinogenic capacity was independent of the clastogen, suggesting that this susceptibility is not related to the initial mechanisms of DNA damage. (author)

  20. Telomere Length and Mortality

    DEFF Research Database (Denmark)

    Kimura, Masayuki; Hjelmborg, Jacob V B; Gardner, Jeffrey P

    2008-01-01

    Leukocyte telomere length, representing the mean length of all telomeres in leukocytes, is ostensibly a bioindicator of human aging. The authors hypothesized that shorter telomeres might forecast imminent mortality in elderly people better than leukocyte telomere length. They performed mortality...

  1. Differential Telomere Shortening in Blood versus Arteries in an Animal Model of Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Samira Tajbakhsh

    2015-01-01

    Full Text Available Vascular dysfunction is an early feature of diabetic vascular disease, due to increased oxidative stress and reduced nitric oxide (NO bioavailability. This can lead to endothelial cell senescence and clinical complications such as stroke. Cells can become senescent by shortened telomeres and oxidative stress is known to accelerate telomere attrition. Sirtuin 1 (SIRT1 has been linked to vascular health by upregulating endothelial nitric oxide synthase (eNOS, suppressing oxidative stress, and attenuating telomere shortening. Accelerated leukocyte telomere attrition appears to be a feature of clinical type 2 diabetes (T2D and therefore the telomere system may be a potential therapeutic target in preventing vascular complications of T2D. However the effect of T2D on vascular telomere length is currently unknown. We hypothesized that T2D gives rise to shortened leukocyte and vascular telomeres alongside reduced vascular SIRT1 expression and increased oxidative stress. Accelerated telomere attrition was observed in circulating leukocytes, but not arteries, in T2D compared to control rats. T2D rats had blunted arterial SIRT1 and eNOS protein expression levels which were associated with reduced antioxidant defense capacity. Our findings suggest that hyperglycemia and a deficit in vascular SIRT1 per se are not sufficient to prematurely shorten vascular telomeres.

  2. Ageing and the telomere connection: An intimate relationship with inflammation.

    Science.gov (United States)

    Zhang, Jingwen; Rane, Grishma; Dai, Xiaoyun; Shanmugam, Muthu K; Arfuso, Frank; Samy, Ramar Perumal; Lai, Mitchell Kim Peng; Kappei, Dennis; Kumar, Alan Prem; Sethi, Gautam

    2016-01-01

    Telomeres are the heterochromatic repeat regions at the ends of eukaryotic chromosomes, whose length is considered to be a determinant of biological ageing. Normal ageing itself is associated with telomere shortening. Here, critically short telomeres trigger senescence and eventually cell death. This shortening rate may be further increased by inflammation and oxidative stress and thus affect the ageing process. Apart from shortened or dysfunctional telomeres, cells undergoing senescence are also associated with hyperactivity of the transcription factor NF-κB and overexpression of inflammatory cytokines such as TNF-α, IL-6, and IFN-γ in circulating macrophages. Interestingly, telomerase, a reverse transcriptase that elongates telomeres, is involved in modulating NF-κB activity. Furthermore, inflammation and oxidative stress are implicated as pre-disease mechanisms for chronic diseases of ageing such as neurodegenerative diseases, cardiovascular disease, and cancer. To date, inflammation and telomere shortening have mostly been studied individually in terms of ageing and the associated disease phenotype. However, the interdependent nature of the two demands a more synergistic approach in understanding the ageing process itself and for developing new therapeutic approaches. In this review, we aim to summarize the intricate association between the various inflammatory molecules and telomeres that together contribute to the ageing process and related diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Telomere lengthening early in development.

    Science.gov (United States)

    Liu, Lin; Bailey, Susan M; Okuka, Maja; Muñoz, Purificación; Li, Chao; Zhou, Lingjun; Wu, Chao; Czerwiec, Eva; Sandler, Laurel; Seyfang, Andreas; Blasco, Maria A; Keefe, David L

    2007-12-01

    Stem cells and cancer cells maintain telomere length mostly through telomerase. Telomerase activity is high in male germ line and stem cells, but is low or absent in mature oocytes and cleavage stage embryos, and then high again in blastocysts. How early embryos reset telomere length remains poorly understood. Here, we show that oocytes actually have shorter telomeres than somatic cells, but their telomeres lengthen remarkably during early cleavage development. Moreover, parthenogenetically activated oocytes also lengthen their telomeres, thus the capacity to elongate telomeres must reside within oocytes themselves. Notably, telomeres also elongate in the early cleavage embryos of telomerase-null mice, demonstrating that telomerase is unlikely to be responsible for the abrupt lengthening of telomeres in these cells. Coincident with telomere lengthening, extensive telomere sister-chromatid exchange (T-SCE) and colocalization of the DNA recombination proteins Rad50 and TRF1 were observed in early cleavage embryos. Both T-SCE and DNA recombination proteins decrease in blastocyst stage embryos, whereas telomerase activity increases and telomeres elongate only slowly. We suggest that telomeres lengthen during the early cleavage cycles following fertilization through a recombination-based mechanism, and that from the blastocyst stage onwards, telomerase only maintains the telomere length established by this alternative mechanism.

  4. Telomere length is associated with ACE I/D polymorphism in hypertensive patients with left ventricular hypertrophy

    DEFF Research Database (Denmark)

    Fyhrquist, Frej; Eriksson, Anders; Saijonmaa, Outi

    2013-01-01

    INTRODUCTION: Short telomeres are often associated with cardiovascular risk factors and age-related diseases, while the angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism (DD, ID, II) has shown such associations less consistently. We hypothesized that telomere length...... and association of telomere length with cardiovascular risk is affected by ACE (I/D) genotype. METHODS: We measured leucocyte telomere length (LTL) by Southern blot and analysed ACE I/D genotypes in 1249 subjects with hypertension and left ventricular hypertrophy (LVH). We examined interactions of ACE I...

  5. A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging.

    Science.gov (United States)

    Nelson, David M; McBryan, Tony; Jeyapalan, Jessie C; Sedivy, John M; Adams, Peter D

    2014-06-01

    Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway, the senescence-associated secretory phenotype. However, cellular senescence is initiated by diverse molecular triggers, such as activated oncogenes and shortened telomeres, and is associated with varied and complex physiological endpoints, such as tumor suppression and tissue aging. The extent to which distinct triggers activate divergent modes of senescence that might be associated with different physiological endpoints is largely unknown. To begin to address this, we performed gene expression profiling to compare the senescence programs associated with two different modes of senescence, oncogene-induced senescence (OIS) and replicative senescence (RS [in part caused by shortened telomeres]). While both OIS and RS are associated with many common changes in gene expression compared to control proliferating cells, they also exhibit substantial differences. These results are discussed in light of potential physiological consequences, tumor suppression and aging.

  6. Disappearance of the telomere dysfunction-induced stress response in fully senescent cells.

    Science.gov (United States)

    Bakkenist, Christopher J; Drissi, Rachid; Wu, Jing; Kastan, Michael B; Dome, Jeffrey S

    2004-06-01

    Replicative senescence is a natural barrier to cellular proliferation that is triggered by telomere erosion and dysfunction. Here, we demonstrate that ATM activation and H2AX-gamma nuclear focus formation are sensitive markers of telomere dysfunction in primary human fibroblasts. Whereas the activated form of ATM and H2AX-gamma foci were rarely observed in early-passage cells, they were readily detected in late-passage cells. The ectopic expression of telomerase in late-passage cells abrogated ATM activation and H2AX-gamma focus formation, suggesting that these stress responses were the consequence of telomere dysfunction. ATM activation was induced in quiescent fibroblasts by inhibition of TRF2 binding to telomeres, indicating that telomere uncapping is sufficient to initiate the telomere signaling response; breakage of chromosomes with telomeric associations is not required for this activation. Although ATM activation and H2AX-gamma foci were readily observed in late-passage cells, they disappeared once cells became fully senescent, indicating that constitutive signaling from dysfunctional telomeres is not required for the maintenance of senescence.

  7. Peroxiredoxin 1 Protects Telomeres from Oxidative Damage and Preserves Telomeric DNA for Extension by Telomerase

    Directory of Open Access Journals (Sweden)

    Eric Aeby

    2016-12-01

    Full Text Available Oxidative damage of telomeres can promote cancer, cardiac failure, and muscular dystrophy. Specific mechanisms protecting telomeres from oxidative damage have not been described. We analyzed telomeric chromatin composition during the cell cycle and show that the antioxidant enzyme peroxiredoxin 1 (PRDX1 is enriched at telomeres during S phase. Deletion of the PRDX1 gene leads to damage of telomeric DNA upon oxidative stress, revealing a protective function of PRDX1 against oxidative damage at telomeres. We also show that the oxidized nucleotide 8-oxo-2′deoxyguanosine-5′-triphosphate (8oxodGTP causes premature chain termination when incorporated by telomerase and that some DNA substrates terminating in 8oxoG prevent extension by telomerase. Thus, PRDX1 safeguards telomeres from oxygen radicals to counteract telomere damage and preserve telomeric DNA for elongation by telomerase.

  8. Telomere Restriction Fragment (TRF) Analysis.

    Science.gov (United States)

    Mender, Ilgen; Shay, Jerry W

    2015-11-20

    While telomerase is expressed in ~90% of primary human tumors, most somatic tissue cells except transiently proliferating stem-like cells do not have detectable telomerase activity (Shay and Wright, 1996; Shay and Wright, 2001). Telomeres progressively shorten with each cell division in normal cells, including proliferating stem-like cells, due to the end replication (lagging strand synthesis) problem and other causes such as oxidative damage, therefore all somatic cells have limited cell proliferation capacity (Hayflick limit) (Hayflick and Moorhead, 1961; Olovnikov, 1973). The progressive telomere shortening eventually leads to growth arrest in normal cells, which is known as replicative senescence (Shay et al. , 1991). Once telomerase is activated in cancer cells, telomere length is stabilized by the addition of TTAGGG repeats to the end of chromosomes, thus enabling the limitless continuation of cell division (Shay and Wright, 1996; Shay and Wright, 2001). Therefore, the link between aging and cancer can be partially explained by telomere biology. There are many rapid and convenient methods to study telomere biology such as Telomere Restriction Fragment (TRF), Telomere Repeat Amplification Protocol (TRAP) (Mender and Shay, 2015b) and Telomere dysfunction Induced Foci (TIF) analysis (Mender and Shay, 2015a). In this protocol paper we describe Telomere Restriction Fragment (TRF) analysis to determine average telomeric length of cells. Telomeric length can be indirectly measured by a technique called Telomere Restriction Fragment analysis (TRF). This technique is a modified Southern blot, which measures the heterogeneous range of telomere lengths in a cell population using the length distribution of the terminal restriction fragments (Harley et al. , 1990; Ouellette et al. , 2000). This method can be used in eukaryotic cells. The description below focuses on the measurement of human cancer cells telomere length. The principle of this method relies on the lack of

  9. Mouse CCDC79 (TERB1) is a meiosis-specific telomere associated protein.

    Science.gov (United States)

    Daniel, Katrin; Tränkner, Daniel; Wojtasz, Lukasz; Shibuya, Hiroki; Watanabe, Yoshinori; Alsheimer, Manfred; Tóth, Attila

    2014-05-22

    associated protein. Based on our findings we propose that CCDC79 plays a role in meiosis-specific telomere functions. In particular, we favour the possibility that CCDC79 is involved in telomere-nuclear envelope attachment and/or the stabilization of meiotic telomeres. These conclusions are consistent with the findings of an independently initiated study that analysed CCDC79/TERB1 functions.

  10. Stochastic variation in telomere shortening rate causes heterogeneity of human fibroblast replicative life span.

    Science.gov (United States)

    Martin-Ruiz, Carmen; Saretzki, Gabriele; Petrie, Joanne; Ladhoff, Juliane; Jeyapalan, Jessie; Wei, Wenyi; Sedivy, John; von Zglinicki, Thomas

    2004-04-23

    The replicative life span of human fibroblasts is heterogeneous, with a fraction of cells senescing at every population doubling. To find out whether this heterogeneity is due to premature senescence, i.e. driven by a nontelomeric mechanism, fibroblasts with a senescent phenotype were isolated from growing cultures and clones by flow cytometry. These senescent cells had shorter telomeres than their cycling counterparts at all population doubling levels and both in mass cultures and in individual subclones, indicating heterogeneity in the rate of telomere shortening. Ectopic expression of telomerase stabilized telomere length in the majority of cells and rescued them from early senescence, suggesting a causal role of telomere shortening. Under standard cell culture conditions, there was a minor fraction of cells that showed a senescent phenotype and short telomeres despite active telomerase. This fraction increased under chronic mild oxidative stress, which is known to accelerate telomere shortening. It is possible that even high telomerase activity cannot fully compensate for telomere shortening in all cells. The data show that heterogeneity of the human fibroblast replicative life span can be caused by significant stochastic cell-to-cell variation in telomere shortening.

  11. The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD.

    Directory of Open Access Journals (Sweden)

    Jee Lee

    Full Text Available Some have suggested that chronic obstructive pulmonary disease (COPD is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR, we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS. The subjects were followed for approximately 7.5 years during which time their vital status, FEV(1 and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy "mid-life" volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy "mid-life" volunteers (p<.001. Compared to individuals in the 4(th quartile of relative telomere length (i.e. longest telomere group, the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; p = 0.0324 and total mortality (HR, 1.29; p = 0.0425. Smoking status did not make a significant difference in peripheral blood cells telomere length. In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD.

  12. Telomere dynamics, end-to-end fusions and telomerase activation during the human fibroblast immortalization process.

    Science.gov (United States)

    Ducray, C; Pommier, J P; Martins, L; Boussin, F D; Sabatier, L

    1999-07-22

    Loss of telomeric repeats during cell proliferation could play a role in senescence. It has been generally assumed that activation of telomerase prevents further telomere shortening and is essential for cell immortalization. In this study, we performed a detailed cytogenetic and molecular characterization of four SV40 transformed human fibroblastic cell lines by regularly monitoring the size distribution of terminal restriction fragments, telomerase activity and the associated chromosomal instability throughout immortalization. The mean TRF lengths progressively decreased in pre-crisis cells during the lifespan of the cultures. At crisis, telomeres reached a critical size, different among the cell lines, contributing to the peak of dicentric chromosomes, which resulted mostly from telomeric associations. We observed a direct correlation between short telomere length at crisis and chromosomal instability. In two immortal cell lines, although telomerase was detected, mean telomere length still continued to decrease whereas the number of dicentric chromosomes associated was stabilized. Thus telomerase could protect specifically telomeres which have reached a critical size against end-to-end dicentrics, while long telomeres continue to decrease, although at a slower rate as before crisis. This suggests a balance between elongation by telomerase and telomere shortening, towards a stabilized 'optimal' length.

  13. Radiation chemically induced telomerization of ethylene with selected telogens

    International Nuclear Information System (INIS)

    Wachtendunk, H.J. von.

    1975-01-01

    The suitability of different compounds for the use as telogenes in the telomerization of ethylene has been studied. In all cases the reactions are initiated by the γ-radiation of a 60 Co-source. Temperature programed gas chromatography has proved to be an adequate method of analysis. In the teleomerization process with ethylene also methane tri carboxylic acid tri-ethylene ester (MTE), ortho-formic acid tri-ethylene ester (o-ASE), formic acid, bromium cyane, chlorine cyane and dicyane have been used. The telomerization of MTE and ethylene has been performed successfully with a high yield. The dependence of the reaction on temperature, pressure, radiation dose has been studied as well as the influence of a solvent (acetonitrile). In the attempt to telomerize ortho-formic acid tri-ethylene ester only high molecular weight solid product could be isolated. No interpretable results could be obtained for the telomerization of formic acid with ethylene. In the case of the radiation induced telomerization of chlorine cyane or di-cyane with ethylene in the gas phase, no reaction products could be found. No telomerization between di-cyane and ethylene has been observed even when palladium (II)-cyanide is used as a catalyst of after cocatalys is with triphenyl-phosphile in acetonitrile. (orig./HK) [de

  14. Fanconi anemia proteins in telomere maintenance.

    Science.gov (United States)

    Sarkar, Jaya; Liu, Yie

    2016-07-01

    Mammalian chromosome ends are protected by nucleoprotein structures called telomeres. Telomeres ensure genome stability by preventing chromosome termini from being recognized as DNA damage. Telomere length homeostasis is inevitable for telomere maintenance because critical shortening or over-lengthening of telomeres may lead to DNA damage response or delay in DNA replication, and hence genome instability. Due to their repetitive DNA sequence, unique architecture, bound shelterin proteins, and high propensity to form alternate/secondary DNA structures, telomeres are like common fragile sites and pose an inherent challenge to the progression of DNA replication, repair, and recombination apparatus. It is conceivable that longer the telomeres are, greater is the severity of such challenges. Recent studies have linked excessively long telomeres with increased tumorigenesis. Here we discuss telomere abnormalities in a rare recessive chromosomal instability disorder called Fanconi Anemia and the role of the Fanconi Anemia pathway in telomere biology. Reports suggest that Fanconi Anemia proteins play a role in maintaining long telomeres, including processing telomeric joint molecule intermediates. We speculate that ablation of the Fanconi Anemia pathway would lead to inadequate aberrant structural barrier resolution at excessively long telomeres, thereby causing replicative burden on the cell. Published by Elsevier B.V.

  15. Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases [version 1; referees: 4 approved

    Directory of Open Access Journals (Sweden)

    Christian Bär

    2016-01-01

    Full Text Available Telomeres, the protective ends of linear chromosomes, shorten throughout an individual’s lifetime. Telomere shortening is a hallmark of molecular aging and is associated with premature appearance of diseases associated with aging. Here, we discuss the role of telomere shortening as a direct cause for aging and age-related diseases. In particular, we draw attention to the fact that telomere length influences longevity. Furthermore, we discuss intrinsic and environmental factors that can impact on human telomere erosion. Finally, we highlight recent advances in telomerase-based therapeutic strategies for the treatment of diseases associated with extremely short telomeres owing to mutations in telomerase, as well as age-related diseases, and ultimately aging itself.

  16. Is telomere erosion a mechanism of species extinction?

    Science.gov (United States)

    Stindl, Reinhard

    2004-03-15

    According to the fossil record, 99.9% of all species that have ever lived on Earth have disappeared. However, only about 4% died out during the five mass extinction events, whereas it seems that the majority of species vanished without any signs of significant earthbound or extraterrestrial physical threats. Clearly, biological extinction mechanisms are by far the most important, but they are subject to serious limitations concerning the worldwide disappearance of species. In view of that, species-inherent mechanisms, which could lead to the worldwide destabilization of a population, might be worth reconsideration. Telomeres, the protective caps of chromosome ends, and the enzyme telomerase have been well preserved in plants and animals during evolution. In the absence of telomerase activity, telomeric DNA has been shown to shorten every time a cell divides. The concept of a mitotic clock based on the gradual erosion of telomeres is now generally accepted and has been confirmed in numerous plants and animals. Chromosomal rearrangements are the hallmarks of two completely different biological phenomena, cancer and speciation. In premalignant cells, gradual telomere erosion beyond a critical threshold is a well-known inducer of chromosomal instability. The species clock hypothesis, as presented here, is based on the idea of a tiny loss of mean telomere length per generation. This mechanism would not rapidly endanger the survival of a particular species. Yet, after many thousands of generations, critically short telomeres could lead to the weakening and even the extinction of old species and would simultaneously create the unstable chromosomal environment that might result in the origination of new species. Copyright 2004 Wiley-Liss, Inc.

  17. Behaviour of telomere and telomerase during aging and regeneration in zebrafish.

    Science.gov (United States)

    Anchelin, Monique; Murcia, Laura; Alcaraz-Pérez, Francisca; García-Navarro, Esther M; Cayuela, María L

    2011-02-09

    Telomere length and telomerase activity are important factors in the pathobiology of human diseases. Age-related diseases and premature aging syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. The zebrafish (Danio rerio) offers multiple experimental manipulation advantages over other vertebrate models and, therefore, it has been recently considered as a potential model for aging, cancer, and regeneration studies. However, it has only partially been exploited to shed light on these fundamental biological processes. The aim of this study was, therefore, to investigate telomere length and telomerase expression and activity in different strains of zebrafish obtained from different stock centres to determine whether they undergo any changes during aging and regeneration. We found that although both telomerase expression and telomere length increased from embryo to adulthood stages, they drastically declined in aged fish despite telomerase activity was detected in different tissues of old fish. In addition, we observed a weaker upregulation of telomerase expression in regenerating fins of old fish, which well correlates with their impaired regeneration capacity. Strikingly, telomeres were elongated or maintained during the fin regeneration process at all ages and after repeated amputations, likely to support high cell proliferation rates. We conclude that the expression of telomerase and telomere length are closely related during the entire life cycle of the fish and that these two parameters can be used as biomarkers of aging in zebrafish. Our results also reveal a direct relationship between the expression of telomerase, telomere length and the efficiency of tissue regeneration.

  18. Single-cell telomere-length quantification couples telomere length to meristem activity and stem cell development in Arabidopsis.

    Science.gov (United States)

    González-García, Mary-Paz; Pavelescu, Irina; Canela, Andrés; Sevillano, Xavier; Leehy, Katherine A; Nelson, Andrew D L; Ibañes, Marta; Shippen, Dorothy E; Blasco, Maria A; Caño-Delgado, Ana I

    2015-05-12

    Telomeres are specialized nucleoprotein caps that protect chromosome ends assuring cell division. Single-cell telomere quantification in animals established a critical role for telomerase in stem cells, yet, in plants, telomere-length quantification has been reported only at the organ level. Here, a quantitative analysis of telomere length of single cells in Arabidopsis root apex uncovered a heterogeneous telomere-length distribution of different cell lineages showing the longest telomeres at the stem cells. The defects in meristem and stem cell renewal observed in tert mutants demonstrate that telomere lengthening by TERT sets a replicative limit in the root meristem. Conversely, the long telomeres of the columella cells and the premature stem cell differentiation plt1,2 mutants suggest that differentiation can prevent telomere erosion. Overall, our results indicate that telomere dynamics are coupled to meristem activity and continuous growth, disclosing a critical association between telomere length, stem cell function, and the extended lifespan of plants. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Telomere shortening unrelated to smoking, body weight, physical activity, and alcohol intake: 4,576 general population individuals with repeat measurements 10 years apart.

    Directory of Open Access Journals (Sweden)

    Maren Weischer

    2014-03-01

    Full Text Available Cross-sectional studies have associated short telomere length with smoking, body weight, physical activity, and possibly alcohol intake; however, whether these associations are due to confounding is unknown. We tested these hypotheses in 4,576 individuals from the general population cross-sectionally, and with repeat measurement of relative telomere length 10 years apart. We also tested whether change in telomere length is associated with mortality and morbidity in the general population. Relative telomere length was measured with quantitative polymerase chain reaction. Cross-sectionally at the first examination, short telomere length was associated with increased age (P for trend across quartiles = 3 × 10(-77, current smoking (P = 8 × 10(-3, increased body mass index (P = 7 × 10(-14, physical inactivity (P = 4 × 10(-17, but not with increased alcohol intake (P = 0.10. At the second examination 10 years later, 56% of participants had lost and 44% gained telomere length with a mean loss of 193 basepairs. Change in leukocyte telomere length during 10 years was associated inversely with baseline telomere length (P<1 × 10(-300 and age at baseline (P = 1 × 10(-27, but not with baseline or 10-year inter-observational tobacco consumption, body weight, physical activity, or alcohol intake. Prospectively during a further 10 years follow-up after the second examination, quartiles of telomere length change did not associate with risk of all-cause mortality, cancer, chronic obstructive pulmonary disease, diabetes mellitus, ischemic cerebrovascular disease, or ischemic heart disease. In conclusion, smoking, increased body weight, and physical inactivity were associated with short telomere length cross-sectionally, but not with telomere length change during 10 years observation, and alcohol intake was associated with neither. Also, change in telomere length did not associate prospectively with mortality or morbidity in the general population.

  20. Diet, nutrition and telomere length.

    Science.gov (United States)

    Paul, Ligi

    2011-10-01

    The ends of human chromosomes are protected by DNA-protein complexes termed telomeres, which prevent the chromosomes from fusing with each other and from being recognized as a double-strand break by DNA repair proteins. Due to the incomplete replication of linear chromosomes by DNA polymerase, telomeric DNA shortens with repeated cell divisions until the telomeres reach a critical length, at which point the cells enter senescence. Telomere length is an indicator of biological aging, and dysfunction of telomeres is linked to age-related pathologies like cardiovascular disease, Parkinson disease, Alzheimer disease and cancer. Telomere length has been shown to be positively associated with nutritional status in human and animal studies. Various nutrients influence telomere length potentially through mechanisms that reflect their role in cellular functions including inflammation, oxidative stress, DNA integrity, DNA methylation and activity of telomerase, the enzyme that adds the telomeric repeats to the ends of the newly synthesized DNA. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. G-quadruplex formation in telomeres enhances POT1/TPP1 protection against RPA binding

    Science.gov (United States)

    Ray, Sujay; Bandaria, Jigar N.; Qureshi, Mohammad H.; Yildiz, Ahmet; Balci, Hamza

    2014-01-01

    Human telomeres terminate with a single-stranded 3′ G overhang, which can be recognized as a DNA damage site by replication protein A (RPA). The protection of telomeres (POT1)/POT1-interacting protein 1 (TPP1) heterodimer binds specifically to single-stranded telomeric DNA (ssTEL) and protects G overhangs against RPA binding. The G overhang spontaneously folds into various G-quadruplex (GQ) conformations. It remains unclear whether GQ formation affects the ability of POT1/TPP1 to compete against RPA to access ssTEL. Using single-molecule Förster resonance energy transfer, we showed that POT1 stably loads to a minimal DNA sequence adjacent to a folded GQ. At 150 mM K+, POT1 loading unfolds the antiparallel GQ, as the parallel conformation remains folded. POT1/TPP1 loading blocks RPA’s access to both folded and unfolded telomeres by two orders of magnitude. This protection is not observed at 150 mM Na+, in which ssTEL forms only a less-stable antiparallel GQ. These results suggest that GQ formation of telomeric overhangs may contribute to suppression of DNA damage signals. PMID:24516170

  2. Early telomere shortening and genomic instability in tubo-ovarian preneoplastic lesions.

    Science.gov (United States)

    Chene, Gautier; Tchirkov, Andrei; Pierre-Eymard, Eleonore; Dauplat, Jacques; Raoelfils, Ines; Cayre, Anne; Watkin, Emmanuel; Vago, Philippe; Penault-Llorca, Frederique

    2013-06-01

    Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and preinvasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC), and tubo-ovarian dysplasia (TOD). Fifty-one TOD from prophylactic salpingo-oophorectomies with BRCA1 or 2 mutation, 12 STICs, 53 tubo-ovarian high-grade serous carcinoma, and 36 noncancerous controls were laser capture microdissected from formalin-fixed, paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time PCR based on the Cawthon's method). TOD and STICs were defined by morphologic scores and immunohistochemical expressions of p53, Ki67, and γH2AX. TOD showed marked telomere shortening compared with noncancerous controls (P STICs had even shorter telomeres than TOD (P = 0.0008). Ovarian carcinoma had shorter telomeres than controls but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in those with BRCA1 mutation than in those with BRCA2 mutation (P = 0.005). In addition, γH2AX expression in TOD and STIC groups with short telomeres was significantly increased (P STICs. The total number of genetic alterations was the highest in ovarian cancers. These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and noninvasive dysplasia are likely an important step in early serous ovarian neoplasia. ©2013 AACR

  3. Genetic association of telomere length with hepatocellular carcinoma risk: A Mendelian randomization analysis.

    Science.gov (United States)

    Cheng, Yue; Yu, Chengxiao; Huang, Mingtao; Du, Fangzhi; Song, Ci; Ma, Zijian; Zhai, Xiangjun; Yang, Yuan; Liu, Jibin; Bei, Jin-Xin; Jia, Weihua; Jin, Guangfu; Li, Shengping; Zhou, Weiping; Liu, Jianjun; Dai, Juncheng; Hu, Zhibin

    2017-10-01

    Observational studies show an association between telomere length and Hepatocellular carcinoma (HCC) risk, but the relationship is controversial. Particularly, it remains unclear whether the association is due to confounding or biases inherent in conventional epidemiological studies. Here, we applied Mendelian randomization approach to evaluate whether telomere length is causally associated with HCC risk. Individual-level data were from HBV-related HCC Genome-wide association studies (1,538 HBV positive HCC patients and 1,465 HBV positive controls). Genetic risk score, as proxy for actual measured telomere length, derived from nine telomere length-associated genetic variants was used to evaluate the effect of telomere length on HCC risk. We observed a significant risk signal between genetically increased telomere length and HBV-related HCC risk (OR=2.09, 95% CI 1.32-3.31, P=0.002). Furthermore, a U-shaped curve was fitted by the restricted cubic spline curve, which indicated that either short or long telomere length would increase HCC risk (P=0.0022 for non-linearity test). Subgroup analysis did not reveal significant heterogeneity between different age, gender, smoking status and drinking status groups. Our results indicated that a genetic background that favors longer or shorter telomere length may increase HBV-related HCC risk-a U-shaped association. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Behaviour of telomere and telomerase during aging and regeneration in zebrafish.

    Directory of Open Access Journals (Sweden)

    Monique Anchelin

    Full Text Available Telomere length and telomerase activity are important factors in the pathobiology of human diseases. Age-related diseases and premature aging syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. The zebrafish (Danio rerio offers multiple experimental manipulation advantages over other vertebrate models and, therefore, it has been recently considered as a potential model for aging, cancer, and regeneration studies. However, it has only partially been exploited to shed light on these fundamental biological processes. The aim of this study was, therefore, to investigate telomere length and telomerase expression and activity in different strains of zebrafish obtained from different stock centres to determine whether they undergo any changes during aging and regeneration. We found that although both telomerase expression and telomere length increased from embryo to adulthood stages, they drastically declined in aged fish despite telomerase activity was detected in different tissues of old fish. In addition, we observed a weaker upregulation of telomerase expression in regenerating fins of old fish, which well correlates with their impaired regeneration capacity. Strikingly, telomeres were elongated or maintained during the fin regeneration process at all ages and after repeated amputations, likely to support high cell proliferation rates. We conclude that the expression of telomerase and telomere length are closely related during the entire life cycle of the fish and that these two parameters can be used as biomarkers of aging in zebrafish. Our results also reveal a direct relationship between the expression of telomerase, telomere length and the efficiency of tissue regeneration.

  5. Structural anatomy of telomere OB proteins.

    Science.gov (United States)

    Horvath, Martin P

    2011-10-01

    Telomere DNA-binding proteins protect the ends of chromosomes in eukaryotes. A subset of these proteins are constructed with one or more OB folds and bind with G+T-rich single-stranded DNA found at the extreme termini. The resulting DNA-OB protein complex interacts with other telomere components to coordinate critical telomere functions of DNA protection and DNA synthesis. While the first crystal and NMR structures readily explained protection of telomere ends, the picture of how single-stranded DNA becomes available to serve as primer and template for synthesis of new telomere DNA is only recently coming into focus. New structures of telomere OB fold proteins alongside insights from genetic and biochemical experiments have made significant contributions towards understanding how protein-binding OB proteins collaborate with DNA-binding OB proteins to recruit telomerase and DNA polymerase for telomere homeostasis. This review surveys telomere OB protein structures alongside highly comparable structures derived from replication protein A (RPA) components, with the goal of providing a molecular context for understanding telomere OB protein evolution and mechanism of action in protection and synthesis of telomere DNA.

  6. Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia.

    Science.gov (United States)

    Narita, Atsushi; Muramatsu, Hideki; Sekiya, Yuko; Okuno, Yusuke; Sakaguchi, Hirotoshi; Nishio, Nobuhiro; Yoshida, Nao; Wang, Xinan; Xu, Yinyan; Kawashima, Nozomu; Doisaki, Sayoko; Hama, Asahito; Takahashi, Yoshiyuki; Kudo, Kazuko; Moritake, Hiroshi; Kobayashi, Masao; Kobayashi, Ryoji; Ito, Etsuro; Yabe, Hiromasa; Ohga, Shouichi; Ohara, Akira; Kojima, Seiji

    2015-12-01

    Acquired aplastic anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in aplastic anemia. We enrolled 113 aplastic anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of aplastic anemia patients was -0.99 standard deviation (SD) (range -4.01-+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P<0.001). The combined absence of a minor paroxysmal nocturnal hemoglobinuria population and a short telomere length is an efficient predictor of poor immunosuppressive therapy response, which should be considered while deciding treatment options: immunosuppressive therapy or first-line hematopoietic stem cell transplantation. The trial was registered in www.umin.ac.jp with number UMIN000017972. Copyright© Ferrata Storti Foundation.

  7. When Telomerase Causes Telomere Loss.

    Science.gov (United States)

    Glousker, Galina; Lingner, Joachim

    2018-02-05

    Telomerase counteracts telomere shortening, preventing cellular senescence. Telomerase deficiency causes telomere syndromes because of premature telomere exhaustion in highly proliferative cells. Paradoxically, in a recent issue of Cell, Margalef et al. (2018) demonstrate that telomerase causes telomere loss in cells lacking the RTEL1 helicase, which is defective in Hoyeraal-Hreidarsson syndrome (HHS). Copyright © 2018 Elsevier Inc. All rights reserved.

  8. The load of short telomeres, estimated by a new method, Universal STELA, correlates with number of senescent cells

    DEFF Research Database (Denmark)

    Bendix, Laila; Horn, Peer Bendix; Jensen, Uffe Birk

    2010-01-01

    history of the cell, superimposed by a more stochastic mechanism, suddenly causing a significant shortening of a single telomere. Previously, studies that have tried to explore the role of critically shortened telomeres have been hampered by methodological problems. With the method presented here...

  9. Q-FISH measurement of hepatocyte telomere lengths in donor liver and graft after pediatric living-donor liver transplantation: donor age affects telomere length sustainability.

    Directory of Open Access Journals (Sweden)

    Youichi Kawano

    Full Text Available Along with the increasing need for living-donor liver transplantation (LDLT, the issue of organ shortage has become a serious problem. Therefore, the use of organs from elderly donors has been increasing. While the short-term results of LDLT have greatly improved, problems affecting the long-term outcome of transplant patients remain unsolved. Furthermore, since contradictory data have been reported with regard to the relationship between donor age and LT/LDLT outcome, the question of whether the use of elderly donors influences the long-term outcome of a graft after LT/LDLT remains unsettled. To address whether hepatocyte telomere length reflects the outcome of LDLT, we analyzed the telomere lengths of hepatocytes in informative biopsy samples from 12 paired donors and recipients (grafts of pediatric LDLT more than 5 years after adult-to-child LDLT because of primary biliary atresia, using quantitative fluorescence in situ hybridization (Q-FISH. The telomere lengths in the paired samples showed a robust relationship between the donor and grafted hepatocytes (r = 0.765, p = 0.0038, demonstrating the feasibility of our Q-FISH method for cell-specific evaluation. While 8 pairs showed no significant difference between the telomere lengths for the donor and the recipient, the other 4 pairs showed significantly shorter telomeres in the recipient than in the donor. Multiple regression analysis revealed that the donors in the latter group were older than those in the former (p = 0.001. Despite the small number of subjects, this pilot study indicates that donor age is a crucial factor affecting telomere length sustainability in hepatocytes after pediatric LDLT, and that the telomeres in grafted livers may be elongated somewhat longer when the grafts are immunologically well controlled.

  10. Telomere length maintenance--an ALTernative mechanism.

    Science.gov (United States)

    Royle, N J; Foxon, J; Jeyapalan, J N; Mendez-Bermudez, A; Novo, C L; Williams, J; Cotton, V E

    2008-01-01

    The Alternative Lengthening of Telomeres (ALT) mechanism is utilised by approximately 10% of human tumours and a higher proportion of some types of sarcomas. ALT+ cell lines and tumours show heterogeneous telomere length, extra-chromosomal circular and linear telomeric DNA, ALT associated promyelocytic bodies (APBs), a high frequency of post-replication exchanges in telomeres (designated as telomere-sister chromatid exchanges, T-SCE) and high instability at a GC-rich minisatellite, MS32 (D1S8). It is clear that there is a link between the minisatellite instability and the mechanism that underpins ALT, however currently the nature of this relationship is uncertain. Single molecule analysis of telomeric DNA from ALT+ cell lines and tumours has revealed complex telomere mutations that have not been seen in cell lines or tumours that express telomerase. These complex telomere mutations cannot be explained by T-SCE but must arise by another inter-molecular process. The break-induced replication (BIR) model that may explain the observed high frequency of T-SCE and the presence of complex telomere mutations is reviewed. Copyright 2008 S. Karger AG, Basel.

  11. Increased Body Mass Index, Elevated C-reactive Protein, and Short Telomere Length

    DEFF Research Database (Denmark)

    Rode, Line; Nordestgaard, Børge G; Weischer, Maren

    2014-01-01

    -reactive protein. SETTING AND DESIGN: We studied 45,069 individuals from the Copenhagen General Population Study with measurements of leukocyte telomere length, BMI, and C-reactive protein in a Mendelian randomization study. Using the three obesity-associated polymorphisms FTO rs9939609, MC4R rs17782313, and TMEM...

  12. Drosophila: Retrotransposons Making up Telomeres.

    Science.gov (United States)

    Casacuberta, Elena

    2017-07-19

    Drosophila and extant species are the best-studied telomerase exception. In this organism, telomere elongation is coupled with targeted retrotransposition of Healing Transposon (HeT-A) and Telomere Associated Retrotransposon (TART) with sporadic additions of Telomere Associated and HeT-A Related (TAHRE), all three specialized non-Long Terminal Repeat (non-LTR) retrotransposons. These three very special retroelements transpose in head to tail arrays, always in the same orientation at the end of the chromosomes but never in interior locations. Apparently, retrotransposon and telomerase telomeres might seem very different, but a detailed view of their mechanisms reveals similarities explaining how the loss of telomerase in a Drosophila ancestor could successfully have been replaced by the telomere retrotransposons. In this review, we will discover that although HeT-A, TART, and TAHRE are still the only examples to date where their targeted transposition is perfectly tamed into the telomere biology of Drosophila, there are other examples of retrotransposons that manage to successfully integrate inside and at the end of telomeres. Because the aim of this special issue is viral integration at telomeres, understanding the base of the telomerase exceptions will help to obtain clues on similar strategies that mobile elements and viruses could have acquired in order to ensure their survival in the host genome.

  13. Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence.

    Science.gov (United States)

    Matsumoto, Ryusaku; Fukuoka, Hidenori; Iguchi, Genzo; Odake, Yukiko; Yoshida, Kenichi; Bando, Hironori; Suda, Kentaro; Nishizawa, Hitoshi; Takahashi, Michiko; Yamada, Shozo; Ogawa, Wataru; Takahashi, Yutaka

    2015-01-01

    Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases. We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts. Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R2 = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence. Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I.

  14. Telomere Maintenance Mechanisms in Cancer

    OpenAIRE

    Tiago Bordeira Gaspar; Ana Sá; José Manuel Lopes; Manuel Sobrinho-Simões; Paula Soares; João Vinagre

    2018-01-01

    Tumour cells can adopt telomere maintenance mechanisms (TMMs) to avoid telomere shortening, an inevitable process due to successive cell divisions. In most tumour cells, telomere length (TL) is maintained by reactivation of telomerase, while a small part acquires immortality through the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. In the last years, a great amount of data was generated, and different TMMs were reported and explained in detail, benefiting from g...

  15. Does oxidative stress shorten telomeres?

    NARCIS (Netherlands)

    Boonekamp, Jelle J.; Bauch, Christina; Mulder, Ellis; Verhulst, Simon

    Oxidative stress shortens telomeres in cell culture, but whether oxidative stress explains variation in telomere shortening in vivo at physiological oxidative stress levels is not well known. We therefore tested for correlations between six oxidative stress markers and telomere attrition in nestling

  16. Shelterin Protects Chromosome Ends by Compacting Telomeric Chromatin

    Science.gov (United States)

    Bandaria, Jigar N.; Qin, Peiwu; Berk, Veysel; Chu, Steven; Yildiz, Ahmet

    2016-01-01

    SUMMARY Telomeres, repetitive DNA sequences at chromosome ends, are shielded against the DNA damage response (DDR) by the shelterin complex. To understand how shelterin protects telomere ends, we investigated the structural organization of telomeric chromatin in human cells using super-resolution microscopy. We found that telomeres form compact globular structures through a complex network of interactions between shelterin subunits and telomeric DNA, and not by DNA methylation, histone deacetylation or histone trimethylation at telomeres and subtelomeric regions. Mutations that abrogate shelterin assembly or removal of individual subunits from telomeres cause up to a 10-fold increase in telomere volume. Decompacted telomeres become more accessible to telomere-associated proteins and accumulate DDR signals. Recompaction of telomeric chromatin using an orthogonal method displaces DDR signals from telomeres. These results reveal the chromatin remodeling activity of shelterin and demonstrate that shelterin-mediated compaction of telomeric chromatin provides robust protection of chromosome ends against the DDR machinery. PMID:26871633

  17. Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence.

    Directory of Open Access Journals (Sweden)

    Ryusaku Matsumoto

    Full Text Available Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases.We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts.Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047. In addition, telomere length in acromegaly was negatively correlated with the disease duration (R2 = 0.210, P = 0.003. In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence.Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I.

  18. Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence

    Science.gov (United States)

    Matsumoto, Ryusaku; Fukuoka, Hidenori; Iguchi, Genzo; Odake, Yukiko; Yoshida, Kenichi; Bando, Hironori; Suda, Kentaro; Nishizawa, Hitoshi; Takahashi, Michiko; Yamada, Shozo; Ogawa, Wataru; Takahashi, Yutaka

    2015-01-01

    Objective Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases. Methods We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts. Results Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R 2 = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence. Conclusion Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I. PMID:26448623

  19. Long G2 accumulates recombination intermediates and disturbs chromosome segregation at dysfunction telomere in Schizosaccharomyces pombe

    Energy Technology Data Exchange (ETDEWEB)

    Habib, Ahmed G.K.; Masuda, Kenta; Yukawa, Masashi; Tsuchiya, Eiko [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8530 (Japan); Ueno, Masaru, E-mail: scmueno@hiroshima-u.ac.jp [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8530 (Japan); Research Center for the Mathematics on Chromatin Live Dynamics, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8530 (Japan)

    2015-08-14

    Protection of telomere (Pot1) is a single-stranded telomere binding protein which is essential for chromosome ends protection. Fission yeast Rqh1 is a member of RecQ helicases family which has essential roles in the maintenance of genomic stability and regulation of homologous recombination. Double mutant between fission yeast pot1Δ and rqh1 helicase dead (rqh1-hd) maintains telomere by homologous recombination. In pot1Δ rqh1-hd double mutant, recombination intermediates accumulate near telomere which disturb chromosome segregation and make cells sensitive to microtubule inhibitors thiabendazole (TBZ). Deletion of chk1{sup +} or mutation of its kinase domain shortens the G2 of pot1Δ rqh1-hd double mutant and suppresses both the accumulation of recombination intermediates and the TBZ sensitivity of that double mutant. In this study, we asked whether the long G2 is the reason for the TBZ sensitivity of pot1Δ rqh1-hd double mutant. We found that shortening the G2 of pot1Δ rqh1-hd double mutant by additional mutations of wee1 and mik1 or gain of function mutation of Cdc2 suppresses both the accumulation of recombination intermediates and the TBZ sensitivity of pot1Δ rqh1-hd double mutant. Our results suggest that long G2 of pot1Δ rqh1-hd double mutant may allow time for the accumulation of recombination intermediates which disturb chromosome segregation and make cells sensitive to TBZ. - Ηighlights: • We show link between long G2 and accumulation of toxic recombination intermediates. • Accumulation of recombination intermediates at telomere results in TBZ sensitivity. • Activation of DNA damage checkpoint worsens cells' viability in presence of TBZ.

  20. Short telomere length is associated with impaired cognitive performance in European ancestry cohorts

    NARCIS (Netherlands)

    Hägg, S.; Zhan, Y.; Karlsson, Robert; Gerritsen, L.; Ploner, A.; Lee, J.S.; Broer, L.; Deelen, J.; Marioni, R.E.; Wong, A.|info:eu-repo/dai/nl/29867291X; Lundquist, A.; Zhu, G.; Hansell, N.K.; Sillanpää, E.; Fedko, I O; Amin, N.A.; Beekman, Jeffrey M.; de Craen, A.J.M.; Degerman, S.; Harris, S.E.; Kan, K.-J.; Martin-Ruiz, C.M.; Montgomery, Grant W.; Adolfsson, A.N.; Reynolds, Chandra A.; Samani, Nilesh J; Suchiman, H.E.D.; Viljanen, A.; Von Zglinicki, T.; Wright, M J; Hottenga, J.J.; Boomsma, Dorret I; Rantanen, T.; Kaprio, J.A.; Nyholt, D.R.; Martin, N.G.|info:eu-repo/dai/nl/314123083; Nyberg, Lars; Adolfsson, R.; Kuh, D.; Starr, John M; Deary, Ian J; Slagboom, P Eline; Van Duijn, C.M.|info:eu-repo/dai/nl/068368232; Codd, V.; Pedersen, Nancy L.

    2017-01-01

    The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR)

  1. Distinct functions for the Drosophila piRNA pathway in genome maintenance and telomere protection.

    Directory of Open Access Journals (Sweden)

    Jaspreet S Khurana

    2010-12-01

    Full Text Available Transposons and other selfish DNA elements can be found in all phyla, and mobilization of these elements can compromise genome integrity. The piRNA (PIWI-interacting RNA pathway silences transposons in the germline, but it is unclear if this pathway has additional functions during development. Here we show that mutations in the Drosophila piRNA pathway genes, armi, aub, ago3, and rhi, lead to extensive fragmentation of the zygotic genome during the cleavage stage of embryonic divisions. Additionally, aub and armi show defects in telomere resolution during meiosis and the cleavage divisions; and mutations in lig-IV, which disrupt non-homologous end joining, suppress these fusions. By contrast, lig-IV mutations enhance chromosome fragmentation. Chromatin immunoprecipitation studies show that aub and armi mutations disrupt telomere binding of HOAP, which is a component of the telomere protection complex, and reduce expression of a subpopulation of 19- to 22-nt telomere-specific piRNAs. Mutations in rhi and ago3, by contrast, do not block HOAP binding or production of these piRNAs. These findings uncover genetically separable functions for the Drosophila piRNA pathway. The aub, armi, rhi, and ago3 genes silence transposons and maintain chromosome integrity during cleavage-stage embryonic divisions. However, the aub and armi genes have an additional function in assembly of the telomere protection complex.

  2. Stimulus-specific suppression preserves information in auditory short-term memory.

    Science.gov (United States)

    Linke, Annika C; Vicente-Grabovetsky, Alejandro; Cusack, Rhodri

    2011-08-02

    Philosophers and scientists have puzzled for millennia over how perceptual information is stored in short-term memory. Some have suggested that early sensory representations are involved, but their precise role has remained unclear. The current study asks whether auditory cortex shows sustained frequency-specific activation while sounds are maintained in short-term memory using high-resolution functional MRI (fMRI). Investigating short-term memory representations within regions of human auditory cortex with fMRI has been difficult because of their small size and high anatomical variability between subjects. However, we overcame these constraints by using multivoxel pattern analysis. It clearly revealed frequency-specific activity during the encoding phase of a change detection task, and the degree of this frequency-specific activation was positively related to performance in the task. Although the sounds had to be maintained in memory, activity in auditory cortex was significantly suppressed. Strikingly, patterns of activity in this maintenance period correlated negatively with the patterns evoked by the same frequencies during encoding. Furthermore, individuals who used a rehearsal strategy to remember the sounds showed reduced frequency-specific suppression during the maintenance period. Although negative activations are often disregarded in fMRI research, our findings imply that decreases in blood oxygenation level-dependent response carry important stimulus-specific information and can be related to cognitive processes. We hypothesize that, during auditory change detection, frequency-specific suppression protects short-term memory representations from being overwritten by inhibiting the encoding of interfering sounds.

  3. Single-strand DNA binding protein SSB1 facilitates TERT recruitment to telomeres and maintains telomere G-overhangs

    Science.gov (United States)

    Pandita, Raj K.; Chow, Tracy T.; Udayakumar, Durga; Bain, Amanda L.; Cubeddu, Liza; Hunt, Clayton R.; Shi, Wei; Horikoshi, Nobuo; Zhao, Yong; Wright, Woodring E.; Khanna, Kum Kum; Shay, Jerry W.; Pandita, Tej K.

    2015-01-01

    Proliferating mammalian stem and cancer cells express telomerase (TERT) in an effort to extend chromosomal G-overhangs and maintain telomere ends. Telomerase-expressing cells also have higher levels of the single-stranded DNA binding protein SSB1, which has a critical role in DNA double-strand break repair. Here we report that SSB1 binds specifically to G-strand telomeric DNA in vitro and associates with telomeres in vivo. SSB1 interacted with the TERT catalytic subunit and regulates its interaction with telomeres. Deletion of SSB1 reduced TERT interaction with telomeres and lead to G-overhang loss. While SSB1 was recruited to DSB sites, we found no corresponding change in TERT levels at these sites, implying that SSB1-TERT interaction relied upon a specific chromatin structure or context. Our findings offer an explanation for how telomerase is recruited to telomeres to facilitate G-strand DNA extension, a critical step in maintaining telomere ends and cell viability in all cancer cells. PMID:25589350

  4. Telomere Homeostasis: Interplay with Magnesium

    Directory of Open Access Journals (Sweden)

    Donogh Maguire

    2018-01-01

    Full Text Available Telomere biology, a key component of the hallmarks of ageing, offers insight into dysregulation of normative ageing processes that accompany age-related diseases such as cancer. Telomere homeostasis is tightly linked to cellular metabolism, and in particular with mitochondrial physiology, which is also diminished during cellular senescence and normative physiological ageing. Inherent in the biochemistry of these processes is the role of magnesium, one of the main cellular ions and an essential cofactor in all reactions that use ATP. Magnesium plays an important role in many of the processes involved in regulating telomere structure, integrity and function. This review explores the mechanisms that maintain telomere structure and function, their influence on circadian rhythms and their impact on health and age-related disease. The pervasive role of magnesium in telomere homeostasis is also highlighted.

  5. Gender and telomere length

    DEFF Research Database (Denmark)

    Gardner, Michael; Bann, David; Wiley, Laura

    2014-01-01

    It is widely believed that females have longer telomeres than males, although results from studies have been contradictory.......It is widely believed that females have longer telomeres than males, although results from studies have been contradictory....

  6. Telomeres, telomerase and premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Renata Košir Pogačnik

    2011-11-01

    Full Text Available Telomeres are specialized structures at the ends of chromosomes, consisting of six repeated nucleotides in TTAGGG sequence. Genome stability is partly maintained by the architecture of telomeres and is gradually lost as telomeres progressively shorten with each cell replication. Critically shortened telomeres are recognized by DNA repair mechanisms as DNA damage and the cell replication cycle stops. The cell eventually dies or undergoes cell apoptosis. Telomere represents a cellular marker of biological age and are therefore also called cell mitotic clock. The enzyme that counteracts telomere shortening by adding nucleotides to the 3’ end of DNA strand is called telomerase. It is composed of the RNA subunit (TR, which is special type of messenger RNA (mRNA, the catalytic protein subunit (TERT, which works as a reverse transcriptase and numerous additional proteins. Telomerase is active in some germline, epithelial and haemopoietic cells, but in most somatic cells the activity is undetectable. In literature, the length of telomeres is closely connected with premature ovarian failure (POF. POF is generally defined as the onset of menopause before the age of 40. The causes of disease are genetical, autoimmune, iatrogenic or if we cannot establish the cause – idiopathic. A lot of studies examined correlation between idiopathic POF, length of telomeres and telomerase activity. The studies mostly show that women with POF have shortened telomeres and decreased activity of telomerase as compared to healthy women.

  7. Single-strand DNA-binding protein SSB1 facilitates TERT recruitment to telomeres and maintains telomere G-overhangs.

    Science.gov (United States)

    Pandita, Raj K; Chow, Tracy T; Udayakumar, Durga; Bain, Amanda L; Cubeddu, Liza; Hunt, Clayton R; Shi, Wei; Horikoshi, Nobuo; Zhao, Yong; Wright, Woodring E; Khanna, Kum Kum; Shay, Jerry W; Pandita, Tej K

    2015-03-01

    Proliferating mammalian stem and cancer cells express telomerase [telomerase reverse transcriptase (TERT)] in an effort to extend chromosomal G-overhangs and maintain telomere ends. Telomerase-expressing cells also have higher levels of the single-stranded DNA-binding protein SSB1, which has a critical role in DNA double-strand break (DSB) repair. Here, we report that SSB1 binds specifically to G-strand telomeric DNA in vitro and associates with telomeres in vivo. SSB1 interacts with the TERT catalytic subunit and regulates its interaction with telomeres. Deletion of SSB1 reduces TERT interaction with telomeres and leads to G-overhang loss. Although SSB1 is recruited to DSB sites, we found no corresponding change in TERT levels at these sites, implying that SSB1-TERT interaction relies upon a specific chromatin structure or context. Our findings offer an explanation for how telomerase is recruited to telomeres to facilitate G-strand DNA extension, a critical step in maintaining telomere ends and cell viability in all cancer cells. Cancer Res; 75(5); 858-69. ©2015 AACR. ©2015 American Association for Cancer Research.

  8. The fetal programming of telomere biology hypothesis: an update.

    Science.gov (United States)

    Entringer, Sonja; de Punder, Karin; Buss, Claudia; Wadhwa, Pathik D

    2018-03-05

    Research on mechanisms underlying fetal programming of health and disease risk has focused primarily on processes that are specific to cell types, organs or phenotypes of interest. However, the observation that developmental conditions concomitantly influence a diverse set of phenotypes, the majority of which are implicated in age-related disorders, raises the possibility that such developmental conditions may additionally exert effects via a common underlying mechanism that involves cellular/molecular ageing-related processes. In this context, we submit that telomere biology represents a process of particular interest in humans because, firstly, this system represents among the most salient antecedent cellular phenotypes for common age-related disorders; secondly, its initial (newborn) setting appears to be particularly important for its long-term effects; and thirdly, its initial setting appears to be plastic and under developmental regulation. We propose that the effects of suboptimal intrauterine conditions on the initial setting of telomere length and telomerase expression/activity capacity may be mediated by the programming actions of stress-related maternal-placental-fetal oxidative, immune, endocrine and metabolic pathways in a manner that may ultimately accelerate cellular dysfunction, ageing and disease susceptibility over the lifespan. This perspectives paper provides an overview of each of the elements underlying this hypothesis, with an emphasis on recent developments, findings and future directions.This article is part of the theme issue 'Understanding diversity in telomere dynamics'. © 2018 The Author(s).

  9. Rif1 Binding and Control of Chromosome-Internal DNA Replication Origins Is Limited by Telomere Sequestration.

    Science.gov (United States)

    Hafner, Lukas; Lezaja, Aleksandra; Zhang, Xu; Lemmens, Laure; Shyian, Maksym; Albert, Benjamin; Follonier, Cindy; Nunes, Jose Manuel; Lopes, Massimo; Shore, David; Mattarocci, Stefano

    2018-04-24

    The Saccharomyces cerevisiae telomere-binding protein Rif1 plays an evolutionarily conserved role in control of DNA replication timing by promoting PP1-dependent dephosphorylation of replication initiation factors. However, ScRif1 binding outside of telomeres has never been detected, and it has thus been unclear whether Rif1 acts directly on the replication origins that it controls. Here, we show that, in unperturbed yeast cells, Rif1 primarily regulates late-replicating origins within 100 kb of a telomere. Using the chromatin endogenous cleavage ChEC-seq technique, we robustly detect Rif1 at late-replicating origins that we show are targets of its inhibitory action. Interestingly, abrogation of Rif1 telomere association by mutation of its Rap1-binding module increases Rif1 binding and origin inhibition elsewhere in the genome. Our results indicate that Rif1 inhibits replication initiation by interacting directly with origins and suggest that Rap1-dependent sequestration of Rif1 increases its effective concentration near telomeres, while limiting its action at chromosome-internal sites. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. Self-initiated coping with Tourette's syndrome: Effect of tic suppression on QOL.

    Science.gov (United States)

    Matsuda, Natsumi; Kono, Toshiaki; Nonaka, Maiko; Fujio, Miyuki; Kano, Yukiko

    2016-02-01

    Because of the semi-voluntary nature of tics, patients with Tourette' syndrome (TS) often report self-initiated coping with tics. Our goals were to understand the experiences of self-initiated coping with tics by individuals with TS (e.g., suppression frequency, suppression ability, and side effects of tic suppression), and investigate the effects of tic control on quality of life (QOL). One hundred participants with TS (38 children and 62 adults) answered a questionnaire concerning tic control, QOL, and other clinical characteristics. Fifty-eight percent of the participants always or frequently tried to suppress tics daily. In contrast, over 90% felt uncomfortable or incomplete when they suppressed tics and needed concentration or extra effort to suppress them. Thirty-four percent could suppress tics for less than one minute and 65% could suppress tics for less than 10min. Higher subjective satisfaction with tic control was positively correlated with life satisfaction and QOL. Individuals with TS often attempt self-initiated coping in their daily lives, especially through tic suppression, despite experiencing subjective discomfort and being aware that the duration of tic suppression is often limited. Moreover, it was found that their subjective satisfaction with tic control and effective tic suppression might have a positive influence on their life satisfaction and QOL. Thus, self-initiated coping with tics is vital for improving the QOL of individuals with TS and intervention aimed at enhancing subjective satisfaction with tic control could help manage TS. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  11. Telomere length analysis in monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia Binet A

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    F.M. Furtado

    Full Text Available Monoclonal B-cell lymphocytosis (MBL is an asymptomatic clinical entity characterized by the proliferation of monoclonal B cells not meeting the diagnosis criteria for chronic lymphocytic leukemia (CLL. MBL may precede the development of CLL, but the molecular mechanisms responsible for disease progression and evolution are not completely known. Telomeres are usually short in CLL and their attrition may contribute to disease evolution. Here, we determined the telomere lengths of CD5+CD19+ cells in MBL, CLL, and healthy volunteers. Twenty-one CLL patients, 11 subjects with high-count MBL, and 6 with low-count MBL were enrolled. Two hundred and sixty-one healthy volunteers aged 0 to 88 years were studied as controls. After diagnosis confirmation, a flow cytometry CD19+CD5+-based cell sorting was performed for the study groups. Telomere length was determined by qPCR. Telomere length was similar in the 3 study groups but shorter in these groups compared to normal age-matched subjects that had been enrolled in a previous study from our group. These findings suggest that telomere shortening is an early event in CLL leukemogenesis.

  12. Leukocyte Telomere Length in the Neonatal Offspring of Mothers with Gestational and Pre-Gestational Diabetes.

    Science.gov (United States)

    Gilfillan, Christopher; Naidu, Pratyusha; Gunawan, Florence; Hassan, Fadwa; Tian, Pei; Elwood, Ngaire

    2016-01-01

    Telomeres undergo shortening with cell division, accelerated by increased oxidative stress. We aimed to demonstrate shortened telomeres in the offspring of mothers who have diabetes as a consequence of exposure to increased oxidative stress during intrauterine development. We examined the level of glycaemia (glucose, HbA1c, fructosamine), oxidative stress (lipid peroxidation) and the levels of antioxidant enzymes (Superoxide dismutase (SOD) and Selenium dependent glutathione peroxidase) and correlate these findings with mean telomere length (TL) in maternal and foetal blood in groups of pregnant women with pre-gestational diabetes (PGD), gestational diabetes (GD) and a euglycaemic control group. Foetal and maternal glucose, maternal HbA1c, and foetal insulin and C-peptide were higher in the PGD group with the GD group being intermediate. Markers of oxidative stress did not vary between groups with the exception of foetal SOD activity that was highest in the GD group. There were no detectable differences in maternal or foetal TL between study groups. An exploratory analysis looking at correlations between glycaemic and oxidative stress parameters and TL revealed a negative correlation between maternal and foetal glucose and TL across the whole study population. This relationship held for the short-term marker of glycaemic control, fructosamine. We were unable to show significant telomere shortening in the offspring of mothers with PGD or GD. Exploratory analysis revealed a relationship between foetal TL and short-term glycaemia particularly in PGD. It is possible that increased telomerase activity can compensate for long-term increased oxidative stress but not for short-term dysglycaemia.

  13. Age-related declines and disease-associated variation in immune cell telomere length in a wild mammal.

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    Christopher Beirne

    Full Text Available Immunosenescence, the deterioration of immune system capability with age, may play a key role in mediating age-related declines in whole-organism performance, but the mechanisms that underpin immunosenescence are poorly understood. Biomedical research on humans and laboratory models has documented age and disease related declines in the telomere lengths of leukocytes ('immune cells', stimulating interest their having a potentially general role in the emergence of immunosenescent phenotypes. However, it is unknown whether such observations generalise to the immune cell populations of wild vertebrates living under ecologically realistic conditions. Here we examine longitudinal changes in the mean telomere lengths of immune cells in wild European badgers (Meles meles. Our findings provide the first evidence of within-individual age-related declines in immune cell telomere lengths in a wild vertebrate. That the rate of age-related decline in telomere length appears to be steeper within individuals than at the overall population level raises the possibility that individuals with short immune cell telomeres and/or higher rates of immune cell telomere attrition may be selectively lost from this population. We also report evidence suggestive of associations between immune cell telomere length and bovine tuberculosis infection status, with individuals detected at the most advanced stage of infection tending to have shorter immune cell telomeres than disease positive individuals. While male European badgers are larger and show higher rates of annual mortality than females, we found no evidence of a sex difference in either mean telomere length or the average rate of within-individual telomere attrition with age. Our findings lend support to the view that age-related declines in the telomere lengths of immune cells may provide one potentially general mechanism underpinning age-related declines in immunocompetence in natural populations.

  14. Binding polarity of RPA to telomeric sequences and influence of G-quadruplex stability.

    Science.gov (United States)

    Safa, Layal; Delagoutte, Emmanuelle; Petruseva, Irina; Alberti, Patrizia; Lavrik, Olga; Riou, Jean-François; Saintomé, Carole

    2014-08-01

    Replication protein A (RPA) is a single-stranded DNA binding protein that plays an essential role in telomere maintenance. RPA binds to and unfolds G-quadruplex (G4) structures formed in telomeric DNA, thus facilitating lagging strand DNA replication and telomerase activity. To investigate the effect of G4 stability on the interactions with human RPA (hRPA), we used a combination of biochemical and biophysical approaches. Our data revealed an inverse relationship between G4 stability and ability of hRPA to bind to telomeric DNA; notably small G4 ligands that enhance G4 stability strongly impaired G4 unfolding by hRPA. To gain more insight into the mechanism of binding and unfolding of telomeric G4 structures by RPA, we carried out photo-crosslinking experiments to elucidate the spatial arrangement of the RPA subunits along the DNA strands. Our results showed that RPA1 and RPA2 are arranged from 5' to 3' along the unfolded telomeric G4, as already described for unstructured single-stranded DNA, while no contact is possible with RPA3 on this short oligonucleotide. In addition, these data are compatible with a 5' to 3' directionality in G4 unfolding by hRPA. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  15. Assessing Telomere Length Using Surface Enhanced Raman Scattering

    Science.gov (United States)

    Zong, Shenfei; Wang, Zhuyuan; Chen, Hui; Cui, Yiping

    2014-11-01

    Telomere length can provide valuable insight into telomeres and telomerase related diseases, including cancer. Here, we present a brand-new optical telomere length measurement protocol using surface enhanced Raman scattering (SERS). In this protocol, two single strand DNA are used as SERS probes. They are labeled with two different Raman molecules and can specifically hybridize with telomeres and centromere, respectively. First, genome DNA is extracted from cells. Then the telomere and centromere SERS probes are added into the genome DNA. After hybridization with genome DNA, excess SERS probes are removed by magnetic capturing nanoparticles. Finally, the genome DNA with SERS probes attached is dropped onto a SERS substrate and subjected to SERS measurement. Longer telomeres result in more attached telomere probes, thus a stronger SERS signal. Consequently, SERS signal can be used as an indicator of telomere length. Centromere is used as the inner control. By calibrating the SERS intensity of telomere probe with that of the centromere probe, SERS based telomere measurement is realized. This protocol does not require polymerase chain reaction (PCR) or electrophoresis procedures, which greatly simplifies the detection process. We anticipate that this easy-operation and cost-effective protocol is a fine alternative for the assessment of telomere length.

  16. Epigenetic telomere protection by Drosophila DNA damage response pathways.

    Science.gov (United States)

    Oikemus, Sarah R; Queiroz-Machado, Joana; Lai, KuanJu; McGinnis, Nadine; Sunkel, Claudio; Brodsky, Michael H

    2006-05-01

    Analysis of terminal deletion chromosomes indicates that a sequence-independent mechanism regulates protection of Drosophila telomeres. Mutations in Drosophila DNA damage response genes such as atm/tefu, mre11, or rad50 disrupt telomere protection and localization of the telomere-associated proteins HP1 and HOAP, suggesting that recognition of chromosome ends contributes to telomere protection. However, the partial telomere protection phenotype of these mutations limits the ability to test if they act in the epigenetic telomere protection mechanism. We examined the roles of the Drosophila atm and atr-atrip DNA damage response pathways and the nbs homolog in DNA damage responses and telomere protection. As in other organisms, the atm and atr-atrip pathways act in parallel to promote telomere protection. Cells lacking both pathways exhibit severe defects in telomere protection and fail to localize the protection protein HOAP to telomeres. Drosophila nbs is required for both atm- and atr-dependent DNA damage responses and acts in these pathways during DNA repair. The telomere fusion phenotype of nbs is consistent with defects in each of these activities. Cells defective in both the atm and atr pathways were used to examine if DNA damage response pathways regulate telomere protection without affecting telomere specific sequences. In these cells, chromosome fusion sites retain telomere-specific sequences, demonstrating that loss of these sequences is not responsible for loss of protection. Furthermore, terminally deleted chromosomes also fuse in these cells, directly implicating DNA damage response pathways in the epigenetic protection of telomeres. We propose that recognition of chromosome ends and recruitment of HP1 and HOAP by DNA damage response proteins is essential for the epigenetic protection of Drosophila telomeres. Given the conserved roles of DNA damage response proteins in telomere function, related mechanisms may act at the telomeres of other organisms.

  17. Leukocyte Telomere Length and Serum Levels of High-Molecular-Weight Adiponectin and Dehydroepiandrosterone-Sulfate Could Reflect Distinct Aspects of Longevity in Japanese Centenarians

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    Yuji Aoki MD, PhD

    2017-03-01

    Full Text Available Leukocyte telomere length and serum levels of high-molecular-weight adiponectin and dehydroepiandrosterone-sulfate (DHEA-S were assessed in association with nutrition and performance status (PS in Japanese centenarians. Twenty-three centenarians (five men, 18 women were classified according to their PS 1 (nearly fully ambulatory, n = 2, 2 (in bed less than 50% of daytime, n = 10, 3 (in bed greater than 50%, n = 6, and 4 (completely bedridden, n = 5. Leukocyte telomere length was determined by the hybridization protection assay, and the adiponectin and DHEA-S levels were measured by chemiluminescent enzyme immunoassay. Among variables of PS, body mass index (BMI, albumin, adiponectin, DHEA-S, and telomere length, there were significant correlations between PS and albumin ( r = −.694, p < .01, between telomere length and BMI ( r = .522, p < .05, between adiponectin and BMI ( r = −.574, p < .01, and between DHEA-S and albumin ( r = .530, p < .01. When excluding two cancer-bearing centenarians with short telomere, telomere length significantly correlated with PS ( r = −.632, p < .01. It was indicated that the short leukocyte telomere was associated with poor PS and cancer development and that the adiponectin or DHEA-S was associated with adiposity or nutritional status. Despite a small number of subjects, these biomarkers seemed to reflect distinct aspects of longevity in Japanese centenarians.

  18. Reactivation of chromosomally integrated human herpesvirus-6 by telomeric circle formation.

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    Bhupesh K Prusty

    Full Text Available More than 95% of the human population is infected with human herpesvirus-6 (HHV-6 during early childhood and maintains latent HHV-6 genomes either in an extra-chromosomal form or as a chromosomally integrated HHV-6 (ciHHV-6. In addition, approximately 1% of humans are born with an inheritable form of ciHHV-6 integrated into the telomeres of chromosomes. Immunosuppression and stress conditions can reactivate latent HHV-6 replication, which is associated with clinical complications and even death. We have previously shown that Chlamydia trachomatis infection reactivates ciHHV-6 and induces the formation of extra-chromosomal viral DNA in ciHHV-6 cells. Here, we propose a model and provide experimental evidence for the mechanism of ciHHV-6 reactivation. Infection with Chlamydia induced a transient shortening of telomeric ends, which subsequently led to increased telomeric circle (t-circle formation and incomplete reconstitution of circular viral genomes containing single viral direct repeat (DR. Correspondingly, short t-circles containing parts of the HHV-6 DR were detected in cells from individuals with genetically inherited ciHHV-6. Furthermore, telomere shortening induced in the absence of Chlamydia infection also caused circularization of ciHHV-6, supporting a t-circle based mechanism for ciHHV-6 reactivation.

  19. Telomeres and human health

    DEFF Research Database (Denmark)

    Bojesen, S E

    2013-01-01

    will be reviewed. In addition, technical difficulties and the reasons why measurement of telomeres has still not been introduced into routine clinical practice will be discussed. Findings from recent studies conducted in many thousands of individuals indicate that telomere length is not-or at best only marginally...

  20. Early-Life Telomere Dynamics Differ between the Sexes and Predict Growth in the Barn Swallow (Hirundo rustica.

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    Marco Parolini

    Full Text Available Telomeres are conserved DNA-protein structures at the termini of eukaryotic chromosomes which contribute to maintenance of genome integrity, and their shortening leads to cell senescence, with negative consequences for organismal functions. Because telomere erosion is influenced by extrinsic and endogenous factors, telomere dynamics may provide a mechanistic basis for evolutionary and physiological trade-offs. Yet, knowledge of fundamental aspects of telomere biology under natural selection regimes, including sex- and context-dependent variation in early-life, and the covariation between telomere dynamics and growth, is scant. In this study of barn swallows (Hirundo rustica we investigated the sex-dependent telomere erosion during nestling period, and the covariation between relative telomere length and body and plumage growth. Finally, we tested whether any covariation between growth traits and relative telomere length depends on the social environment, as influenced by sibling sex ratio. Relative telomere length declined on average over the period of nestling maximal growth rate (between 7 and 16 days of age and differently covaried with initial relative telomere length in either sex. The frequency distribution of changes in relative telomere length was bimodal, with most nestlings decreasing and some increasing relative telomere length, but none of the offspring traits predicted the a posteriori identified group to which individual nestlings belonged. Tail and wing length increased with relative telomere length, but more steeply in males than females, and this relationship held both at the within- and among-broods levels. Moreover, the increase in plumage phenotypic values was steeper when the sex ratio of an individual's siblings was female-biased. Our study provides evidence for telomere shortening during early life according to subtly different dynamics in either sex. Furthermore, it shows that the positive covariation between growth and

  1. Telomere length modulation in human astroglial brain tumors.

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    Domenico La Torre

    Full Text Available BACKGROUND: Telomeres alteration during carcinogenesis and tumor progression has been described in several cancer types. Telomeres length is stabilized by telomerase (h-TERT and controlled by several proteins that protect telomere integrity, such as the Telomere Repeat-binding Factor (TRF 1 and 2 and the tankyrase-poli-ADP-ribose polymerase (TANKs-PARP complex. OBJECTIVE: To investigate telomere dysfunction in astroglial brain tumors we analyzed telomeres length, telomerase activity and the expression of a panel of genes controlling the length and structure of telomeres in tissue samples obtained in vivo from astroglial brain tumors with different grade of malignancy. MATERIALS AND METHODS: Eight Low Grade Astrocytomas (LGA, 11 Anaplastic Astrocytomas (AA and 11 Glioblastoma Multiforme (GBM samples were analyzed. Three samples of normal brain tissue (NBT were used as controls. Telomeres length was assessed through Southern Blotting. Telomerase activity was evaluated by a telomere repeat amplification protocol (TRAP assay. The expression levels of TRF1, TRF2, h-TERT and TANKs-PARP complex were determined through Immunoblotting and RT-PCR. RESULTS: LGA were featured by an up-regulation of TRF1 and 2 and by shorter telomeres. Conversely, AA and GBM were featured by a down-regulation of TRF1 and 2 and an up-regulation of both telomerase and TANKs-PARP complex. CONCLUSIONS: In human astroglial brain tumours, up-regulation of TRF1 and TRF2 occurs in the early stages of carcinogenesis determining telomeres shortening and genomic instability. In a later stage, up-regulation of PARP-TANKs and telomerase activation may occur together with an ADP-ribosylation of TRF1, causing a reduced ability to bind telomeric DNA, telomeres elongation and tumor malignant progression.

  2. Telomere stability and telomerase in mesenchymal stem cells

    DEFF Research Database (Denmark)

    Serakinci, Nedime; Graakjaer, Jesper; Kølvrå, Steen

    2008-01-01

    Telomeres are repetitive genetic material that cap and thereby protect the ends of chromosomes. Each time a cell divides, telomeres get shorter. Telomere length is mainly maintained by telomerase. This enzyme is present in high concentrations in the embryonic stem cells and in fast growing...... embryonic cells, and declines with age. It is still unclear to what extent there is telomerase in adult stem cells, but since these are the founder cells of cells of all the tissues in the body, understanding the telomere dynamics and expression of telomerase in adult stem cells is very important....... In the present communication we focus on telomere expression and telomere length in stem cells, with a special focus on mesenchymal stem cells. We consider different mechanisms by which stem cells can maintain telomeres and also focus on the dynamics of telomere length in mesenchymal stem cells, both the overall...

  3. Silica inhalation altered telomere length and gene expression of telomere regulatory proteins in lung tissue of rats.

    Science.gov (United States)

    Shoeb, Mohammad; Joseph, Pius; Kodali, Vamsi; Mustafa, Gul; Farris, Breanne Y; Umbright, Christina; Roberts, Jenny R; Erdely, Aaron; Antonini, James M

    2017-12-11

    Exposure to silica can cause lung fibrosis and cancer. Identification of molecular targets is important for the intervention and/or prevention of silica-induced lung diseases. Telomeres consist of tandem repeats of DNA sequences at the end of chromosomes, preventing chromosomal fusion and degradation. Regulator of telomere length-1 (RTEL1) and telomerase reverse transcriptase (TERT), genes involved in telomere regulation and function, play important roles in maintaining telomere integrity and length. The goal of this study was to assess the effect of silica inhalation on telomere length and the regulation of RTEL1 and TERT. Lung tissues and blood samples were collected from rats at 4, 32, and 44 wk after exposure to 15 mg/m 3 of silica × 6 h/d × 5 d. Controls were exposed to air. At all-time points, RTEL1 expression was significantly decreased in lung tissue of the silica-exposed animals compared to controls. Also, significant increases in telomere length and TERT were observed in the silica group at 4 and 32 wk. Telomere length, RTEL1 and TERT expression may serve as potential biomarkers related to silica exposure and may offer insight into the molecular mechanism of silica-induced lung disease and tumorigeneses.

  4. Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy.

    Science.gov (United States)

    Liu, Chang Ching; Ma, Dong Liang; Yan, Ting-Dong; Fan, XiuBo; Poon, Zhiyong; Poon, Lai-Fong; Goh, Su-Ann; Rozen, Steve G; Hwang, William Ying Khee; Tergaonkar, Vinay; Tan, Patrick; Ghosh, Sujoy; Virshup, David M; Goh, Eyleen L K; Li, Shang

    2016-10-01

    In most human somatic cells, the lack of telomerase activity results in progressive telomere shortening during each cell division. Eventually, DNA damage responses triggered by critically short telomeres induce an irreversible cell cycle arrest termed replicative senescence. However, the cellular responses of human pluripotent stem cells to telomere uncapping remain unknown. We generated telomerase knockout human embryonic stem (ES) cells through gene targeting. Telomerase inactivation in ES cells results in progressive telomere shortening. Telomere DNA damage in ES cells and neural progenitor cells induces rapid apoptosis when telomeres are uncapped, in contrast to fibroblast cells that enter a state of replicative senescence. Significantly, telomerase inactivation limits the proliferation capacity of human ES cells without affecting their pluripotency. By targeting telomerase activity, we can functionally separate the two unique properties of human pluripotent stem cells, namely unlimited self-renewal and pluripotency. We show that the potential of ES cells to form teratomas in vivo is dictated by their telomere length. By controlling telomere length of ES cells through telomerase inactivation, we can inhibit teratoma formation and potentially improve the safety of cell therapies involving terminally differentiated cells as well as specific progenitor cells that do not require sustained cellular proliferation in vivo, and thus sustained telomerase activity. Stem Cells 2016;34:2471-2484. © 2016 AlphaMed Press.

  5. DNA-PKcs is critical for telomere capping

    Energy Technology Data Exchange (ETDEWEB)

    Gilley, David; Tanaka, Hiromi; Hande, M. Prakash; Kurimasa,Akihiro; Li, Gloria C.; Chen, David J.

    2001-04-10

    The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is critical for DNA repair via the non-homologous end joining (NHEJ) pathway. Previously, it was reported that bone marrow cells and spontaneously transformed fibroblasts from SCID (severe combined immunodeficiency) mice have defects in telomere maintenance. The genetically defective SCID mouse arose spontaneously from its parental strain CB17. One known genomic alteration in SCID mice is a truncation of the extreme carboxyl-terminus of DNA-PKcs, but other as yet unidentified alterations may also exist. We have used a defined system, the DNA-PKcs knockout mouse, to investigate specifically the role DNA-PKcs specifically plays in telomere maintenance. We report that primary mouse embryonic fibroblasts (MEFs) and primary cultured kidney cells from 6-8 month old DNA-PKcs deficient mice accumulate a large number of telomere fusions, yet still retain wildtype telomere length. Thus, the phenotype of this defect separates the two-telomere related phenotypes, capping and length maintenance. DNA-PKcs deficient MEFs also exhibit elevated levels of chromosome fragments and breaks, which correlate with increased telomere fusions. Based on the high levels of telomere fusions observed in DNA-PKcs deficient cells, we conclude that DNA-PKcs plays an important capping role at the mammalian telomere.

  6. Loss and recovery of Arabidopsis-type telomere repeat sequences 5'-(TTTAGGG)(n)-3' in the evolution of a major radiation of flowering plants.

    OpenAIRE

    Adams, S. P.; Hartman, T. P.; Lim, K. Y.; Chase, M. W.; Bennett, M. D.; Leitch, I. J.; Leitch, A. R.

    2001-01-01

    Fluorescent in situ hybridization and Southern blotting were used for showing the predominant absence of the Arabidopsis-type telomere repeat sequence (TRS) 5'-(TTTAGGG)(n)-3' (the 'typical' telomere) in a monocot clade which comprises up to 6300 species within Asparagales. Initially, two apparently disparate genera that lacked the typical telomere were identified. Here, we used the new angiosperm phylogenetic classification for predicting in which other related families such telomeres might ...

  7. Sexual differences in telomere selection in the wild.

    Science.gov (United States)

    Olsson, Mats; Pauliny, Angela; Wapstra, Erik; Uller, Tobias; Schwartz, Tonia; Miller, Emily; Blomqvist, Donald

    2011-05-01

    Telomere length is restored primarily through the action of the reverse transcriptase telomerase, which may contribute to a prolonged lifespan in some but not all species and may result in longer telomeres in one sex than the other. To what extent this is an effect of proximate mechanisms (e.g. higher stress in males, higher oestradiol/oestrogen levels in females), or is an evolved adaptation (stronger selection for telomere length in one sex), usually remains unknown. Sand lizard (Lacerta agilis) females have longer telomeres than males and better maintain telomere length through life than males do. We also show that telomere length more strongly contributes to life span and lifetime reproductive success in females than males and that telomere length is under sexually diversifying selection in the wild. Finally, we performed a selection analysis with number of recruited offspring into the adult population as a response variable with telomere length, life span and body size as predictor variables. This showed significant differences in selection pressures between the sexes with strong ongoing selection in females, with these three predictors explaining 63% of the variation in recruitment. Thus, the sexually dimorphic telomere dynamics with longer telomeres in females is a result of past and ongoing selection in sand lizards. Finally, we compared the results from our selection analyses based on Telometric-derived data to the results based on data generated by the software ImageJ. ImageJ resulted in shorter average telomere length, but this difference had virtually no qualitative effect on the patterns of ongoing selection. © 2011 Blackwell Publishing Ltd.

  8. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.

    Science.gov (United States)

    Stuart, Bridget D; Choi, Jungmin; Zaidi, Samir; Xing, Chao; Holohan, Brody; Chen, Rui; Choi, Mihwa; Dharwadkar, Pooja; Torres, Fernando; Girod, Carlos E; Weissler, Jonathan; Fitzgerald, John; Kershaw, Corey; Klesney-Tait, Julia; Mageto, Yolanda; Shay, Jerry W; Ji, Weizhen; Bilguvar, Kaya; Mane, Shrikant; Lifton, Richard P; Garcia, Christine Kim

    2015-05-01

    Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 × 10(-8)); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 × 10(-6)). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain ~7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.

  9. HSV-1 Remodels Host Telomeres to Facilitate Viral Replication

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    Zhong Deng

    2014-12-01

    Full Text Available Telomeres protect the ends of cellular chromosomes. We show here that infection with herpes simplex virus 1 (HSV-1 results in chromosomal structural aberrations at telomeres and the accumulation of telomere dysfunction-induced DNA damage foci (TIFs. At the molecular level, HSV-1 induces transcription of telomere repeat-containing RNA (TERRA, followed by the proteolytic degradation of the telomere protein TPP1 and loss of the telomere repeat DNA signal. The HSV-1-encoded E3 ubiquitin ligase ICP0 is required for TERRA transcription and facilitates TPP1 degradation. Small hairpin RNA (shRNA depletion of TPP1 increases viral replication, indicating that TPP1 inhibits viral replication. Viral replication protein ICP8 forms foci that coincide with telomeric proteins, and ICP8-null virus failed to degrade telomere DNA signal. These findings suggest that HSV-1 reorganizes telomeres to form ICP8-associated prereplication foci and to promote viral genomic replication.

  10. Telomere Shortening in Hematological Malignancies with Tetraploidization—A Mechanism for Chromosomal Instability?

    Directory of Open Access Journals (Sweden)

    Eigil Kjeldsen

    2017-11-01

    cells and cells with T/NT karyotypes. We find that the telomeres are particularly short in cells with T/NT karyotypes as compared with normal cells, and in T/NT karyotypes harboring additional chromosomal aberrations as well. These findings suggest that telomere dysfunction in hematological malignancies may be a mechanism for tetraploidization and CIN.

  11. RPA and POT1: friends or foes at telomeres?

    Science.gov (United States)

    Flynn, Rachel Litman; Chang, Sandy; Zou, Lee

    2012-02-15

    Telomere maintenance in cycling cells relies on both DNA replication and capping by the protein complex shelterin. Two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomere 1 (POT1) play critical roles in DNA replication and telomere capping, respectively. While RPA binds to ssDNA in a non-sequence-specific manner, POT1 specifically recognizes singlestranded TTAGGG telomeric repeats. Loss of POT1 leads to aberrant accumulation of RPA at telomeres and activation of the ataxia telangiectasia and Rad3-related kinase (ATR)-mediated checkpoint response, suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. The requirement for both POT1 and RPA in telomere maintenance and the antagonism between the two proteins raises the important question of how they function in concert on telomeric ssDNA. Two interesting models were proposed by recent studies to explain the regulation of POT1 and RPA at telomeres. Here, we discuss how these models help unravel the coordination, and also the antagonism, between POT1 and RPA during the cell cycle.

  12. Telomere lengthening and other functions of telomerase.

    Science.gov (United States)

    Rubtsova, M P; Vasilkova, D P; Malyavko, A N; Naraikina, Yu V; Zvereva, M I; Dontsova, O A

    2012-04-01

    Telomerase is an enzyme that maintains the length of the telomere. The telomere length specifies the number of divisions a cell can undergo before it finally dies (i.e. the proliferative potential of cells). For example, telomerase is activated in embryonic cell lines and the telomere length is maintained at a constant level; therefore, these cells have an unlimited fission potential. Stem cells are characterized by a lower telomerase activity, which enables only partial compensation for the shortening of telomeres. Somatic cells are usually characterized by the absence of telomerase activity. Telomere shortening leads to the attainment of the Hayflick limit, the transition of cells to a state of senescence. The cells subsequently enter a state of crisis, accompanied by massive cell death. The surviving cells become cancer cells, which are capable both of dividing indefinitely and maintaining telomere length (usually with the aid of telomerase). Telomerase is a reverse transcriptase. It consists of two major components: telomerase RNA (TER) and reverse transcriptase (TERT). TER is a non-coding RNA, and it contains the region which serves as a template for telomere synthesis. An increasing number of articles focussing on the alternative functions of telomerase components have recently started appearing. The present review summarizes data on the structure, biogenesis, and functions of telomerase.

  13. Telomere maintenance through recruitment of internal genomic regions.

    Science.gov (United States)

    Seo, Beomseok; Kim, Chuna; Hills, Mark; Sung, Sanghyun; Kim, Hyesook; Kim, Eunkyeong; Lim, Daisy S; Oh, Hyun-Seok; Choi, Rachael Mi Jung; Chun, Jongsik; Shim, Jaegal; Lee, Junho

    2015-09-18

    Cells surviving crisis are often tumorigenic and their telomeres are commonly maintained through the reactivation of telomerase. However, surviving cells occasionally activate a recombination-based mechanism called alternative lengthening of telomeres (ALT). Here we establish stably maintained survivors in telomerase-deleted Caenorhabditis elegans that escape from sterility by activating ALT. ALT survivors trans-duplicate an internal genomic region, which is already cis-duplicated to chromosome ends, across the telomeres of all chromosomes. These 'Template for ALT' (TALT) regions consist of a block of genomic DNA flanked by telomere-like sequences, and are different between two genetic background. We establish a model that an ancestral duplication of a donor TALT region to a proximal telomere region forms a genomic reservoir ready to be incorporated into telomeres on ALT activation.

  14. Mechanisms of telomere loss and their consequences for chromosome instability

    International Nuclear Information System (INIS)

    Muraki, Keiko; Nyhan, Kristine; Han, Limei; Murnane, John P.

    2012-01-01

    The ends of chromosomes in mammals, called telomeres, are composed of a 6-bp repeat sequence, TTAGGG, which is added on by the enzyme telomerase. In combination with a protein complex called shelterin, these telomeric repeat sequences form a cap that protects the ends of chromosomes. Due to insufficient telomerase expression, telomeres shorten gradually with each cell division in human somatic cells, which limits the number of times they can divide. The extensive cell division involved in cancer cell progression therefore requires that cancer cells must acquire the ability to maintain telomeres, either through expression of telomerase, or through an alternative mechanism involving recombination. It is commonly thought that the source of many chromosome rearrangements in cancer cells is a result of the extensive telomere shortening that occurs prior to the expression of telomerase. However, despite the expression of telomerase, tumor cells can continue to show chromosome instability due to telomere loss. Dysfunctional telomeres in cancer cells can result from oncogene-induced replication stress, which results in double-strand breaks (DSBs) at fragile sites, including telomeres. DSBs near telomeres are especially prone to chromosome rearrangements, because telomeric regions are deficient in DSB repair. The deficiency in DSB repair near telomeres is also an important mechanism for ionizing radiation-induced replicative senescence in normal human cells. In addition, DSBs near telomeres can result in chromosome instability in mouse embryonic stem cells, suggesting that telomere loss can contribute to heritable chromosome rearrangements. Consistent with this possibility, telomeric regions in humans are highly heterogeneous, and chromosome rearrangements near telomeres are commonly involved in human genetic disease. Understanding the mechanisms of telomere loss will therefore provide important insights into both human cancer and genetic disease.

  15. Mechanisms of telomere loss and their consequences for chromosome instability

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    Keiko eMuraki

    2012-10-01

    Full Text Available The ends of chromosomes in mammals, called telomeres, are composed of a 6 base pair repeat sequence, TTAGGG, which is added on by the enzyme telomerase. In combination with a protein complex called shelterin, these telomeric repeat sequences form a cap that protects the ends of chromosomes. Due to insufficient telomerase expression, telomeres shorten gradually with each cell division in human somatic cells, which limits the number of times they can divide. The extensive cell division involved in cancer cell progression therefore requires that cancer cells must acquire the ability to maintain telomeres, either through expression of telomerase, or through an alternative mechanism involving recombination. It is commonly thought that the source of many chromosome rearrangements in cancer cells is a result of the extensive telomere shortening that occurs prior to the expression of telomerase. However, despite the expression of telomerase, tumor cells can continue to show chromosome instability due to telomere loss. Dysfunctional telomeres in cancer cells can result from oncogene-induced replication stress, which results in double-strand breaks (DSBs at fragile sites, including telomeres. DSBs near telomeres are especially prone to chromosome rearrangements, because telomeric regions are deficient in DSB repair. The deficiency in DSB repair near telomeres is also an important mechanism for ionizing radiation-induced replicative senescence in normal human cells. In addition, DSBs near telomeres can result in chromosome instability in mouse embryonic stem cells, suggesting that telomere loss can contribute to heritable chromosome rearrangements. Consistent with this possibility, telomeric regions in humans are highly heterogeneous, and chromosome rearrangements near telomeres are commonly involved in human genetic disease. Understanding the mechanisms of telomere loss will therefore provide important insights into both human cancer and genetic disease.

  16. Mechanisms of telomere loss and their consequences for chromosome instability

    Energy Technology Data Exchange (ETDEWEB)

    Muraki, Keiko; Nyhan, Kristine; Han, Limei; Murnane, John P., E-mail: jmurnane@radonc.ucsf.edu [Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA (United States)

    2012-10-04

    The ends of chromosomes in mammals, called telomeres, are composed of a 6-bp repeat sequence, TTAGGG, which is added on by the enzyme telomerase. In combination with a protein complex called shelterin, these telomeric repeat sequences form a cap that protects the ends of chromosomes. Due to insufficient telomerase expression, telomeres shorten gradually with each cell division in human somatic cells, which limits the number of times they can divide. The extensive cell division involved in cancer cell progression therefore requires that cancer cells must acquire the ability to maintain telomeres, either through expression of telomerase, or through an alternative mechanism involving recombination. It is commonly thought that the source of many chromosome rearrangements in cancer cells is a result of the extensive telomere shortening that occurs prior to the expression of telomerase. However, despite the expression of telomerase, tumor cells can continue to show chromosome instability due to telomere loss. Dysfunctional telomeres in cancer cells can result from oncogene-induced replication stress, which results in double-strand breaks (DSBs) at fragile sites, including telomeres. DSBs near telomeres are especially prone to chromosome rearrangements, because telomeric regions are deficient in DSB repair. The deficiency in DSB repair near telomeres is also an important mechanism for ionizing radiation-induced replicative senescence in normal human cells. In addition, DSBs near telomeres can result in chromosome instability in mouse embryonic stem cells, suggesting that telomere loss can contribute to heritable chromosome rearrangements. Consistent with this possibility, telomeric regions in humans are highly heterogeneous, and chromosome rearrangements near telomeres are commonly involved in human genetic disease. Understanding the mechanisms of telomere loss will therefore provide important insights into both human cancer and genetic disease.

  17. Telomeres, age and reproduction in a long-lived reptile.

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    Virginie Plot

    Full Text Available A major interest has recently emerged in understanding how telomere shortening, mechanism triggering cell senescence, is linked to organism ageing and life history traits in wild species. However, the links between telomere length and key history traits such as reproductive performances have received little attention and remain unclear to date. The leatherback turtle Dermochelys coriacea is a long-lived species showing rapid growth at early stages of life, one of the highest reproductive outputs observed in vertebrates and a dichotomised reproductive pattern related to migrations lasting 2 or 3 years, supposedly associated with different environmental conditions. Here we tested the prediction of blood telomere shortening with age in this species and investigated the relationship between blood telomere length and reproductive performances in leatherback turtles nesting in French Guiana. We found that blood telomere length did not differ between hatchlings and adults. The absence of blood telomere shortening with age may be related to an early high telomerase activity. This telomere-restoring enzyme was formerly suggested to be involved in preventing early telomere attrition in early fast-growing and long-lived species, including squamate reptiles. We found that within one nesting cycle, adult females having performed shorter migrations prior to the considered nesting season had shorter blood telomeres and lower reproductive output. We propose that shorter blood telomeres may result from higher oxidative stress in individuals breeding more frequently (i.e., higher costs of reproduction and/or restoring more quickly their body reserves in cooler feeding areas during preceding migration (i.e., higher foraging costs. This first study on telomeres in the giant leatherback turtle suggests that blood telomere length predicts not only survival chances, but also reproductive performances. Telomeres may therefore be a promising new tool to evaluate

  18. Are intragastric N-nitroso compounds elevated after short-term acid suppression?

    NARCIS (Netherlands)

    Houben, G.M.P.; Hooi, J.D.; Brummer, R.J.M.; Stobberingh, E.E.; Stockbrügger, R.W.

    1996-01-01

    Are intragastric N-nitroso compounds elevated after short-term acid suppression? Houben GM, Hooi J, Brummer RJ, Stobberingh EE, Stockbrugger RW. Department of Gastroenterolgy, Academic Hospital Maastricht, The Netherlands. Publication Types: Clinical Trial Randomized Controlled Trial

  19. Measurement of Telomere Length in Colorectal Cancers for Improved Molecular Diagnosis

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    Eric Le Balc’h

    2017-08-01

    Full Text Available All tumors have in common to reactivate a telomere maintenance mechanism to allow for unlimited proliferation. On the other hand, genetic instability found in some tumors can result from the loss of telomeres. Here, we measured telomere length in colorectal cancers (CRCs using TRF (Telomere Restriction Fragment analysis. Telomeric DNA content was also quantified as the ratio of total telomeric (TTAGGG sequences over that of the invariable Alu sequences. In most of the 125 CRCs analyzed, there was a significant diminution in telomere length compared with that in control healthy tissue. Only 34 tumors exhibited no telomere erosion and, in some cases, a slight telomere lengthening. Telomere length did not correlate with age, gender, tumor stage, tumor localization or stage of tumor differentiation. In addition, while telomere length did not correlate with the presence of a mutation in BRAF (V-raf murine sarcoma viral oncogene homolog B, PIK3CA (phosphatidylinositol 3-kinase catalytic subunit, or MSI status, it was significantly associated with the occurrence of a mutation in KRAS. Interestingly, we found that the shorter the telomeres in healthy tissue of a patient, the larger an increase in telomere length in the tumor. Our study points to the existence of two types of CRCs based on telomere length and reveals that telomere length in healthy tissue might influence telomere maintenance mechanisms in the tumor.

  20. Telomere Length Dynamics and the Evolution of Cancer Genome Architecture

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    Kez Cleal

    2018-02-01

    Full Text Available Telomeres are progressively eroded during repeated rounds of cell division due to the end replication problem but also undergo additional more substantial stochastic shortening events. In most cases, shortened telomeres induce a cell-cycle arrest or trigger apoptosis, although for those cells that bypass such signals during tumour progression, a critical length threshold is reached at which telomere dysfunction may ensue. Dysfunction of the telomere nucleoprotein complex can expose free chromosome ends to the DNA double-strand break (DSB repair machinery, leading to telomere fusion with both telomeric and non-telomeric loci. The consequences of telomere fusions in promoting genome instability have long been appreciated through the breakage–fusion–bridge (BFB cycle mechanism, although recent studies using high-throughput sequencing technologies have uncovered evidence of involvement in a wider spectrum of genomic rearrangements including chromothripsis. A critical step in cancer progression is the transition of a clone to immortality, through the stabilisation of the telomere repeat array. This can be achieved via the reactivation of telomerase, or the induction of the alternative lengthening of telomeres (ALT pathway. Whilst telomere dysfunction may promote genome instability and tumour progression, by limiting the replicative potential of a cell and enforcing senescence, telomere shortening can act as a tumour suppressor mechanism. However, the burden of senescent cells has also been implicated as a driver of ageing and age-related pathology, and in the promotion of cancer through inflammatory signalling. Considering the critical role of telomere length in governing cancer biology, we review questions related to the prognostic value of studying the dynamics of telomere shortening and fusion, and discuss mechanisms and consequences of telomere-induced genome rearrangements.

  1. Does Reproductive Investment Decrease Telomere Length in Menidia menidia?

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    Jin Gao

    Full Text Available Given finite resources, intense investment in one life history trait is expected to reduce investment in others. Although telomere length appears to be strongly tied to age in many taxa, telomere maintenance requires energy. We therefore hypothesize that telomere maintenance may trade off against other life history characters. We used natural variation in laboratory populations of Atlantic silversides (Menidia menidia to study the relationship between growth, fecundity, life expectancy, and relative telomere length. In keeping with several other studies on fishes, we found no clear dependence of telomere length on age. However, we did find that more fecund fish tended to have both reduced life expectancy and shorter telomeres. This result is consistent with the hypothesis that there is a trade-off between telomere maintenance and reproductive output.

  2. Telomere Q-PNA-FISH--reliable results from stochastic signals.

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    Andrea Cukusic Kalajzic

    Full Text Available Structural and functional analysis of telomeres is very important for understanding basic biological functions such as genome stability, cell growth control, senescence and aging. Recently, serious concerns have been raised regarding the reliability of current telomere measurement methods such as Southern blot and quantitative polymerase chain reaction. Since telomere length is associated with age related pathologies, including cardiovascular disease and cancer, both at the individual and population level, accurate interpretation of measured results is a necessity. The telomere Q-PNA-FISH technique has been widely used in these studies as well as in commercial analysis for the general population. A hallmark of telomere Q-PNA-FISH is the wide variation among telomere signals which has a major impact on obtained results. In the present study we introduce a specific mathematical and statistical analysis of sister telomere signals during cell culture senescence which enabled us to identify high regularity in their variations. This phenomenon explains the reproducibility of results observed in numerous telomere studies when the Q-PNA-FISH technique is used. In addition, we discuss the molecular mechanisms which probably underlie the observed telomere behavior.

  3. Cells with dysfunctional telomeres are susceptible to reactive oxygen species hydrogen peroxide via generation of multichromosomal fusions and chromosomal fragments bearing telomeres

    Energy Technology Data Exchange (ETDEWEB)

    Woo, Seon Rang [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Department of Biochemistry, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Park, Jeong-Eun; Juhn, Kyoung-Mi; Ju, Yeun-Jin; Jeong, Jaemin [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Kang, Chang-Mo; Yun, Hyun Jin [Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Yun, Mi Yong; Shin, Hyun-Jin; Joo, Hyun-Yoo; Park, Eun-Ran; Park, In-Chul; Hong, Sung Hee; Hwang, Sang-Gu [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Kim, Haekwon [Department of Biotechnology, Seoul Woman' s University, Seoul 139-774 (Korea, Republic of); Cho, Myung-Haing [Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 151-742 (Korea, Republic of); Kim, Sang Hoon [Department of Biology, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Park, Gil Hong [Department of Biochemistry, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Lee, Kee-Ho, E-mail: khlee@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Under conditions of telomere erosion, cells become extremely sensitive to H{sub 2}O{sub 2}. Black-Right-Pointing-Pointer Chromosomal regions adjacent to telomeres are cleaved by H{sub 2}O{sub 2} under such conditions. Black-Right-Pointing-Pointer H{sub 2}O{sub 2} thus causes multichromosomal fusions and generation of small chromosomal fragments. Black-Right-Pointing-Pointer N-acetylcysteine prevents H{sub 2}O{sub 2}-induced chromosomal aberrations. -- Abstract: During genotoxic stress, reactive oxygen species hydrogen peroxide (H{sub 2}O{sub 2}) is a prime mediator of the DNA damage response. Telomeres function both to assist in DNA damage repair and to inhibit chromosomal end-to-end fusion. Here, we show that telomere dysfunction renders cells susceptible to H{sub 2}O{sub 2}, via generation of multichromosomal fusion and chromosomal fragments. H{sub 2}O{sub 2} caused formation of multichromosomal end-to-end fusions involving more than three chromosomes, preferentially when telomeres were erosive. Interestingly, extensive chromosomal fragmentation (yielding small-sized fragments) occurred only in cells exhibiting such multichromosomal fusions. Telomeres were absent from fusion points, being rather present in the small fragments, indicating that H{sub 2}O{sub 2} cleaves chromosomal regions adjacent to telomeres. Restoration of telomere function or addition of the antioxidant N-acetylcysteine prevented development of chromosomal aberrations and rescued the observed hypersensitivity to H{sub 2}O{sub 2}. Thus, chromosomal regions adjacent to telomeres become sensitive to reactive oxygen species hydrogen peroxide when telomeres are dysfunctional, and are cleaved to produce multichromosomal fusions and small chromosomal fragments bearing the telomeres.

  4. Self-initiated actions result in suppressed auditory but amplified visual evoked components in healthy participants.

    Science.gov (United States)

    Mifsud, Nathan G; Oestreich, Lena K L; Jack, Bradley N; Ford, Judith M; Roach, Brian J; Mathalon, Daniel H; Whitford, Thomas J

    2016-05-01

    Self-suppression refers to the phenomenon that sensations initiated by our own movements are typically less salient, and elicit an attenuated neural response, compared to sensations resulting from changes in the external world. Evidence for self-suppression is provided by previous ERP studies in the auditory modality, which have found that healthy participants typically exhibit a reduced auditory N1 component when auditory stimuli are self-initiated as opposed to externally initiated. However, the literature investigating self-suppression in the visual modality is sparse, with mixed findings and experimental protocols. An EEG study was conducted to expand our understanding of self-suppression across different sensory modalities. Healthy participants experienced either an auditory (tone) or visual (pattern-reversal) stimulus following a willed button press (self-initiated), a random interval (externally initiated, unpredictable onset), or a visual countdown (externally initiated, predictable onset-to match the intrinsic predictability of self-initiated stimuli), while EEG was continuously recorded. Reduced N1 amplitudes for self- versus externally initiated tones indicated that self-suppression occurred in the auditory domain. In contrast, the visual N145 component was amplified for self- versus externally initiated pattern reversals. Externally initiated conditions did not differ as a function of their predictability. These findings highlight a difference in sensory processing of self-initiated stimuli across modalities, and may have implications for clinical disorders that are ostensibly associated with abnormal self-suppression. © 2016 Society for Psychophysiological Research.

  5. Tumour-cell apoptosis after cisplatin treatment is not telomere dependent.

    Science.gov (United States)

    Jeyapalan, Jessie C; Saretzki, Gabriele; Leake, Alan; Tilby, Michael J; von Zglinicki, Thomas

    2006-06-01

    Cisplatin is a major chemotherapeutic agent, especially for the treatment of neuroblastoma. Telomeres with their sequence (TTAGGG)n are probable targets for cisplatin intrastrand cross-linking, but the role of telomeres in mediating cisplatin cytotoxicity is not clear. After exposure to cisplatin as single dose or continuous treatment, we found no loss of telomeres in either SHSY5Y neuroblastoma cells (telomere length, approximately 4 kbp), HeLa 229 cells (telomere length, 20 kbp) or in the acute lymphoblastic T cell line 1301 (telomere length, approximately 80 kbp). There was no induction of telomeric single strand breaks, telomeric overhangs were not degraded and telomerase activity was down-regulated only after massive onset of apoptosis. In contrast, cisplatin induced a delayed formation of DNA strand breaks and induced DNA damage foci containing gamma-H2A.X at nontelomeric sites. Interstitial DNA damage appears to be more important than telomere loss or telomeric damage as inducer of the signal pathway towards apoptosis and/or growth arrest in cisplatin-treated tumour cells.

  6. Telomere shortening and survival in free-living corvids

    NARCIS (Netherlands)

    Salomons, H.M.; Mulder, G.A.; Zande, L. van de; Haussmann, M.F.; Linskens, M.H.K.; Verhulst, S.

    2009-01-01

    Evidence accumulates that telomere shortening reflects lifestyle and predicts remaining lifespan, but little is known of telomere dynamics and their relation to survival under natural conditions. We present longitudinal telomere data in free-living jackdaws (Corvus monedula) and test hypotheses on

  7. Telomere Length in Peripheral Blood Leukocytes Is Associated with Severity of Biliary Atresia.

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    Wanvisa Udomsinprasert

    Full Text Available The purpose of this study was to investigate the association of telomere length in peripheral blood leukocytes with the severity of biliary atresia (BA.One hundred and fourteen BA patients and 114 age-matched healthy controls were enrolled. Relative telomere length (RTL was assessed using a quantitative real-time polymerase chain reaction. Multivariate regression analysis was used to estimate RTL as an independent risk factor of BA. Receiver operating characteristic curve analysis was used to calculate the accuracy of biomarkers in the prediction of liver cirrhosis.BA patients had significantly shorter telomeres than healthy controls (p < 0.0001. The RTL in BA patients with jaundice was considerably lower than that of patients without jaundice (p = 0.005. Moreover, RTL was markedly shorter in patients with cirrhosis (F4, as compared to patients with mild fibrosis (F2 and non-fibrosis (F0-F1, p < 0.0001. Logistic regression analysis indicated that short RTL was associated with a higher risk of liver cirrhosis in BA. Tertile analysis showed a dose-response effect for this association (p trend < 0.0001. Additionally, RTL in BA children revealed a negative correlation with age (r = -0.50, p < 0.001. We noted an association between reduction of RTL and liver stiffness scores, adjusted for age and gender (b = -0.01, p < 0.0001. Short RTL can be employed to distinguish cirrhosis patients from non-cirrhosis patients (AUC = 0.78. Further analysis showed a linear correlation between leukocyte RTL and liver RTL in BA patients (r = 0.83, p < 0.001.The findings of this study provide evidence that telomere shortening is associated with an elevated risk of liver cirrhosis in BA.

  8. Mode of ATM-dependent suppression of chromosome translocation

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    Yamauchi, Motohiro, E-mail: motoyama@nagasaki-u.ac.jp [Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Suzuki, Keiji; Oka, Yasuyoshi; Suzuki, Masatoshi; Kondo, Hisayoshi; Yamashita, Shunichi [Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)

    2011-12-09

    Highlights: Black-Right-Pointing-Pointer We addressed how ATM suppresses frequency of chromosome translocation. Black-Right-Pointing-Pointer We found ATM/p53-dependent G1 checkpoint suppresses translocation frequency. Black-Right-Pointing-Pointer We found ATM and DNA-PKcs function in a common pathway to suppress translocation. -- Abstract: It is well documented that deficiency in ataxia telangiectasia mutated (ATM) protein leads to elevated frequency of chromosome translocation, however, it remains poorly understood how ATM suppresses translocation frequency. In the present study, we addressed the mechanism of ATM-dependent suppression of translocation frequency. To know frequency of translocation events in a whole genome at once, we performed centromere/telomere FISH and scored dicentric chromosomes, because dicentric and translocation occur with equal frequency and by identical mechanism. By centromere/telomere FISH analysis, we confirmed that chemical inhibition or RNAi-mediated knockdown of ATM causes 2 to 2.5-fold increase in dicentric frequency at first mitosis after 2 Gy of gamma-irradiation in G0/G1. The FISH analysis revealed that ATM/p53-dependent G1 checkpoint suppresses dicentric frequency, since RNAi-mediated knockdown of p53 elevated dicentric frequency by 1.5-fold. We found ATM also suppresses dicentric occurrence independently of its checkpoint role, as ATM inhibitor showed additional effect on dicentric frequency in the context of p53 depletion and Chk1/2 inactivation. Epistasis analysis using chemical inhibitors revealed that ATM kinase functions in the same pathway that requires kinase activity of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress dicentric frequency. From the results in the present study, we conclude that ATM minimizes translocation frequency through its commitment to G1 checkpoint and DNA double-strand break repair pathway that requires kinase activity of DNA-PKcs.

  9. Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer.

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    Lisa A Boardman

    Full Text Available Colorectal cancer (CRC tumor DNA is characterized by chromosomal damage termed chromosomal instability (CIN and excessively shortened telomeres. Up to 80% of CRC is microsatellite stable (MSS and is historically considered to be chromosomally unstable (CIN+. However, tumor phenotyping depicts some MSS CRC with little or no genetic changes, thus being chromosomally stable (CIN-. MSS CIN- tumors have not been assessed for telomere attrition.MSS rectal cancers from patients ≤50 years old with Stage II (B2 or higher or Stage III disease were assessed for CIN, telomere length and telomere maintenance mechanism (telomerase activation [TA]; alternative lengthening of telomeres [ALT]. Relative telomere length was measured by qPCR in somatic epithelial and cancer DNA. TA was measured with the TRAPeze assay, and tumors were evaluated for the presence of C-circles indicative of ALT. p53 mutation status was assessed in all available samples. DNA copy number changes were evaluated with Spectral Genomics aCGH.Tumors were classified as chromosomally stable (CIN- and chromosomally instable (CIN+ by degree of DNA copy number changes. CIN- tumors (35%; n=6 had fewer copy number changes (<17% of their clones with DNA copy number changes than CIN+ tumors (65%; n=13 which had high levels of copy number changes in 20% to 49% of clones. Telomere lengths were longer in CIN- compared to CIN+ tumors (p=0.0066 and in those in which telomerase was not activated (p=0.004. Tumors exhibiting activation of telomerase had shorter tumor telomeres (p=0.0040; and tended to be CIN+ (p=0.0949.MSS rectal cancer appears to represent a heterogeneous group of tumors that may be categorized both on the basis of CIN status and telomere maintenance mechanism. MSS CIN- rectal cancers appear to have longer telomeres than those of MSS CIN+ rectal cancers and to utilize ALT rather than activation of telomerase.

  10. Genomic instability and telomere fusion of canine osteosarcoma cells.

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    Junko Maeda

    Full Text Available Canine osteosarcoma (OSA is known to present with highly variable and chaotic karyotypes, including hypodiploidy, hyperdiploidy, and increased numbers of metacentric chromosomes. The spectrum of genomic instabilities in canine OSA has significantly augmented the difficulty in clearly defining the biological and clinical significance of the observed cytogenetic abnormalities. In this study, eight canine OSA cell lines were used to investigate telomere fusions by fluorescence in situ hybridization (FISH using a peptide nucleotide acid probe. We characterized each cell line by classical cytogenetic studies and cellular phenotypes including telomere associated factors and then evaluated correlations from this data. All eight canine OSA cell lines displayed increased abnormal metacentric chromosomes and exhibited numerous telomere fusions and interstitial telomeric signals. Also, as evidence of unstable telomeres, colocalization of γ-H2AX and telomere signals in interphase cells was observed. Each cell line was characterized by a combination of data representing cellular doubling time, DNA content, chromosome number, metacentric chromosome frequency, telomere signal level, cellular radiosensitivity, and DNA-PKcs protein expression level. We have also studied primary cultures from 10 spontaneous canine OSAs. Based on the observation of telomere aberrations in those primary cell cultures, we are reasonably certain that our observations in cell lines are not an artifact of prolonged culture. A correlation between telomere fusions and the other characteristics analyzed in our study could not be identified. However, it is important to note that all of the canine OSA samples exhibiting telomere fusion utilized in our study were telomerase positive. Pending further research regarding telomerase negative canine OSA cell lines, our findings may suggest telomere fusions can potentially serve as a novel marker for canine OSA.

  11. Insights into Cdc13 Dependent Telomere Length Regulation

    Energy Technology Data Exchange (ETDEWEB)

    M Mason; E Skordalakes

    2011-12-31

    Cdc13 is a single stranded telomere binding protein that specifically localizes to the telomere ends of budding yeasts and is essential for cell viability. It caps the ends of chromosomes thus preventing chromosome end-to-end fusions and exonucleolytic degradation, events that could lead to genomic instability and senescence, the hallmark of aging. Cdc13 is also involved in telomere length regulation by recruiting or preventing access of telomerase to the telomeric overhang. Recruitment of telomerase to the telomeres for G-strand extension is required for continuous cell division, while preventing its access to the telomeres through capping the chromosome ends prevents mitotic events that could lead to cell immortality, the hall mark of carcinogenesis. Cdc13 and its putative homologues human CTC1 and POT1 are therefore key to many biological processes directly associated with life extension and cancer prevention and can be viewed as an ideal target for cancer and age related therapies.

  12. Telomere shortening impairs regeneration of the olfactory epithelium in response to injury but not under homeostatic conditions.

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    Masami Watabe-Rudolph

    Full Text Available Atrophy of the olfactory epithelium (OE associated with impaired olfaction and dry nose represents one of the most common phenotypes of human aging. Impairment in regeneration of a functional olfactory epithelium can also occur in response to injury due to infection or nasal surgery. These complications occur more frequently in aged patients. Although age is the most unifying risk factor for atrophic changes and functional decline of the olfactory epithelium, little is known about molecular mechanisms that could influence maintenance and repair of the olfactory epithelium. Here, we analyzed the influence of telomere shortening (a basic mechanism of cellular aging on homeostasis and regenerative reserve in response to chemical induced injury of the OE in late generation telomere knockout mice (G3 mTerc(-/- with short telomeres compared to wild type mice (mTerc(+/+ with long telomeres. The study revealed no significant influence of telomere shortening on homeostatic maintenance of the OE during mouse aging. In contrast, the regenerative response to chemical induced injury of the OE was significantly impaired in G3 mTerc(-/- mice compared to mTerc(+/+ mice. Seven days after chemical induced damage, G3 mTerc(-/- mice exhibited significantly enlarged areas of persisting atrophy compared to mTerc(+/+ mice (p = 0.031. Telomere dysfunction was associated with impairments in cell proliferation in the regenerating epithelium. Deletion of the cell cycle inhibitor, Cdkn1a (p21 rescued defects in OE regeneration in telomere dysfunctional mice. Together, these data indicate that telomere shortening impairs the regenerative capacity of the OE by impairing cell cycle progression in a p21-dependent manner. These findings could be relevant for the impairment in OE function in elderly people.

  13. Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration.

    Science.gov (United States)

    Gilbert-Girard, Shella; Gravel, Annie; Artusi, Sara; Richter, Sara N; Wallaschek, Nina; Kaufer, Benedikt B; Flamand, Louis

    2017-07-15

    Human herpesviruses 6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of human chromosomes using a mechanism that remains poorly understood. To achieve a better understanding of the HHV-6A/B integration mechanism, we made use of BRACO-19, a compound that stabilizes G-quadruplex secondary structures and prevents telomere elongation by the telomerase complex. First, we analyzed the folding of telomeric sequences into G-quadruplex structures and their binding to BRACO-19 using G-quadruplex-specific antibodies and surface plasmon resonance. Circular dichroism studies indicate that BRACO-19 modifies the conformation and greatly stabilizes the G-quadruplexes formed in G-rich telomeric DNA. Subsequently we assessed the effects of BRACO-19 on the HHV-6A initial phase of infection. Our results indicate that BRACO-19 does not affect entry of HHV-6A DNA into cells. We next investigated if stabilization of G-quadruplexes by BRACO-19 affected HHV-6A's ability to integrate its genome into host chromosomes. Incubation of telomerase-expressing cells with BRACO-19, such as HeLa and MCF-7, caused a significant reduction in the HHV-6A integration frequency ( P integration frequency in U2OS cells that lack telomerase activity and elongate their telomeres through alternative lengthening mechanisms. Our data suggest that the fluidity of telomeres is important for efficient chromosomal integration of HHV-6A and that interference with telomerase activity negatively affects the generation of cellular clones containing integrated HHV-6A. IMPORTANCE HHV-6A/B can integrate their genomes into the telomeres of infected cells. Telomeres consist of repeated hexanucleotides (TTAGGG) of various lengths (up to several kilobases) and end with a single-stranded 3' extension. To avoid recognition and induce a DNA damage response, the single-stranded overhang folds back on itself and forms a telomeric loop (T-loop) or adopts a tertiary structure, referred to as a G-quadruplex. In the

  14. Dissecting the telomere-inner nuclear membrane interface formed in meiosis.

    Science.gov (United States)

    Pendlebury, Devon F; Fujiwara, Yasuhiro; Tesmer, Valerie M; Smith, Eric M; Shibuya, Hiroki; Watanabe, Yoshinori; Nandakumar, Jayakrishnan

    2017-12-01

    Tethering telomeres to the inner nuclear membrane (INM) allows homologous chromosome pairing during meiosis. The meiosis-specific protein TERB1 binds the telomeric protein TRF1 to establish telomere-INM connectivity and is essential for mouse fertility. Here we solve the structure of the human TRF1-TERB1 interface to reveal the structural basis for telomere-INM linkage. Disruption of this interface abrogates binding and compromises telomere-INM attachment in mice. An embedded CDK-phosphorylation site within the TRF1-binding region of TERB1 provides a mechanism for cap exchange, a late-pachytene phenomenon involving the dissociation of the TRF1-TERB1 complex. Indeed, further strengthening this interaction interferes with cap exchange. Finally, our biochemical analysis implicates distinct complexes for telomere-INM tethering and chromosome-end protection during meiosis. Our studies unravel the structure, stoichiometry, and physiological implications underlying telomere-INM tethering, thereby providing unprecedented insights into the unique function of telomeres in meiosis.

  15. Telomere Length – a New Biomarker in Medicine

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    Agnieszka Kozłowska

    2015-12-01

    Full Text Available A number of xenobiotics in the environment and workplace influences on our health and life. Biomarkers are tools for measuring such exposures and their effects in the organism. Nowadays, telomere length, epigenetic changes, mutations and changes in gene expression pattern have become new molecular biomarkers. Telomeres play the role of molecular clock, which influences on expectancy of cell life and thus aging, the formation of damages, development diseases and carcinogenesis. The telomere length depends on mechanisms of replication and the activity of telomerase. Telomere length is currently used as a biomarker of susceptibility and/or exposure. This paper describes the role of telomere length as a biomarker of aging cells, oxidative stress, a marker of many diseases including cancer, and as a marker of environmental and occupational exposure.

  16. A computational model for telomere-dependent cell-replicative aging.

    Science.gov (United States)

    Portugal, R D; Land, M G P; Svaiter, B F

    2008-01-01

    Telomere shortening provides a molecular basis for the Hayflick limit. Recent data suggest that telomere shortening also influence mitotic rate. We propose a stochastic growth model of this phenomena, assuming that cell division in each time interval is a random process which probability decreases linearly with telomere shortening. Computer simulations of the proposed stochastic telomere-regulated model provides good approximation of the qualitative growth of cultured human mesenchymal stem cells.

  17. Ancestral telomere shortening: a countdown that will increase mean life span?

    Science.gov (United States)

    Hertzog, Radu G

    2006-01-01

    Like cells, all mammals have a limited life span. Among cells there are a few exceptions (e.g., immortal cells), among mammals not, even if some of them live longer. Many in vitro and in vivo studies support the consensus that telomere length is strongly correlated with life span. At the somatic cellular level, long telomeres have been associated with longer life span. A different situation can be seen in immortal cells, such as cancer, germ and stem cells, where telomeres are maintained by telomerase, a specialized reverse transcriptase that is involved in synthesis of telomeres. Irrespective of telomere length, if telomerase is active, telomeres can be maintained at a sufficient length to ensure cell survival. To the contrary, telomeres shorten progressively with each cell division and when a critical telomere length (Hayflick limit) is reached, the cells undergo senescence and subsequently apoptosis. In mammals, those with the longest telomeres (e.g., mice) have the shortest life span. Furthermore, the shorter the mean telomere length, the longer the mean life span, as observed in humans (10-14 kpb) and bowhead-whales (undetermined telomere length), which have the longest mean life span among mammals. Over the past centuries, human average life span has increased. The hypothesis presented here suggests that this continual increase in the mean life span could be due to a decrease of mean telomere length over the last hundreds years. Actually, the life span is not directly influenced by length of telomeres, but rather by telomere length - dependent gene expression pattern. According to Greider, "rather than average telomere length, it is the shortest telomere length that makes the biggest difference to a cell". In the context of fast-growing global elderly population due to increase in life expectancy, it also seem to be an age related increase in cancer incidence. Nevertheless, extending healthy life span could depend on how good cells achieve, during the

  18. Dysfunctional telomeres in human BRCA2 mutated breast tumors and cell lines

    International Nuclear Information System (INIS)

    Bodvarsdottir, Sigridur K.; Steinarsdottir, Margret; Bjarnason, Hordur; Eyfjord, Jorunn E.

    2012-01-01

    In the present study the possible involvement of telomeres in chromosomal instability of breast tumors and cell lines from BRCA2 mutation carriers was examined. Breast tumors from BRCA2 mutation carriers showed significantly higher frequency of chromosome end-to-end fusions (CEFs) than tumors from non-carriers despite normal telomere DNA content. Frequent CEFs were also found in four different BRCA2 heterozygous breast epithelial cell lines, occasionally with telomere signal at the fusion point, indicating telomere capping defects. Extrachromosomal telomeric repeat (ECTR) DNA was frequently found scattered around metaphase chromosomes and interstitial telomere sequences (ITSs) were also common. Telomere sister chromatid exchanges (T-SCEs), characteristic of cells using alternative lengthening of telomeres (ALT), were frequently detected in all heterozygous BRCA2 cell lines as well as the two ALT positive cell lines tested. Even though T-SCE frequency was similar in BRCA2 heterozygous and ALT positive cell lines they differed in single telomere signal loss and ITSs. Chromatid type alterations were more prominent in the BRCA2 heterozygous cell lines that may have propensity for telomere based chromosome healing. Telomere dysfunction-induced foci (TIFs) formation, identified by co-localization of telomeres and γ-H2AX, supported telomere associated DNA damage response in BRCA2 heterozygous cell lines. TIFs were found in interphase nuclei, at chromosome ends, ITSs and ECTR DNA. In conclusion, our results suggest that BRCA2 has an important role in telomere stabilization by repressing CEFs through telomere capping and the prevention of telomere loss by replication stabilization.

  19. Dysfunctional telomeres in human BRCA2 mutated breast tumors and cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Bodvarsdottir, Sigridur K., E-mail: skb@hi.is [Cancer Research Laboratory, BioMedical Centre, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik (Iceland); Steinarsdottir, Margret [Chromosome Laboratory, Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik (Iceland); Bjarnason, Hordur; Eyfjord, Jorunn E. [Cancer Research Laboratory, BioMedical Centre, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik (Iceland)

    2012-01-03

    In the present study the possible involvement of telomeres in chromosomal instability of breast tumors and cell lines from BRCA2 mutation carriers was examined. Breast tumors from BRCA2 mutation carriers showed significantly higher frequency of chromosome end-to-end fusions (CEFs) than tumors from non-carriers despite normal telomere DNA content. Frequent CEFs were also found in four different BRCA2 heterozygous breast epithelial cell lines, occasionally with telomere signal at the fusion point, indicating telomere capping defects. Extrachromosomal telomeric repeat (ECTR) DNA was frequently found scattered around metaphase chromosomes and interstitial telomere sequences (ITSs) were also common. Telomere sister chromatid exchanges (T-SCEs), characteristic of cells using alternative lengthening of telomeres (ALT), were frequently detected in all heterozygous BRCA2 cell lines as well as the two ALT positive cell lines tested. Even though T-SCE frequency was similar in BRCA2 heterozygous and ALT positive cell lines they differed in single telomere signal loss and ITSs. Chromatid type alterations were more prominent in the BRCA2 heterozygous cell lines that may have propensity for telomere based chromosome healing. Telomere dysfunction-induced foci (TIFs) formation, identified by co-localization of telomeres and {gamma}-H2AX, supported telomere associated DNA damage response in BRCA2 heterozygous cell lines. TIFs were found in interphase nuclei, at chromosome ends, ITSs and ECTR DNA. In conclusion, our results suggest that BRCA2 has an important role in telomere stabilization by repressing CEFs through telomere capping and the prevention of telomere loss by replication stabilization.

  20. Molecular recognition in complexes of TRF proteins with telomeric DNA.

    Directory of Open Access Journals (Sweden)

    Miłosz Wieczór

    Full Text Available Telomeres are specialized nucleoprotein assemblies that protect the ends of linear chromosomes. In humans and many other species, telomeres consist of tandem TTAGGG repeats bound by a protein complex known as shelterin that remodels telomeric DNA into a protective loop structure and regulates telomere homeostasis. Shelterin recognizes telomeric repeats through its two major components known as Telomere Repeat-Binding Factors, TRF1 and TRF2. These two homologous proteins are therefore essential for the formation and normal function of telomeres. Indeed, TRF1 and TRF2 are implicated in a plethora of different cellular functions and their depletion leads to telomere dysfunction with chromosomal fusions, followed by apoptotic cell death. More specifically, it was found that TRF1 acts as a negative regulator of telomere length, and TRF2 is involved in stabilizing the loop structure. Consequently, these proteins are of great interest, not only because of their key role in telomere maintenance and stability, but also as potential drug targets. In the current study, we investigated the molecular basis of telomeric sequence recognition by TRF1 and TRF2 and their DNA binding mechanism. We used molecular dynamics (MD to calculate the free energy profiles for binding of TRFs to telomeric DNA. We found that the predicted binding free energies were in good agreement with experimental data. Further, different molecular determinants of binding, such as binding enthalpies and entropies, the hydrogen bonding pattern and changes in surface area, were analyzed to decompose and examine the overall binding free energies at the structural level. With this approach, we were able to draw conclusions regarding the consecutive stages of sequence-specific association, and propose a novel aspartate-dependent mechanism of sequence recognition. Finally, our work demonstrates the applicability of computational MD-based methods to studying protein-DNA interactions.

  1. Stress appraisals and cellular aging: A key role for anticipatory threat in the relationship between psychological stress and telomere length

    Science.gov (United States)

    O’Donovan, Aoife; Tomiyama, A. Janet; Lin, Jue; Puterman, Eli; Adler, Nancy E.; Kemeny, Margaret; Wolkowitz, Owen M.; Blackburn, Elizabeth H.; Epel, Elissa S.

    2012-01-01

    Chronic psychological stressis a risk factor formultiple diseases of aging. Accelerated cellular aging as indexed by short telomere length has emerged as a potential common biological mechanism linking various forms of psychological stress and diseases of aging. Stress appraisals determine the degree and type of biological stress responses and altered stress appraisals may be a common psychological mechanism linking psychological stress and diseases of aging. However, no previous studies have examined the relationship between stress appraisals and telomere length. We exposed chronically stressed female caregivers and non-caregiving controls (N= 50; M age = 62.14±6.10) to a standardized acute laboratory stressor and measured their anticipatory and retrospective threat and challenge appraisals of the stressor. We hypothesized that threat and challenge appraisals would be associated with shorter and longer telomere length respectively, and that chronic care giving stress would influence telomere length through altered stress appraisals. Higher anticipatory threat appraisals were associated with shorter age-adjusted telomere length (β = −.32, p = .03), but challenge appraisals and retrospective threat appraisals showed no independent association with telomere length. Caregivers reported significantly higher anticipatory (β = −.36, p = .006)and retrospective (β = −.29, p = .03) threat appraisals than controls, but similar challenge appraisals. Although there was no significant main effect of caregiver status on telomere length, care giving had a significant indirect effect on telomere length through anticipatory threat appraisals. Exaggerated anticipatory threat appraisals may be a common and modifiable psychological mechanism of psychological stress effects on cellular aging. PMID:22293459

  2. [Telomere lengthening by trichostatin A treatment in cloned pigs].

    Science.gov (United States)

    Xie, Bing-Teng; Ji, Guang-Zhen; Kong, Qing-Ran; Mao, Jian; Shi, Yong-Qian; Liu, Shi-Chao; Wu, Mei-Ling; Wang, Juan; Liu, Lin; Liu, Zhong-Hua

    2012-12-01

    Telomeres are repeated GC rich sequences at the end of chromosomes, and shorten with each cell division due to DNA end replication problem. Previously, reprogrammed somatic cells of cloned animals display variable telomere elongation. However, it was reported that the cloned animals including Dolly do not reset telomeres and show premature aging. In this study, we investigated telomere function in cloned or transgenic cloned pigs, including the cloned Northeast Min pigs, eGFP, Mx, and PGC1α transgenic cloned pigs, and found that the telomere lengths of cloned pigs were significantly shorter than the nuclear donor adult fibroblasts and age-matched noncloned pigs (Pstage for 24 h. Consistent with previous reports, the developmental rate of SCNT embryos to the blastocyst stage was significantly increased compared with those of the control group (16.35% vs. 27.09%, 21.60% vs. 34.90%, Plengthen the telomere lengths of cloned pigs.

  3. Bottom of the heap: having heavier competitors accelerates early-life telomere loss in the European starling, Sturnus vulgaris.

    Directory of Open Access Journals (Sweden)

    Daniel Nettle

    Full Text Available Early-life adversity is associated with poorer health and survival in adulthood in humans and other animals. One pathway by which early-life environmental stressors could affect the adult phenotype is via effects on telomere dynamics. Several studies have shown that early-life adversity is associated with relatively short telomeres, but these are often cross-sectional and usually correlational in design. Here, we present a novel experimental system for studying the relationship between early-life adversity and telomere dynamics using a wild bird, the European starling (Sturnus vulgaris. We used cross-fostering to experimentally assign sibling chicks to either small or large broods for twelve days of the growth period. We measured telomere length in red blood cells using quantitative PCR near the beginning of the experimental manipulation (4 days old, at the end of the experimental manipulation (15 days old, and once the birds were independent (55 days old. Being in a larger brood slowed growth and retarded wing development and the timing of fledging. We found no evidence that overall brood size affected telomere dynamics. However, the greater the number of competitors above the focal bird in the within-brood size hierarchy, the greater was the telomere loss during the period of the experimental manipulation. The number of competitors below the focal in the hierarchy had no effect. The effect of heavier competitors was still evident when we controlled for the weight of the focal bird at the end of the manipulation, suggesting it was not due to retarded growth per se. Moreover, the impact of early competition on telomeres was still evident at independence, suggesting persistence beyond early life. Our study provides experimental support for the hypothesis that social stress, in this case induced by the presence of a greater number of dominant competitors, accelerates the rate of telomere loss.

  4. Social isolation shortens telomeres in African Grey parrots (Psittacus erithacus erithacus.

    Directory of Open Access Journals (Sweden)

    Denise Aydinonat

    Full Text Available Telomeres, the caps of eukaryotic chromosomes, control chromosome stability and cellular senescence, but aging and exposure to chronic stress are suspected to cause attrition of telomere length. We investigated the effect of social isolation on telomere length in the highly social and intelligent African Grey parrot (Psittacus erithacus erithacus. Our study population consisted of single-housed (n = 26 and pair-housed (n = 19 captive individuals between 0.75 to 45 years of age. Relative telomere length of erythrocyte DNA was measured by quantitative real-time PCR. We found that telomere length declined with age (p<0.001, and socially isolated parrots had significantly shorter telomeres compared to pair-housed birds (p<0.001 - even among birds of similar ages. Our findings provide the first evidence that social isolation affects telomere length, which supports the hypothesis that telomeres provide a biomarker indicating exposure to chronic stress.

  5. E-type cyclins modulate telomere integrity in mammalian male meiosis.

    Science.gov (United States)

    Manterola, Marcia; Sicinski, Piotr; Wolgemuth, Debra J

    2016-06-01

    We have shown that E-type cyclins are key regulators of mammalian male meiosis. Depletion of cyclin E2 reduced fertility in male mice due to meiotic defects, involving abnormal pairing and synapsis, unrepaired DNA, and loss of telomere structure. These defects were exacerbated by additional loss of cyclin E1, and complete absence of both E-type cyclins produces a meiotic catastrophe. Here, we investigated the involvement of E-type cyclins in maintaining telomere integrity in male meiosis. Spermatocytes lacking cyclin E2 and one E1 allele (E1+/-E2-/-) displayed a high rate of telomere abnormalities but can progress to pachytene and diplotene stages. We show that their telomeres exhibited an aberrant DNA damage repair response during pachynema and that the shelterin complex proteins TRF2 and RAP2 were significantly decreased in the proximal telomeres. Moreover, the insufficient level of these proteins correlated with an increase of γ-H2AX foci in the affected telomeres and resulted in telomere associations involving TRF1 and telomere detachment in later prophase-I stages. These results suggest that E-type cyclins are key modulators of telomere integrity during meiosis by, at least in part, maintaining the balance of shelterin complex proteins, and uncover a novel role of E-type cyclins in regulating chromosome structure during male meiosis.

  6. Telomere Maintenance Mechanisms in Cancer

    Directory of Open Access Journals (Sweden)

    Tiago Bordeira Gaspar

    2018-05-01

    Full Text Available Tumour cells can adopt telomere maintenance mechanisms (TMMs to avoid telomere shortening, an inevitable process due to successive cell divisions. In most tumour cells, telomere length (TL is maintained by reactivation of telomerase, while a small part acquires immortality through the telomerase-independent alternative lengthening of telomeres (ALT mechanism. In the last years, a great amount of data was generated, and different TMMs were reported and explained in detail, benefiting from genome-scale studies of major importance. In this review, we address seven different TMMs in tumour cells: mutations of the TERT promoter (TERTp, amplification of the genes TERT and TERC, polymorphic variants of the TERT gene and of its promoter, rearrangements of the TERT gene, epigenetic changes, ALT, and non-defined TMM (NDTMM. We gathered information from over fifty thousand patients reported in 288 papers in the last years. This wide data collection enabled us to portray, by organ/system and histotypes, the prevalence of TERTp mutations, TERT and TERC amplifications, and ALT in human tumours. Based on this information, we discuss the putative future clinical impact of the aforementioned mechanisms on the malignant transformation process in different setups, and provide insights for screening, prognosis, and patient management stratification.

  7. Telomere biology in aging and cancer: early history and perspectives.

    Science.gov (United States)

    Hayashi, Makoto T

    2018-01-20

    The ends of eukaryotic linear chromosomes are protected from undesired enzymatic activities by a nucleoprotein complex called the telomere. Expanding evidence indicates that telomeres have central functions in human aging and tumorigenesis. While it is undoubtedly important to follow current advances in telomere biology, it is also fruitful to be well informed in seminal historical studies for a comprehensive understanding of telomere biology, and for the anticipation of future directions. With this in mind, I here summarize the early history of telomere biology and current advances in the field, mostly focusing on mammalian studies relevant to aging and cancer.

  8. Cancer telomeres and white crows.

    Science.gov (United States)

    Meeker, Alan K

    2018-01-01

    This mini-review article discusses past and present prostate-focused research on telomere and telomerase biology conducted at Johns Hopkins, through the eyes of a Donald S Coffey trainee. Included are past discoveries of abnormalities in telomere biology in the context of prostate cancer and its pre-malignant precursor prostatic intraepithelial neoplasia (PIN); the finding that telomerase activity is androgen-regulated in the prostate, and the potential role of telomerase in prostate epithelial stem cells. Also reviewed are more recent results showing that in situ telomere length measurements in patient tissue specimens may have utility in risk assessment and as a prognostic biomarker. Highlighted throughout the article are some of the training and mentorship approaches employed by the late Dr. Coffey, former Director of Urologic Research at the Brady Urological Research Institute, which inspired new research ideas, team science, and discovery.

  9. The Huntington disease locus is most likely within 325 kilobases of the chromosome 4p telomere

    International Nuclear Information System (INIS)

    Doggett, N.A.; Cheng, J.F.; Smith, C.L.; Cantor, C.R.

    1989-01-01

    The genetic defect responsible for Huntington disease was originally localized near the tip of the short arm of chromosome 4 by genetic linkage to the locus D4S10. Several markers closer to Huntington disease have since been isolated, but these all appear to be proximal to the defect. A physical map that extends from the most distal of these loci, D4S90, to the telomere of chromosome 4 was constructed. This map identifies at least two CpG islands as markers for Huntington disease candidate genes and places the most likely location of the Huntington disease defect remarkably close (within 325 kilobases) to the telomere

  10. Mastication suppresses initial gastric emptying by modulating gastric activity.

    Science.gov (United States)

    Ohmure, H; Takada, H; Nagayama, K; Sakiyama, T; Tsubouchi, H; Miyawaki, S

    2012-03-01

    Because various mastication-related factors influence gastric activity, the functional relationship between mastication and gastric function has not been fully elucidated. To investigate the influence of mastication on gastric emptying and motility, we conducted a randomized trial to compare the effects of mastication on gastric emptying and gastric myoelectrical activity under conditions that excluded the influences of food comminution, taste, and olfaction. A (13)C-acetate breath test with electrogastrography and electrocardiography was performed in 14 healthy men who ingested a test meal with or without chewing gum. Autonomic nerve activity was evaluated by fluctuation analysis of heart rate. Gastric emptying was significantly delayed in the 'ingestion with mastication' group. Gastric myoelectrical activity was significantly suppressed during mastication and increased gradually in the post-mastication phase. A decrease in the high-frequency power of heart rate variability was observed coincidentally with gastric myoelectrical activity suppression. These findings suggest that initial gastric emptying is suppressed by mastication, and that the suppression is caused by mastication-induced inhibition of gastric activity (UMIN Clinical Trial Registration no. UMIN000005351).

  11. The molecular genetics of the telomere biology disorders.

    Science.gov (United States)

    Bertuch, Alison A

    2016-08-02

    The importance of telomere function for human health is exemplified by a collection of Mendelian disorders referred to as the telomere biology disorders (TBDs), telomeropathies, or syndromes of telomere shortening. Collectively, the TBDs cover a spectrum of conditions from multisystem disease presenting in infancy to isolated disease presentations in adulthood, most notably idiopathic pulmonary fibrosis. Eleven genes have been found mutated in the TBDs to date, each of which is linked to some aspect of telomere maintenance. This review summarizes the molecular defects that result from mutations in these genes, highlighting recent advances, including the addition of PARN to the TBD gene family and the discovery of heterozygous mutations in RTEL1 as a cause of familial pulmonary fibrosis.

  12. Visual short-term memory load suppresses temporo-parietal junction activity and induces inattentional blindness.

    Science.gov (United States)

    Todd, J Jay; Fougnie, Daryl; Marois, René

    2005-12-01

    The right temporo-parietal junction (TPJ) is critical for stimulus-driven attention and visual awareness. Here we show that as the visual short-term memory (VSTM) load of a task increases, activity in this region is increasingly suppressed. Correspondingly, increasing VSTM load impairs the ability of subjects to consciously detect the presence of a novel, unexpected object in the visual field. These results not only demonstrate that VSTM load suppresses TPJ activity and induces inattentional blindness, but also offer a plausible neural mechanism for this perceptual deficit: suppression of the stimulus-driven attentional network.

  13. Initialization bias suppression in iterative Monte Carlo calculations: benchmarks on criticality calculation

    International Nuclear Information System (INIS)

    Richet, Y.; Jacquet, O.; Bay, X.

    2005-01-01

    The accuracy of an Iterative Monte Carlo calculation requires the convergence of the simulation output process. The present paper deals with a post processing algorithm to suppress the transient due to initialization applied on criticality calculations. It should be noticed that this initial transient suppression aims only at obtaining a stationary output series, then the convergence of the calculation needs to be guaranteed independently. The transient suppression algorithm consists in a repeated truncation of the first observations of the output process. The truncation of the first observations is performed as long as a steadiness test based on Brownian bridge theory is negative. This transient suppression method was previously tuned for a simplified model of criticality calculations, although this paper focuses on the efficiency on real criticality calculations. The efficiency test is based on four benchmarks with strong source convergence problems: 1) a checkerboard storage of fuel assemblies, 2) a pin cell array with irradiated fuel, 3) 3 one-dimensional thick slabs, and 4) an array of interacting fuel spheres. It appears that the transient suppression method needs to be more widely validated on real criticality calculations before any blind using as a post processing in criticality codes

  14. Survival and growth of yeast without telomere capping by Cdc13 in the absence of Sgs1, Exo1, and Rad9.

    Directory of Open Access Journals (Sweden)

    Hien-Ping Ngo

    2010-08-01

    Full Text Available Maintenance of telomere capping is absolutely essential to the survival of eukaryotic cells. Telomere capping proteins, such as Cdc13 and POT1, are essential for the viability of budding yeast and mammalian cells, respectively. Here we identify, for the first time, three genetic modifications that allow budding yeast cells to survive without telomere capping by Cdc13. We found that simultaneous inactivation of Sgs1, Exo1, and Rad9, three DNA damage response (DDR proteins, is sufficient to allow cell division in the absence of Cdc13. Quantitative amplification of ssDNA (QAOS was used to show that the RecQ helicase Sgs1 plays an important role in the resection of uncapped telomeres, especially in the absence of checkpoint protein Rad9. Strikingly, simultaneous deletion of SGS1 and the nuclease EXO1, further reduces resection at uncapped telomeres and together with deletion of RAD9 permits cell survival without CDC13. Pulsed-field gel electrophoresis studies show that cdc13-1 rad9Delta sgs1Delta exo1Delta strains can maintain linear chromosomes despite the absence of telomere capping by Cdc13. However, with continued passage, the telomeres of such strains eventually become short and are maintained by recombination-based mechanisms. Remarkably, cdc13Delta rad9Delta sgs1Delta exo1Delta strains, lacking any Cdc13 gene product, are viable and can grow indefinitely. Our work has uncovered a critical role for RecQ helicases in limiting the division of cells with uncapped telomeres, and this may provide one explanation for increased tumorigenesis in human diseases associated with mutations of RecQ helicases. Our results reveal the plasticity of the telomere cap and indicate that the essential role of telomere capping is to counteract specific aspects of the DDR.

  15. Telomere dynamics in a long-lived bird, the barnacle goose

    Directory of Open Access Journals (Sweden)

    Pauliny Angela

    2012-12-01

    Full Text Available Abstract Background Theories of ageing predict a trade-off between metabolism, reproduction, and maintenance. Species with low investment in early reproduction are thus expected to be able to evolve more efficient maintenance and repair mechanisms, allowing for a longer potential life span (intrinsic longevity. The erosion of telomeres, the protective caps at the ends of linear chromosomes, plays an important role in cellular and organismal senescence, signalling the onset of age-related disease due to accumulation of unrepaired somatic damage. Using extensive longitudinal data from a long-term study of a natural population of barnacle geese Branta leucopsis, we investigated individual rates of telomere length changes over two years in 34 birds between 0 and 22 years of age, covering almost 80% of the species’ lifespan. Results We show that telomeres in this long-lived bird are very well maintained, as theoretically expected, with an average loss rate of only 5 base pairs per year among adults. We thus found no significant relationship between change in telomere length and age. However, telomeres tended to shorten at a faster pace in juveniles compared to adults. For the first time, we demonstrate a faster telomere attrition rate in females compared to males. We found no correlation between telomere loss rate and adult survival or change in body mass. Conclusions Our results add further support for a link between longevity and telomere maintenance, and highlight the complexities of telomere dynamics in natural populations.

  16. Telomeres, Nutrition, and Longevity: Can We Really Navigate Our Aging?

    Science.gov (United States)

    Vidacek, Nikolina Škrobot; Nanic, Lucia; Ravlic, Sanda; Sopta, Mary; Geric, Marko; Gajski, Goran; Garaj-Vrhovac, Vera; Rubelj, Ivica

    2017-12-12

    Telomeres are dynamic chromosome-end structures that serve as guardians of genome stability. They are known to be one of the major determinants of aging and longevity in higher mammals. Studies have demonstrated a direct correlation between telomere length and life expectancy, stress, DNA damage, and onset of aging-related diseases. This review discusses the most important factors that influence our telomeres. Various genetic and environmental factors such as diet, physical activity, obesity, and stress are known to influence health and longevity as well as telomere dynamics. Individuals currently have the opportunity to modulate the dynamics of their aging and health span, monitor these processes, and even make future projections by following their telomere dynamics. As telomeres react to positive as well as negative health factors, we should be able to directly influence our telomere metabolism, slow their deterioration, and diminish our aging and perhaps extend our life and health span. © The Author(s) 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  17. Telomere biology in healthy aging and disease

    NARCIS (Netherlands)

    Oeseburg, Hisko; de Boer, Rudolf A.; van Gilst, Wiek H.; van der Harst, Pim

    Aging is a biological process that affects most cells, organisms and species. Telomeres have been postulated as a universal biological clock that shortens in parallel with aging in cells. Telomeres are located at the end of the chromosomes and consist of an evolutionary conserved repetitive

  18. The longest telomeres: a general signature of adult stem cell compartments

    Science.gov (United States)

    Flores, Ignacio; Canela, Andres; Vera, Elsa; Tejera, Agueda; Cotsarelis, George; Blasco, María A.

    2008-01-01

    Identification of adult stem cells and their location (niches) is of great relevance for regenerative medicine. However, stem cell niches are still poorly defined in most adult tissues. Here, we show that the longest telomeres are a general feature of adult stem cell compartments. Using confocal telomere quantitative fluorescence in situ hybridization (telomapping), we find gradients of telomere length within tissues, with the longest telomeres mapping to the known stem cell compartments. In mouse hair follicles, we show that cells with the longest telomeres map to the known stem cell compartments, colocalize with stem cell markers, and behave as stem cells upon treatment with mitogenic stimuli. Using K15-EGFP reporter mice, which mark hair follicle stem cells, we show that GFP-positive cells have the longest telomeres. The stem cell compartments in small intestine, testis, cornea, and brain of the mouse are also enriched in cells with the longest telomeres. This constitutes the description of a novel general property of adult stem cell compartments. Finally, we make the novel finding that telomeres shorten with age in different mouse stem cell compartments, which parallels a decline in stem cell functionality, suggesting that telomere loss may contribute to stem cell dysfunction with age. PMID:18283121

  19. Acacetin and Chrysin, Two Polyphenolic Compounds, Alleviate Telomeric Position Effect in Human Cells

    Directory of Open Access Journals (Sweden)

    Amina Boussouar

    2013-01-01

    Full Text Available We took advantage of the ability of human telomeres to silence neighboring genes (telomere position effect or TPE to design a high-throughput screening assay for drugs altering telomeres. We identified, for the first time, that two dietary flavones, acacetin and chrysin, are able to specifically alleviate TPE in human cells. We further investigated their influence on telomere integrity and showed that both drugs drastically deprotect telomeres against DNA damage response. However, telomere deprotection triggered by shelterin dysfunction does not affect TPE, indicating that acacetin and chrysin target several functions of telomeres. These results show that TPE-based screening assays represent valuable methods to discover new compounds targeting telomeres.

  20. Multifunctional Role of ATM/Tel1 Kinase in Genome Stability: From the DNA Damage Response to Telomere Maintenance

    Science.gov (United States)

    2014-01-01

    The mammalian protein kinase ataxia telangiectasia mutated (ATM) is a key regulator of the DNA double-strand-break response and belongs to the evolutionary conserved phosphatidylinositol-3-kinase-related protein kinases. ATM deficiency causes ataxia telangiectasia (AT), a genetic disorder that is characterized by premature aging, cerebellar neuropathy, immunodeficiency, and predisposition to cancer. AT cells show defects in the DNA damage-response pathway, cell-cycle control, and telomere maintenance and length regulation. Likewise, in Saccharomyces cerevisiae, haploid strains defective in the TEL1 gene, the ATM ortholog, show chromosomal aberrations and short telomeres. In this review, we outline the complex role of ATM/Tel1 in maintaining genomic stability through its control of numerous aspects of cellular survival. In particular, we describe how ATM/Tel1 participates in the signal transduction pathways elicited by DNA damage and in telomere homeostasis and its importance as a barrier to cancer development. PMID:25247188

  1. Correlating telomere length and radiosensitivity in cancer patients

    International Nuclear Information System (INIS)

    Sprung, C.N.; Davey, D.S.P.; McKay, M.J.

    2003-01-01

    Approximately three percent of cancer patients suffer from significant side effects in normal tissue exposed to ionising radiation during radiotherapy (RT). Although RT is an effective therapy for cancer treatment, the treatment dose intensity is generally restricted to minimize the incidence of these severe reactions. This imposes tumour control limitations on most patients. A major goal of radiation biology research is to develop efficient predictive assays that could identify these hyper-radiosensitive (hRS) individuals prior to treatment. This predictive ability would enable the individualisation of RT doses, which should result in improvement of tumour control rates and a reduction in the incidence of RT side effects. Recent studies have reported a correlation between cellular and organismal RS and shortened telomeres. Interestingly, a number of DNA repair proteins have been found to be associated with telomeres. Additionally, individuals with cancer-proneness and RS syndromes, such as ataxia telangiectasia and Fanconi anemia, have shortened telomeres. In animal models, mutations in DNA repair genes such as Ku, has resulted in shortened telomeres. We have a unique bank of blood samples and lymphoblastoid cell lines (LCLs) from over 50 hRS patients. We have used traditional methods of telomere length assessment and a clinically relevant method, flow cytometry fluorescence in situ hybridisation (flow-FISH) to determine the telomere length in both LCLs and peripheral blood mononuclear cells from the hRS patients. Results from the screening of these samples will be presented. If clinical hRS can be correlated with shortened telomeres in some patients, flow-FISH may have utility as part of a pre-treatment hRS assay for use in the clinic

  2. Ndj1, a telomere-associated protein, regulates centrosome separation in budding yeast meiosis

    Science.gov (United States)

    Li, Ping; Shao, Yize; Jin, Hui

    2015-01-01

    Yeast centrosomes (called spindle pole bodies [SPBs]) remain cohesive for hours during meiotic G2 when recombination takes place. In contrast, SPBs separate within minutes after duplication in vegetative cells. We report here that Ndj1, a previously known meiosis-specific telomere-associated protein, is required for protecting SPB cohesion. Ndj1 localizes to the SPB but dissociates from it ∼16 min before SPB separation. Without Ndj1, meiotic SPBs lost cohesion prematurely, whereas overproduction of Ndj1 delayed SPB separation. When produced ectopically in vegetative cells, Ndj1 caused SPB separation defects and cell lethality. Localization of Ndj1 to the SPB depended on the SUN domain protein Mps3, and removal of the N terminus of Mps3 allowed SPB separation and suppressed the lethality of NDJ1-expressing vegetative cells. Finally, we show that Ndj1 forms oligomeric complexes with Mps3, and that the Polo-like kinase Cdc5 regulates Ndj1 protein stability and SPB separation. These findings reveal the underlying mechanism that coordinates yeast centrosome dynamics with meiotic telomere movement and cell cycle progression. PMID:25897084

  3. A meta-analysis of the relationship between anxiety and telomere length.

    Science.gov (United States)

    Malouff, John M; Schutte, Nicola S

    2017-05-01

    Telomeres are protective caps at the ends of chromosomes, and shorter telomeres are associated with poor physical health. The present study set out to consolidate the varying effect sizes found so far in studies of anxiety and telomere length. A meta-analytic investigation of the relationship between anxiety and telomere length used information from 17 different samples comprising a total of 19,424 participants. The results showed a small but significant association, r = -.06, between higher anxiety and shorter telomeres. Studies comparing individuals diagnosed with an anxiety disorder with other individuals had a significant effect size, and studies that did not use this comparison threshold did not have a significant effect size. Anxiety is associated with an important biomarker related to health. Future experimental studies that examine the impact of interventions intended to reduce anxiety in conjunction with measurement of telomere length can further clarify the impact of anxiety on telomere length.

  4. Caspase-Dependent Apoptosis Induced by Telomere Cleavage and TRF2 Loss

    Directory of Open Access Journals (Sweden)

    Asha S. Multani

    2000-07-01

    Full Text Available Chromosomal abnormalities involving telomeric associations (TAs often precede replicative senescence and abnormal chromosome configurations. We report here that telomere cleavage following exposure to proapoptotic agents is an early event in apoptosis. Exposure of human and murine cancer cells to a variety of pro-apoptotic stimuli (staurosporine, thapsigargin, anti-Fas antibody, cancer chemotherapeutic agents resulted in telomere cleavage and aggregation, finally their extrusion from the nuclei. Telomere loss was associated with arrest of cells in G2/M phase and preceded DNA fragmentation. Telomere erosion and subsequent large-scale chromatin cleavage were inhibited by overexpression of the anti -apoptotic protein, bcl-2, two peptide caspase inhibitors (BACMK and zVADfmk, indicating that both events are regulated by caspase activation. The results demonstrate that telomere cleavage is an early chromatin alteration detected in various cancer cell lines leading to drug-induced apoptosis, suggest that this event contributes to mitotic catastrophe and induction of cell death. Results also suggest that the decrease of telomeric-repeat binding factor 2 (TRF2 may be the earliest event in the ara-C-induced telomere shortening, induction of endoreduplication and chromosomal fragmentation leading to cell death.

  5. Socioeconomic Status, Financial Strain, and Leukocyte Telomere Length in a Sample of African American Midlife Men.

    Science.gov (United States)

    Schrock, Joshua M; Adler, Nancy E; Epel, Elissa S; Nuru-Jeter, Amani M; Lin, Jue; Blackburn, Elizabeth H; Taylor, Robert Joseph; Chae, David H

    2017-06-20

    African American men in the USA experience poorer aging-related health outcomes compared to their White counterparts, partially due to socioeconomic disparities along racial lines. Greater exposure to socioeconomic strains among African American men may adversely impact health and aging at the cellular level, as indexed by shorter leukocyte telomere length (LTL). This study examined associations between socioeconomic factors and LTL among African American men in midlife, a life course stage when heterogeneity in both health and socioeconomic status are particularly pronounced. Using multinomial logistic regression, we examined associations between multiple measures of SES and tertiles of LTL in a sample of 92 African American men between 30 to 50 years of age. Reports of greater financial strain were associated with higher odds of short versus medium LTL (odds ratio (OR)=2.21, p = 0.03). Higher income was associated with lower odds of short versus medium telomeres (OR=0.97, p = 0.04). Exploratory analyses revealed a significant interaction between educational attainment and employment status (χ 2  = 4.07, p = 0.04), with greater education associated with lower odds of short versus long telomeres only among those not employed (OR=0.10, p = 0.040). Cellular aging associated with multiple dimensions of socioeconomic adversity may contribute to poor aging-related health outcomes among African American men. Subjective appraisal of financial difficulty may impact LTL independently of objective dimensions of SES. Self-appraised success in fulfilling traditionally masculine gender roles, including being an economic provider, may be a particularly salient aspect of identity for African American men and have implications for cellular aging in this population.

  6. AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.

    KAUST Repository

    Burla, Romina

    2015-06-25

    Telomeres are nucleoprotein complexes that protect the ends of linear chromosomes from incomplete replication, degradation and detection as DNA breaks. Mammalian telomeres are protected by shelterin, a multiprotein complex that binds the TTAGGG telomeric repeats and recruits a series of additional factors that are essential for telomere function. Although many shelterin-associated proteins have been so far identified, the inventory of shelterin-interacting factors required for telomere maintenance is still largely incomplete. Here, we characterize AKTIP/Ft1 (human AKTIP and mouse Ft1 are orthologous), a novel mammalian shelterin-bound factor identified on the basis of its homology with the Drosophila telomere protein Pendolino. AKTIP/Ft1 shares homology with the E2 variant ubiquitin-conjugating (UEV) enzymes and has been previously implicated in the control of apoptosis and in vesicle trafficking. RNAi-mediated depletion of AKTIP results in formation of telomere dysfunction foci (TIFs). Consistent with these results, AKTIP interacts with telomeric DNA and binds the shelterin components TRF1 and TRF2 both in vivo and in vitro. Analysis of AKTIP- depleted human primary fibroblasts showed that they are defective in PCNA recruiting and arrest in the S phase due to the activation of the intra S checkpoint. Accordingly, AKTIP physically interacts with PCNA and the RPA70 DNA replication factor. Ft1-depleted p53-/- MEFs did not arrest in the S phase but displayed significant increases in multiple telomeric signals (MTS) and sister telomere associations (STAs), two hallmarks of defective telomere replication. In addition, we found an epistatic relation for MST formation between Ft1 and TRF1, which has been previously shown to be required for replication fork progression through telomeric DNA. Ch-IP experiments further suggested that in AKTIP-depleted cells undergoing the S phase, TRF1 is less tightly bound to telomeric DNA than in controls. Thus, our results collectively

  7. AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.

    KAUST Repository

    Burla, Romina; Carcuro, Mariateresa; Raffa, Grazia D; Galati, Alessandra; Raimondo, Domenico; Rizzo, Angela; La Torre, Mattia; Micheli, Emanuela; Ciapponi, Laura; Cenci, Giovanni; Cundari, Enrico; Musio, Antonio; Biroccio, Annamaria; Cacchione, Stefano; Gatti, Maurizio; Saggio, Isabella

    2015-01-01

    Telomeres are nucleoprotein complexes that protect the ends of linear chromosomes from incomplete replication, degradation and detection as DNA breaks. Mammalian telomeres are protected by shelterin, a multiprotein complex that binds the TTAGGG telomeric repeats and recruits a series of additional factors that are essential for telomere function. Although many shelterin-associated proteins have been so far identified, the inventory of shelterin-interacting factors required for telomere maintenance is still largely incomplete. Here, we characterize AKTIP/Ft1 (human AKTIP and mouse Ft1 are orthologous), a novel mammalian shelterin-bound factor identified on the basis of its homology with the Drosophila telomere protein Pendolino. AKTIP/Ft1 shares homology with the E2 variant ubiquitin-conjugating (UEV) enzymes and has been previously implicated in the control of apoptosis and in vesicle trafficking. RNAi-mediated depletion of AKTIP results in formation of telomere dysfunction foci (TIFs). Consistent with these results, AKTIP interacts with telomeric DNA and binds the shelterin components TRF1 and TRF2 both in vivo and in vitro. Analysis of AKTIP- depleted human primary fibroblasts showed that they are defective in PCNA recruiting and arrest in the S phase due to the activation of the intra S checkpoint. Accordingly, AKTIP physically interacts with PCNA and the RPA70 DNA replication factor. Ft1-depleted p53-/- MEFs did not arrest in the S phase but displayed significant increases in multiple telomeric signals (MTS) and sister telomere associations (STAs), two hallmarks of defective telomere replication. In addition, we found an epistatic relation for MST formation between Ft1 and TRF1, which has been previously shown to be required for replication fork progression through telomeric DNA. Ch-IP experiments further suggested that in AKTIP-depleted cells undergoing the S phase, TRF1 is less tightly bound to telomeric DNA than in controls. Thus, our results collectively

  8. Utility of telomere length measurements for age determination of humpback whales

    Directory of Open Access Journals (Sweden)

    Morten Tange Olsen

    2014-12-01

    Full Text Available This study examines the applicability of telomere length measurements by quantitative PCR as a tool for minimally invasive age determination of free-ranging cetaceans. We analysed telomere length in skin samples from 28 North Atlantic humpback whales (Megaptera novaeangliae, ranging from 0 to 26 years of age. The results suggested a significant correlation between telomere length and age in humpback whales. However, telomere length was highly variable among individuals of similar age, suggesting that telomere length measured by quantitative PCR is an imprecise determinant of age in humpback whales. The observed variation in individual telomere length was found to be a function of both experimental and biological variability, with the latter perhaps reflecting patterns of inheritance, resource allocation trade-offs, and stochasticity of the marine environment.

  9. Shot Noise Suppression in a Quantum Point Contact with Short Channel Length

    International Nuclear Information System (INIS)

    Jeong, Heejun

    2015-01-01

    An experimental study on the current shot noise of a quantum point contact with short channel length is reported. The experimentally measured maximum energy level spacing between the ground and the first excited state of the device reached up to 7.5 meV, probably due to the hard wall confinement by using shallow electron gas and sharp point contact geometry. The two-dimensional non-equilibrium shot noise contour map shows noise suppression characteristics in a wide range of bias voltage. Fano factor analysis indicates spin-polarized transport through a short quantum point contact. (paper)

  10. Re: Role of Telomeres and Telomerase in Cancer

    Directory of Open Access Journals (Sweden)

    Shay JW

    2016-03-01

    Full Text Available The most important difference between cancer and normall cells is the ability to continuous proliferation. This activation works due to telomeres and telomerase enzyme. Fifty years ago, Leonard Hayflick discovered that cultured normal humans cells have a limited capacity to divide. Today, this withdrawal from the cell cycle after a certain number of cellular divisions (replicative senescence is known to be triggered as a result of shortened telomeres. Studies on telomeres and telomerase have begun to provide additional information about aging and cancer development and have created new opportunities in the field of regenerative medicine for telomeropathies. Progressive telomere shortening from cell division (replicative aging provides a barrier for tumor progression. Continuous cell growth in malignancy correlates with the reactivation of telomerase. Telomerase is a cellular reverse transcriptase that adds new deoxyribonucleic acid (DNA onto the telomeres that are located at the ends of chromosomes. Telomeres consist of many kilobases of TTAGGG nucleotide repeats. The telomeric nucleotide repeats shorten with each cell division due to replication problems (DNA repair and oxidative damage. Quiescent/senescent state of the cell bypass can be accomplished by abrogating cell cycle checkpoint genes (such as TP53, p16INK4a, pRb. Telomerase is detected in approximately 90% of all malignant tumors. This telomerase activation has emerged as a target for cancer treatment. Telomerase therapeutics are classified as gene therapy (hTERT-telomerase catalytic protein component, hTR-telomerase functional, immunotherapy (Imetalstat-telomerase template antagonist, and small molecule inhibitors. In the near future, more specific researches on telomers and telomerase will contribute to aging/immortality studies (as stem cells and to discover new biomarkers for malignant tissue or anticancer therapeutics.

  11. Tiptoeing to chromosome tips: facts, promises and perils of today's human telomere biology.

    Science.gov (United States)

    Fajkus, J; Simícková, M; Maláska, J

    2002-04-29

    The past decade has witnessed an explosion of knowledge concerning the structure and function of chromosome terminal structures-telomeres. Today's telomere research has advanced from a pure descriptive approach of DNA and protein components to an elementary understanding of telomere metabolism, and now to promising applications in medicine. These applications include 'passive' ones, among which the use of analysis of telomeres and telomerase (a cellular reverse transcriptase that synthesizes telomeres) for cancer diagnostics is the best known. The 'active' applications involve targeted downregulation or upregulation of telomere synthesis, either to mortalize immortal cancer cells, or to rejuvenate mortal somatic cells and tissues for cellular transplantations, respectively. This article reviews the basic data on structure and function of human telomeres and telomerase, as well as both passive and active applications of human telomere biology.

  12. Association of Telomere Length with Breast Cancer Prognostic Factors.

    Directory of Open Access Journals (Sweden)

    Kaoutar Ennour-Idrissi

    Full Text Available Telomere length, a marker of cell aging, seems to be affected by the same factors thought to be associated with breast cancer prognosis.To examine associations of peripheral blood cell-measured telomere length with traditional and potential prognostic factors in breast cancer patients.We conducted a cross-sectional analysis of data collected before surgery from 162 breast cancer patients recruited consecutively between 01/2011 and 05/2012, at a breast cancer reference center. Data on the main lifestyle factors (smoking, alcohol consumption, physical activity were collected using standardized questionnaires. Anthropometric factors were measured. Tumor biological characteristics were extracted from pathology reports. Telomere length was measured using a highly reproducible quantitative PCR method in peripheral white blood cells. Spearman partial rank-order correlations and multivariate general linear models were used to evaluate relationships between telomere length and prognostic factors.Telomere length was positively associated with total physical activity (rs = 0.17, P = 0.033; Ptrend = 0.069, occupational physical activity (rs = 0.15, P = 0.054; Ptrend = 0.054 and transportation-related physical activity (rs = 0.19, P = 0.019; P = 0.005. Among post-menopausal women, telomere length remained positively associated with total physical activity (rs = 0.27, P = 0.016; Ptrend = 0.054 and occupational physical activity (rs = 0.26, P = 0.021; Ptrend = 0.056 and was only associated with transportation-related physical activity among pre-menopausal women (rs = 0.27, P = 0.015; P = 0.004. No association was observed between telomere length and recreational or household activities, other lifestyle factors or traditional prognostic factors.Telomeres are longer in more active breast cancer patients. Since white blood cells are involved in anticancer immune responses, these findings suggest that even regular low-intensity physical activity, such as that

  13. Telomeres and genomic damage repair. Their implication in human pathology

    International Nuclear Information System (INIS)

    Perez, Maria del R.; Dubner, Diana; Michelin, Severino; Gisone, Pablo; Carosella, Edgardo D.

    2002-01-01

    Telomeres, functional complexed that protect eukaryotic chromosome ends, participate in the regulation of cell proliferation and could play a role in the stabilization of genomic regions in response to genotoxic stress. Their significance in human pathology becomes evident in several diseases sharing genomic instability as a common trait, in which alterations of the telomere metabolism have been demonstrated. Many of them are also associated with hypersensitivity to ionizing radiation and cancer susceptibility. Besides the specific proteins belonging to the telomeric complex, other proteins involved in the DNA repair machinery, such as ATM, BRCA1, BRCA2, PARP/tankyrase system, DNA-PK and RAD50-MRE11-NBS1 complexes, are closely related with the telomere. This suggests that the telomere sequesters DNA repair proteins for its own structure maintenance, with could also be released toward damaged sites in the genomic DNA. This communication describes essential aspects of telomere structure and function and their links with homologous recombination, non-homologous end-joining (NHEJ), V(D)J system and mismatch-repair (MMR). Several pathological conditions exhibiting alterations in some of these mechanisms are also considered. The cell response to ionizing radiation and its relationship with the telomeric metabolism is particularly taken into account as a model for studying genotoxicity. (author)

  14. Relationship between leukocyte telomere length and personality traits in healthy subjects.

    Science.gov (United States)

    Sadahiro, R; Suzuki, A; Enokido, M; Matsumoto, Y; Shibuya, N; Kamata, M; Goto, K; Otani, K

    2015-02-01

    It has been shown that certain personality traits are related to mortality and disease morbidity, but the biological mechanism linking them remains unclear. Telomeres are tandem repeat DNA sequences located at the ends of chromosomes, and shorter telomere length is a predictor of mortality and late-life disease morbidity. Thus, it is possible that personality traits influence telomere length. In the present study, we examined the relationship of leukocyte telomere length with personality traits in healthy subjects. The subjects were 209 unrelated healthy Japanese who were recruited from medical students at 4th-5th grade. Assessment of personality traits was performed by the Revised NEO Personality Inventory (NEO-PI-R) and the Temperament and Character Inventory (TCI). Leukocyte relative telomere length was determined by a quantitative real-time PCR method for a ratio of telomere/single copy gene. In the stepwise multiple regression analysis, shorter telomere length was related to lower scores of neuroticism (Ppersonality traits, and this association may be implicated in the relationship between personality traits and mortality. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  15. Getting in (and out of) the loop: regulating higher order telomere structures.

    Science.gov (United States)

    Luke-Glaser, Sarah; Poschke, Heiko; Luke, Brian

    2012-01-01

    The DNA at the ends of linear chromosomes (the telomere) folds back onto itself and forms an intramolecular lariat-like structure. Although the telomere loop has been implicated in the protection of chromosome ends from nuclease-mediated resection and unscheduled DNA repair activities, it potentially poses an obstacle to the DNA replication machinery during S-phase. Therefore, the coordinated regulation of telomere loop formation, maintenance, and resolution is required in order to establish a balance between protecting the chromosome ends and promoting their duplication prior to cell division. Until recently, the only factor known to influence telomere looping in human cells was TRF2, a component of the shelterin complex. Recent work in yeast and mouse cells has uncovered additional regulatory factors that affect the loop structure at telomeres. In the following "perspective" we outline what is known about telomere looping and highlight the latest results regarding the regulation of this chromosome end structure. We speculate about how the manipulation of the telomere loop may have therapeutic implications in terms of diseases associated with telomere dysfunction and uncontrolled proliferation.

  16. Telomere dynamics and cytogenetic changes in human hematologic neoplasias: a working hypothesis.

    Science.gov (United States)

    Ohyashiki, K; Ohyashiki, J H

    1997-03-01

    Chromosome termini, termed telomeres, provide important protection to avoid loss of master gene(s) that may exist at subtelomeric regions. Moreover, erosion of telomeres by cell division through end-replication problems resulted in telomeric-associated cytogenetic aberrations. To maintain a telomere length related to cell immortality, telomerase activity is upregulated in cancer cells, therefore, telomerase is considered to be a new marker of neoplasias. In this paper, we review and make suggestions regarding key aspects of telomere dynamics in both normal hematopoiesis and in malignant hematologic diseases.

  17. Dynamic telomerase gene suppression via network effects of GSK3 inhibition.

    Directory of Open Access Journals (Sweden)

    Alan E Bilsland

    2009-07-01

    Full Text Available Telomerase controls telomere homeostasis and cell immortality and is a promising anti-cancer target, but few small molecule telomerase inhibitors have been developed. Reactivated transcription of the catalytic subunit hTERT in cancer cells controls telomerase expression. Better understanding of upstream pathways is critical for effective anti-telomerase therapeutics and may reveal new targets to inhibit hTERT expression.In a focused promoter screen, several GSK3 inhibitors suppressed hTERT reporter activity. GSK3 inhibition using 6-bromoindirubin-3'-oxime suppressed hTERT expression, telomerase activity and telomere length in several cancer cell lines and growth and hTERT expression in ovarian cancer xenografts. Microarray analysis, network modelling and oligonucleotide binding assays suggested that multiple transcription factors were affected. Extensive remodelling involving Sp1, STAT3, c-Myc, NFkappaB, and p53 occurred at the endogenous hTERT promoter. RNAi screening of the hTERT promoter revealed multiple kinase genes which affect the hTERT promoter, potentially acting through these factors. Prolonged inhibitor treatments caused dynamic expression both of hTERT and of c-Jun, p53, STAT3, AR and c-Myc.Our results indicate that GSK3 activates hTERT expression in cancer cells and contributes to telomere length homeostasis. GSK3 inhibition is a clinical strategy for several chronic diseases. These results imply that it may also be useful in cancer therapy. However, the complex network effects we show here have implications for either setting.

  18. Selaginella moellendoffii telomeres: conserved and unique features in an ancient land plant lineage

    Directory of Open Access Journals (Sweden)

    Eugene V Shakirov

    2012-07-01

    Full Text Available Telomeres, the essential terminal regions of linear eukaryotic chromosomes, consist of G-rich DNA repeats bound by a plethora of associated proteins. While the general pathways of telomere maintenance are evolutionarily conserved, individual telomere complex components show remarkable variation between eukaryotic lineages and even within closely related species. The recent genome sequencing of the lycophyte Selaginella moellendoffii and the availability of an ever-increasing number of flowering plant genomes provides a unique opportunity to evaluate the molecular and functional evolution of telomere components from the early evolving non-seed plants to the more developmentally advanced angiosperms. Here we analyzed telomere sequence in S. moellendorffii and found it to consist of TTTAGGG repeats, typical of most plants. Telomere tracts in S. moellendorffii range from 1-5.5 kb, closely resembling Arabidopsis thaliana. We identified several S. moellendorffii genes encoding sequence homologues of proteins involved in telomere maintenance in other organisms, including CST complex components and the telomere-binding proteins POT1 and TRFL. Notable sequence similarities and differences were uncovered among the telomere-related genes in some of the plant lineages. Taken together, the data indicate that comparative analysis of the telomere complex in early diverging land plants such as S. moellendorffii and green algae will yield important insights into the evolution of telomeres and their protein constituents.

  19. Impaired Telomere Maintenance and Decreased Canonical WNT Signaling but Normal Ribosome Biogenesis in Induced Pluripotent Stem Cells from X-Linked Dyskeratosis Congenita Patients

    OpenAIRE

    Gu, Bai-Wei; Apicella, Marisa; Mills, Jason; Fan, Jian-Meng; Reeves, Dara A.; French, Deborah; Podsakoff, Gregory M.; Bessler, Monica; Mason, Philip J.

    2015-01-01

    Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by the presence of short telomeres at presentation. Mutations in ten different genes, whose products are involved in the telomere maintenance pathway, have been shown to cause DC. The X-linked form is the most common form of the disease and is caused by mutations in the gene DKC1, encoding the protein dyskerin. Dyskerin is required for the assembly and stability of telomerase and is also involved in ribosom...

  20. Mutation mechanisms that underlie turnover of a human telomere-adjacent segmental duplication containing an unstable minisatellite.

    Science.gov (United States)

    Hills, Mark; Jeyapalan, Jennie N; Foxon, Jennifer L; Royle, Nicola J

    2007-04-01

    Subterminal regions, juxtaposed to telomeres on human chromosomes, contain a high density of segmental duplications, but relatively little is known about the evolutionary processes that underlie sequence turnover in these regions. We have characterized a segmental duplication adjacent to the Xp/Yp telomere, each copy containing a hypervariable array of the DXYS14 minisatellite. Both DXYS14 repeat arrays mutate at a high rate (0.3 and 0.2% per gamete) but linkage disequilibrium analysis across 27 SNPs and a direct crossover assay show that recombination during meiosis is suppressed. Therefore instability at DXYS14a and b is dominated by intra-allelic processes or possibly conversion limited to the repeat arrays. Furthermore some chromosomes (14%) carry only one copy of the duplicon, including one DXYS14 repeat array that is also highly mutable (1.2% per gamete). To explain these and other observations, we propose there is another low-rate mutation process that causes copy number change in part or all of the duplicon.

  1. Hybrid ligand-alkylating agents targeting telomeric G-quadruplex structures.

    Science.gov (United States)

    Doria, Filippo; Nadai, Matteo; Folini, Marco; Di Antonio, Marco; Germani, Luca; Percivalle, Claudia; Sissi, Claudia; Zaffaroni, Nadia; Alcaro, Stefano; Artese, Anna; Richter, Sara N; Freccero, Mauro

    2012-04-14

    The synthesis, physico-chemical properties and biological effects of a new class of naphthalene diimides (NDIs) capable of reversibly binding telomeric DNA and alkylate it through an electrophilic quinone methide moiety (QM), are reported. FRET and circular dichroism assays showed a marked stabilization and selectivity towards telomeric G4 DNA folded in a hybrid topology. NDI-QMs' alkylating properties revealed a good reactivity on single nucleosides and selectivity towards telomeric G4. A selected NDI was able to significantly impair the growth of melanoma cells by causing telomere dysfunction and down-regulation of telomerase expression. These findings points to our hybrid ligand-alkylating NDIs as possible tools for the development of novel targeted anticancer therapies. This journal is © The Royal Society of Chemistry 2012

  2. Telomere Length, Proviral Load and Neurologic Impairment in HTLV-1 and HTLV-2-Infected Subjects

    Directory of Open Access Journals (Sweden)

    Benjamin Usadi

    2016-08-01

    Full Text Available Short or damaged telomeres have been implicated in degenerative conditions. We hypothesized that analysis of telomere length (TL in human T-cell lymphotropic virus (HTLV infection and HTLV-associated neuropathy might provide clues to the etiology of HTLV-associated disease and viral dynamics. A subset of 45 human T-cell lymphotropic virus type 1 (HTLV-1, 45 human T-cell lymphotropic virus type 2 (HTLV-2, and 45 seronegative subjects was selected from the larger HTLV Outcomes Study (HOST cohort, matched on age, sex and race/ethnicity. Telomere-to-single-copy gene (T/S ratio (a measure of TL and HTLV-1 and HTLV-2 proviral loads were measured in peripheral blood mononuclear cells (PBMCs using quantitative PCR (qPCR. Vibration sensation measured by tuning fork during neurologic examinations performed as part of the HOST study allowed for an assessment of peripheral neuropathy. TL was compared between groups using t-tests, linear and logistic regression. Mean T/S ratio was 1.02 ± 0.16 in HTLV-1, 1.03 ± 0.17 in HTLV-2 and 0.99 ± 0.18 in HTLV seronegative subjects (p = 0.322. TL was not associated with HTLV-1 or -2 proviral load. Shorter TL was significantly associated with impaired vibration sense in the HTLV-2 positive group only. Overall, we found no evidence that telomere length was affected by chronic HTLV-1 and HTLV-2 infection. That TL was only associated with peripheral neuropathy in the HTLV-2-positive group is intriguing, but should be interpreted cautiously. Studies with larger sample size and telomere length measurement in lymphocyte subsets may clarify the relationship between TL and HTLV-infection.

  3. Getting in (and out of the loop: regulating higher order telomere structures

    Directory of Open Access Journals (Sweden)

    Sarah eLuke-Glaser

    2012-11-01

    Full Text Available The DNA at the ends of linear chromosomes (the telomere folds back onto itself and forms an intramolecular lariat-like structure. Although the telomere loop has been implicated in the protection of chromosome ends from nuclease-mediated resection and unscheduled DNA repair activities, it potentially poses an obstacle to the DNA replication machinery during S phase. Therefore, the coordinated regulation of telomere loop formation, maintenance and resolution is required in order to establish a balance between protecting the chromosome ends and promoting their duplication prior to cell division. Until recently, the only factor know to influence telomere looping in human cells was TRF2, a component of the shelterin complex. Recent work in yeast and mouse cells has uncovered additional regulatory factors that affect the loop structure at telomeres. In the following perspective we will outline what is known about telomere looping and highlight the latest results regarding the regulation of this chromosome end structure. We will speculate about how the manipulation of the telomere loop may have therapeutic implications in terms of diseases associated with telomere dysfunction and uncontrolled proliferation.

  4. Involvement of DNA repair in telomere maintenance and chromosomal instability in human cells

    International Nuclear Information System (INIS)

    Ayouaz, Ali

    2008-01-01

    Telomeres are a major actor of cell immortalization, precursor of a carcinogenesis process. Thus, it appears that the maintenance of telomeres is crucial in the implementation of carcinogenesis process. Due to their structures and under some conditions, telomeres can be assimilated in some respects to chromosomal breakages. Within this perspective, this research thesis aims at determining under which circumstances telomeres can be taken as targets by DNA repair mechanisms. More precisely, the author addressed the respective contributions of two repair mechanisms (the Non-Homologous End-Joining or NHEJ, and Homologous Recombination or HR) in the maintenance of telomere integrity. The author first discusses knowledge related to the interaction between chromosomal extremities and repair mechanisms. Then, he defines the behaviour of these mechanisms with respect to telomeres. He shows that, in absence of recombination mechanisms, the integrity of telomeres is not affected. Finally, he reports the attempt to determine their respective contributions in telomeric homeostasis [fr

  5. Parental care influences leukocyte telomere length with gender specificity in parents and offsprings.

    Science.gov (United States)

    Enokido, Masanori; Suzuki, Akihito; Sadahiro, Ryoichi; Matsumoto, Yoshihiko; Kuwahata, Fumikazu; Takahashi, Nana; Goto, Kaoru; Otani, Koichi

    2014-10-03

    There have been several reports suggesting that adverse childhood experiences such as physical maltreatment and long institutionalization influence telomere length. However, there has been no study examining the relationship of telomere length with variations in parental rearing. In the present study, we examined the relationship of leukocyte telomere length with parental rearing in healthy subjects. The subjects were 581 unrelated healthy Japanese subjects. Perceived parental rearing was assessed by the Parental Bonding Instrument consisting of the care and protection factors. Leukocyte relative telomere length was determined by a quantitative real-time PCR method for a ratio of telomere/single copy gene. In the multiple regression analyses, shorter telomere length in males was related to lower scores of paternal care (β = 0.139, p care (β = 0.195, p parental care and telomere length which covers both lower and higher ends of parental care, and that the effects of parental care on telomere length are gender-specific in parents and offsprings.

  6. Elucidate the Mechanism of Telomere Maintenance in STAG2 Mutated Tumor Cells

    Science.gov (United States)

    2017-12-01

    normal human cells.; Cancer Research; 2017. Nothing to report. Tumor and Stem Cell Biology Loss of Tumor Suppressor STAG2 Promotes Telomere...total G- strand telomeric DNA. Themean telomere lengthwas determinedusing Telometric (Fox Chase Cancer Center). C-circle assay The C-circle assay was...bodies (APB; ref. 36) and partially single- stranded telomeric extrachromosomal (CCCTAA) DNA circles (C-circles; ref. 27), and the absence of telomerase

  7. Television Watching and Telomere Length Among Adults in Southwest China.

    Science.gov (United States)

    Xue, Hong-Mei; Liu, Qian-Qian; Tian, Guo; Quan, Li-Ming; Zhao, Yong; Cheng, Guo

    2017-09-01

    To explore the independent associations of sedentary behavior and physical activity with telomere length among Chinese adults. Data on total time of sedentary behavior, screen-based sedentary behavior (including television watching and computer or phone use), moderate to vigorous physical activity, and dietary intake of 518 adults in Chengdu, Guizhou, and Xiamen in China (54.25% women) aged 20 to 70 years were obtained between 2013 and 2015 through questionnaires. Height, weight, and waist circumference were measured to calculate body mass index and percentage of body fat. Telomere length was measured through Southern blot technique. Television watching was inversely related to adjusted telomere length (-71.75 base pair; SE = 34.40; P  = .04). Furthermore, a similar trend between telomere length and television watching was found in the group aged 20 to 40 years after adjusting for all covariates. Adults aged 20 to 40 years in the highest tertile of daily time spent on watching television had 4.0% shorter telomere length than adults in the lowest tertile (P = .03). Although the association is modest, television watching is inversely related to telomere length among Chinese adults, warranting further investigation in large prospective studies.

  8. Human telomeres are hypersensitive to UV-induced DNA Damage and refractory to repair.

    Directory of Open Access Journals (Sweden)

    Patrick J Rochette

    2010-04-01

    Full Text Available Telomeric repeats preserve genome integrity by stabilizing chromosomes, a function that appears to be important for both cancer and aging. In view of this critical role in genomic integrity, the telomere's own integrity should be of paramount importance to the cell. Ultraviolet light (UV, the preeminent risk factor in skin cancer development, induces mainly cyclobutane pyrimidine dimers (CPD which are both mutagenic and lethal. The human telomeric repeat unit (5'TTAGGG/CCCTAA3' is nearly optimal for acquiring UV-induced CPD, which form at dipyrimidine sites. We developed a ChIP-based technique, immunoprecipitation of DNA damage (IPoD, to simultaneously study DNA damage and repair in the telomere and in the coding regions of p53, 28S rDNA, and mitochondrial DNA. We find that human telomeres in vivo are 7-fold hypersensitive to UV-induced DNA damage. In double-stranded oligonucleotides, this hypersensitivity is a property of both telomeric and non-telomeric repeats; in a series of telomeric repeat oligonucleotides, a phase change conferring UV-sensitivity occurs above 4 repeats. Furthermore, CPD removal in the telomere is almost absent, matching the rate in mitochondria known to lack nucleotide excision repair. Cells containing persistent high levels of telomeric CPDs nevertheless proliferate, and chronic UV irradiation of cells does not accelerate telomere shortening. Telomeres are therefore unique in at least three respects: their biophysical UV sensitivity, their prevention of excision repair, and their tolerance of unrepaired lesions. Utilizing a lesion-tolerance strategy rather than repair would prevent double-strand breaks at closely-opposed excision repair sites on opposite strands of a damage-hypersensitive repeat.

  9. Suppressive oligodeoxynucleotides containing TTAGGG motifs inhibit cGAS activation in human monocytes.

    Science.gov (United States)

    Steinhagen, Folkert; Zillinger, Thomas; Peukert, Konrad; Fox, Mario; Thudium, Marcus; Barchet, Winfried; Putensen, Christian; Klinman, Dennis; Latz, Eicke; Bode, Christian

    2018-04-01

    Type I interferon (IFN) is a critical mediator of autoimmune diseases such as systemic lupus erythematosus (SLE) and Aicardi-Goutières Syndrome (AGS). The recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of type I IFN in response to cytosolic DNA and is potentially linked to SLE and AGS. Suppressive oligodeoxynucleotides (ODN) containing repetitive TTAGGG motifs present in mammalian telomeres have proven useful in the treatment of autoimmune diseases including SLE. In this study, we demonstrate that the suppressive ODN A151 effectively inhibits activation of cGAS in response to cytosolic DNA, thereby inhibiting type I IFN production by human monocytes. In addition, A151 abrogated cGAS activation in response to endogenous accumulation of DNA using TREX1-deficient monocytes. We demonstrate that A151 prevents cGAS activation in a manner that is competitive with DNA. This suppressive activity of A151 was dependent on both telomeric sequence and phosphorothioate backbone. To our knowledge this report presents the first cGAS inhibitor capable of blocking self-DNA. Collectively, these findings might lead to the development of new therapeutics against IFN-driven pathologies due to cGAS activation. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. FTO associations with obesity and telomere length.

    Science.gov (United States)

    Zhou, Yuling; Hambly, Brett D; McLachlan, Craig S

    2017-09-01

    This review examines the biology of the Fat mass- and obesity-associated gene (FTO), and the implications of genetic association of FTO SNPs with obesity and genetic aging. Notably, we focus on the role of FTO in the regulation of methylation status as possible regulators of weight gain and genetic aging. We present a theoretical review of the FTO gene with a particular emphasis on associations with UCP2, AMPK, RBL2, IRX3, CUX1, mTORC1 and hormones involved in hunger regulation. These associations are important for dietary behavior regulation and cellular nutrient sensing via amino acids. We suggest that these pathways may also influence telomere regulation. Telomere length (TL) attrition may be influenced by obesity-related inflammation and oxidative stress, and FTO gene-involved pathways. There is additional emerging evidence to suggest that telomere length and obesity are bi-directionally associated. However, the role of obesity risk-related genotypes and associations with TL are not well understood. The FTO gene may influence pathways implicated in regulation of TL, which could help to explain some of the non-consistent relationship between weight phenotype and telomere length that is observed in population studies investigating obesity.

  11. Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.

    Science.gov (United States)

    Lindqvist, Daniel; Epel, Elissa S; Mellon, Synthia H; Penninx, Brenda W; Révész, Dóra; Verhoeven, Josine E; Reus, Victor I; Lin, Jue; Mahan, Laura; Hough, Christina M; Rosser, Rebecca; Bersani, F Saverio; Blackburn, Elizabeth H; Wolkowitz, Owen M

    2015-08-01

    Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly. Moreover, certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie this association. Shortened LTL reflects a cell's mitotic history and cumulative exposure to inflammation and oxidation as well as the availability of telomerase, a telomere-lengthening enzyme. Critically short telomeres can cause cells to undergo senescence, apoptosis or genomic instability, and shorter LTL correlates with poorer health and predicts mortality. Emerging data suggest that LTL may be reduced in certain psychiatric illnesses, perhaps in proportion to exposure to the psychiatric illnesses, although conflicting data exist. Telomerase has been less well characterized in psychiatric illnesses, but a role in depression and in antidepressant and neurotrophic effects has been suggested by preclinical and clinical studies. In this article, studies on LTL and telomerase activity in psychiatric illnesses are critically reviewed, potential mediators are discussed, and future directions are suggested. A deeper understanding of cellular aging in psychiatric illnesses could lead to re-conceptualizing them as systemic illnesses with manifestations inside and outside the brain and could identify new treatment targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Offspring's Leukocyte Telomere Length, Paternal Age, and Telomere Elongation in Sperm

    DEFF Research Database (Denmark)

    Kimura, Masayuki; Cherkas, Lynn F; Kato, Bernet S

    2008-01-01

    ), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (50 years) donors. Paternal age...... had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice......Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different...

  13. RTEL1 contributes to DNA replication and repair and telomere maintenance

    NARCIS (Netherlands)

    Uringa, Evert-Jan; Lisaingo, Kathleen; Pickett, Hilda A.; Brind'Amour, Julie; Rohde, Jan-Hendrik; Zelensky, Alex; Essers, Jeroen; Lansdorp, Peter M.

    2012-01-01

    Telomere maintenance and DNA repair are important processes that protect the genome against instability. mRtel1, an essential helicase, is a dominant factor setting telomere length in mice. In addition, mRtel1 is involved in DNA double-strand break repair. The role of mRtel1 in telomere maintenance

  14. RTEL1 contributes to DNA replication and repair and telomere maintenance

    NARCIS (Netherlands)

    E.J. Uringa; K. Lisaingo (Kathleen); H.A. Pickett (Hilda); J. Brind'Amour (Julie); J.-H. Rohde (Jan-Hendrik); A. Zelensky (Alexander); J. Essers (Jeroen); P.M. Lansdorp (Peter)

    2012-01-01

    textabstractTelomere maintenance and DNA repair are important processes that protect the genome against instability. mRtel1, an essential helicase, is a dominant factor setting telomere length in mice. In addition, mRtel1 is involved in DNA double-strand break repair. The role of mRtel1 in telomere

  15. Association of Leukocyte Telomere Length with Fatigue in Nondisabled Older Adults

    DEFF Research Database (Denmark)

    Bendix, Laila; Thinggaard, Mikael; Kimura, Masayuki

    2014-01-01

    Introduction. Fatigue is often present in older adults with no identified underlying cause. The accruing burden of oxidative stress and inflammation might be underlying factors of fatigue. We therefore hypothesized that leukocyte telomere length (LTL) is relatively short in older adults who...... experience fatigue. Materials and Methods. We assessed 439 older nondisabled Danish twins. LTL was measured using Southern blots of terminal restriction fragments. Fatigue was measured by the Mob-T Scale based on questions on whether the respondents felt fatigued after performing six mobility items. Results...

  16. Analysis of poly(ADP-Ribose polymerases in Arabidopsis telomere biology.

    Directory of Open Access Journals (Sweden)

    Kara A Boltz

    Full Text Available Maintaining the length of the telomere tract at chromosome ends is a complex process vital to normal cell division. Telomere length is controlled through the action of telomerase as well as a cadre of telomere-associated proteins that facilitate replication of the chromosome end and protect it from eliciting a DNA damage response. In vertebrates, multiple poly(ADP-ribose polymerases (PARPs have been implicated in the regulation of telomere length, telomerase activity and chromosome end protection. Here we investigate the role of PARPs in plant telomere biology. We analyzed Arabidopsis thaliana mutants null for PARP1 and PARP2 as well as plants treated with the PARP competitive inhibitor 3-AB. Plants deficient in PARP were hypersensitive to genotoxic stress, and expression of PARP1 and PARP2 mRNA was elevated in response to MMS or zeocin treatment or by the loss of telomerase. Additionally, PARP1 mRNA was induced in parp2 mutants, and conversely, PARP2 mRNA was induced in parp1 mutants. PARP3 mRNA, by contrast, was elevated in both parp1 and parp2 mutants, but not in seedlings treated with 3-AB or zeocin. PARP mutants and 3-AB treated plants displayed robust telomerase activity, no significant changes in telomere length, and no end-to-end chromosome fusions. Although there remains a possibility that PARPs play a role in Arabidopsis telomere biology, these findings argue that the contribution is a minor one.

  17. Analysis of Poly(ADP-Ribose) Polymerases in Arabidopsis Telomere Biology

    Science.gov (United States)

    Townley, Jennifer M.; Shippen, Dorothy E.

    2014-01-01

    Maintaining the length of the telomere tract at chromosome ends is a complex process vital to normal cell division. Telomere length is controlled through the action of telomerase as well as a cadre of telomere-associated proteins that facilitate replication of the chromosome end and protect it from eliciting a DNA damage response. In vertebrates, multiple poly(ADP-ribose) polymerases (PARPs) have been implicated in the regulation of telomere length, telomerase activity and chromosome end protection. Here we investigate the role of PARPs in plant telomere biology. We analyzed Arabidopsis thaliana mutants null for PARP1 and PARP2 as well as plants treated with the PARP competitive inhibitor 3-AB. Plants deficient in PARP were hypersensitive to genotoxic stress, and expression of PARP1 and PARP2 mRNA was elevated in response to MMS or zeocin treatment or by the loss of telomerase. Additionally, PARP1 mRNA was induced in parp2 mutants, and conversely, PARP2 mRNA was induced in parp1 mutants. PARP3 mRNA, by contrast, was elevated in both parp1 and parp2 mutants, but not in seedlings treated with 3-AB or zeocin. PARP mutants and 3-AB treated plants displayed robust telomerase activity, no significant changes in telomere length, and no end-to-end chromosome fusions. Although there remains a possibility that PARPs play a role in Arabidopsis telomere biology, these findings argue that the contribution is a minor one. PMID:24551184

  18. Telomere length and early severe social deprivation: linking early adversity and cellular aging

    Science.gov (United States)

    Drury, SS; Theall, K; Gleason, MM; Smyke, AT; De Vivo, I; Wong, JYY; Fox, NA; Zeanah, CH; Nelson, CA

    2012-01-01

    Accelerated telomere length attrition has been associated with psychological stress and early adversity in adults; however, no studies have examined whether telomere length in childhood is associated with early experiences. The Bucharest Early Intervention Project is a unique randomized controlled trial of foster care placement compared with continued care in institutions. As a result of the study design, participants were exposed to a quantified range of time in institutional care, and represented an ideal population in which to examine the association between a specific early adversity, institutional care and telomere length. We examined the association between average relative telomere length, telomere repeat copy number to single gene copy number (T/S) ratio and exposure to institutional care quantified as the percent of time at baseline (mean age 22 months) and at 54 months of age that each child lived in the institution. A significant negative correlation between T/S ratio and percentage of time was observed. Children with greater exposure to institutional care had significantly shorter relative telomere length in middle childhood. Gender modified this main effect. The percentage of time in institutional care at baseline significantly predicted telomere length in females, whereas the percentage of institutional care at 54 months was strongly predictive of telomere length in males. This is the first study to demonstrate an association between telomere length and institutionalization, the first study to find an association between adversity and telomere length in children, and contributes to the growing literature linking telomere length and early adversity. PMID:21577215

  19. Telomeres and the ethics of human cloning.

    Science.gov (United States)

    Allhoff, Fritz

    2004-01-01

    In search of a potential problem with cloning, I investigate the phenomenon of telomere shortening which is caused by cell replication; clones created from somatic cells will have shortened telomeres and therefore reach a state of senescence more rapidly. While genetic intervention might fix this problem at some point in the future, I ask whether, absent technological advances, this biological phenomenon undermines the moral permissibility of cloning.

  20. Identification of the functional domains of the telomere protein Rap1 in Schizosaccharomyces pombe.

    Directory of Open Access Journals (Sweden)

    Ikumi Fujita

    Full Text Available The telomere at the end of a linear chromosome plays crucial roles in genome stability. In the fission yeast Schizosaccharomyces pombe, the Rap1 protein, one of the central players at the telomeres, associates with multiple proteins to regulate various telomere functions, such as the maintenance of telomere DNA length, telomere end protection, maintenance of telomere heterochromatin, and telomere clustering in meiosis. The molecular bases of the interactions between Rap1 and its partners, however, remain largely unknown. Here, we describe the identification of the interaction domains of Rap1 with its partners. The Bqt1/Bqt2 complex, which is required for normal meiotic progression, Poz1, which is required for telomere length control, and Taz1, which is required for the recruitment of Rap1 to telomeres, bind to distinct domains in the C-terminal half of Rap1. Intriguingly, analyses of a series of deletion mutants for rap1(+ have revealed that the long N-terminal region (1-456 a.a. [amino acids] of Rap1 (full length: 693 a.a. is not required for telomere DNA length control, telomere end protection, and telomere gene silencing, whereas the C-terminal region (457-693 a.a. containing Poz1- and Taz1-binding domains plays important roles in those functions. Furthermore, the Bqt1/Bqt2- and Taz1-binding domains are essential for normal spore formation after meiosis. Our results suggest that the C-terminal half of Rap1 is critical for the primary telomere functions, whereas the N-terminal region containing the BRCT (BRCA1 C-terminus and Myb domains, which are evolutionally conserved among the Rap1 family proteins, does not play a major role at the telomeres.

  1. Telomere length and fetal programming: A review of recent scientific advances.

    Science.gov (United States)

    Whiteman, Valerie E; Goswami, Anjali; Salihu, Hamisu M

    2017-05-01

    We sought to synthesize a comprehensive literature review comprising recent research linking fetal programming to fetal telomere length. We also explored the potential effects fetal telomere length shortening has on fetal phenotypes. Utilizing the PubMed database as our primary search engine, we retrieved and reviewed 165 articles of published research. The inclusion criteria limited the articles to those that appeared within the last ten years, were pertinent to humans, and without restriction to language of publication. Our results showed that socio-demographic factors like age, sex, genetic inheritance, and acquired disease impact telomere length. Further, we found several maternal characteristics to be associated with fetal telomere length shortening, and these include maternal chemical exposure (eg, tobacco smoke), maternal stress during pregnancy, maternal nutritional and sleeping disorders during pregnancy as well as maternal disease status. Due to paucity of data, our review could not synthesize evidence directly linking fetal phenotypes to telomere length shortening. Although the research summarized in this review shows some association between determinants of intrauterine programming and fetal telomere length, there is still significant work that needs to be done to delineate the direct relationship of telomere attrition with specific fetal phenotypes. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. L-Carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts

    International Nuclear Information System (INIS)

    Shao Lan; Li Qinghuan; Tan Zheng

    2004-01-01

    Telomere is the repetitive DNA sequence at the end of chromosomes, which shortens progressively with cell division and limits the replicative potential of normal human somatic cells. L-Carnosine, a naturally occurring dipeptide, has been reported to delay the replicative senescence, and extend the lifespan of cultured human diploid fibroblasts. In this work, we studied the effect of carnosine on the telomeric DNA of cultured human fetal lung fibroblast cells. Cells continuously grown in 20 mM carnosine exhibited a slower telomere shortening rate and extended lifespan in population doublings. When kept in a long-term nonproliferating state, they accumulated much less damages in the telomeric DNA when cultured in the presence of carnosine. We suggest that the reduction in telomere shortening rate and damages in telomeric DNA made an important contribution to the life-extension effect of carnosine

  3. Childhood adversity, social support, and telomere length among perinatal women.

    Science.gov (United States)

    Mitchell, Amanda M; Kowalsky, Jennifer M; Epel, Elissa S; Lin, Jue; Christian, Lisa M

    2018-01-01

    Adverse perinatal health outcomes are heightened among women with psychosocial risk factors, including childhood adversity and a lack of social support. Biological aging could be one pathway by which such outcomes occur. However, data examining links between psychosocial factors and indicators of biological aging among perinatal women are limited. The current study examined the associations of childhood socioeconomic status (SES), childhood trauma, and current social support with telomere length in peripheral blood mononuclear cells (PBMCs) in a sample of 81 women assessed in early, mid, and late pregnancy as well as 7-11 weeks postpartum. Childhood SES was defined as perceived childhood social class and parental educational attainment. Measures included the Childhood Trauma Questionnaire, Center for Epidemiologic Studies-Depression Scale, Multidimensional Scale of Perceived Social Support, and average telomere length in PBMCs. Per a linear mixed model, telomere length did not change across pregnancy and postpartum visits; thus, subsequent analyses defined telomere length as the average across all available timepoints. ANCOVAs showed group differences by perceived childhood social class, maternal and paternal educational attainment, and current family social support, with lower values corresponding with shorter telomeres, after adjustment for possible confounds. No effects of childhood trauma or social support from significant others or friends on telomere length were observed. Findings demonstrate that while current SES was not related to telomeres, low childhood SES, independent of current SES, and low family social support were distinct risk factors for cellular aging in women. These data have relevance for understanding potential mechanisms by which early life deprivation of socioeconomic and relationship resources affect maternal health. In turn, this has potential significance for intergenerational transmission of telomere length. The predictive value of

  4. Growing old, yet staying young: The role of telomeres in bats' exceptional longevity.

    Science.gov (United States)

    Foley, Nicole M; Hughes, Graham M; Huang, Zixia; Clarke, Michael; Jebb, David; Whelan, Conor V; Petit, Eric J; Touzalin, Frédéric; Farcy, Olivier; Jones, Gareth; Ransome, Roger D; Kacprzyk, Joanna; O'Connell, Mary J; Kerth, Gerald; Rebelo, Hugo; Rodrigues, Luísa; Puechmaille, Sébastien J; Teeling, Emma C

    2018-02-01

    Understanding aging is a grand challenge in biology. Exceptionally long-lived animals have mechanisms that underpin extreme longevity. Telomeres are protective nucleotide repeats on chromosome tips that shorten with cell division, potentially limiting life span. Bats are the longest-lived mammals for their size, but it is unknown whether their telomeres shorten. Using >60 years of cumulative mark-recapture field data, we show that telomeres shorten with age in Rhinolophus ferrumequinum and Miniopterus schreibersii , but not in the bat genus with greatest longevity, Myotis . As in humans, telomerase is not expressed in Myotis myotis blood or fibroblasts. Selection tests on telomere maintenance genes show that ATM and SETX , which repair and prevent DNA damage, potentially mediate telomere dynamics in Myotis bats. Twenty-one telomere maintenance genes are differentially expressed in Myotis , of which 14 are enriched for DNA repair, and 5 for alternative telomere-lengthening mechanisms. We demonstrate how telomeres, telomerase, and DNA repair genes have contributed to the evolution of exceptional longevity in Myotis bats, advancing our understanding of healthy aging.

  5. Telomeres and Telomerase in the Radiation Response: implications for instability, reprogramming, and carcinogenesis

    Directory of Open Access Journals (Sweden)

    Brock James Sishc

    2015-11-01

    Full Text Available Telomeres are nucleoprotein complexes comprised of tandem arrays of repetitive DNA sequence that serve to protect chromosomal termini from inappropriate degradation, as well as to prevent these natural DNA ends from being recognized as broken DNA (double-strand breaks; DSBs and triggering of inappropriate DNA damage responses. Preservation of telomere length requires telomerase, the specialized reverse transcriptase capable of maintaining telomere length via template-mediated addition of telomeric repeats onto the ends of newly synthesized chromosomes. Loss of either end-capping function or telomere length maintenance has been associated with genomic instability or senescence in a variety of settings; therefore telomeres and telomerase have well-established connections to cancer and aging. It has long been recognized that oxidative stress promotes shortening of telomeres, and that telomerase activity is a radiation-inducible function. However, the effects of ionizing radiation (IR exposure on telomeres per se are much less well understood and appreciated. To gain a deeper understanding of the roles telomeres and telomerase play in the response of human cells to ionizing radiations of different qualities, we tracked changes in telomeric end-capping function, telomere length, and telomerase activity in panels of mammary epithelial and hematopoietic cell lines exposed to low linear energy transfer (LET gamma(γ-rays or high LET high charge, high energy (HZE particles, delivered either acutely or at low dose rates (LDR. In addition to demonstrating that dysfunctional telomeres contribute to IR-induced mutation frequencies and genome instability, we reveal non-canonical roles for telomerase, in that telomerase activity was required for IR-induced enrichment of mammary epithelial putative stem/progenitor cell populations, a finding also suggestive of cellular reprogramming. Taken together, the results reported here establish the critical importance of

  6. Organization and evolution of Drosophila terminin: similarities and differences between Drosophila and human telomeres

    Directory of Open Access Journals (Sweden)

    Grazia Daniela Raffa

    2013-05-01

    Full Text Available Drosophila lacks telomerase and fly telomeres are elongated by occasional transposition of three specialized retroelements. Drosophila telomeres do not terminate with GC-rich repeats and are assembled independently of the sequence of chromosome ends. Recent work has shown that Drosophila telomeres are capped by the terminin complex, which includes the fast-evolving proteins HOAP, HipHop, Moi and Ver. These proteins are not conserves outside Drosophilidae and localize and function exclusively at telomeres, protecting them from fusion events. Other proteins required to prevent end-to-end fusion in flies include HP1, Eff/UbcD1, ATM, the components of the Mre11-Rad50-Nbs (MRN complex, and the Woc transcription factor. These proteins do not share the terminin properties; they are evolutionarily conserved non-fast-evolving proteins that do not accumulate only telomeres and do not serve telomere-specific functions. We propose that following telomerase loss, Drosophila rapidly evolved terminin to bind chromosome ends in a sequence-independent manner. This hypothesis suggests that terminin is the functional analog of the shelterin complex that protects human telomeres. The non-terminin proteins are instead likely to correspond to ancestral telomere-associated proteins that did not evolve as rapidly as terminin because of the functional constraints imposed by their involvement in diverse cellular processes. Thus, it appears that the main difference between Drosophila and human telomeres is in the protective complexes that specifically associate with the DNA termini. We believe that Drosophila telomeres offer excellent opportunities for investigations on human telomere biology. The identification of additional Drosophila genes encoding non-terminin proteins involved in telomere protection might lead to the discovery of novel components of human telomeres.

  7. On the interplay of telomeres, nevi and the risk of melanoma.

    Directory of Open Access Journals (Sweden)

    Clara Bodelon

    Full Text Available The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.

  8. Telomere biology: Rationale for diagnostics and therapeutics in cancer.

    Science.gov (United States)

    Rousseau, Philippe; Autexier, Chantal

    2015-01-01

    The key step of carcinogenesis is the malignant transformation which is fundamentally a telomere biology dysfunction permitting cells to bypass the Hayflick limit and to divide indefinitely and uncontrollably. Thus all partners and structures involved in normal and abnormal telomere maintenance, protection and lengthening can be considered as potential anti-cancer therapeutic targets. In this Point of View we discuss, highlight and provide new perspectives from the current knowledge and understanding to position the different aspects of telomere biology and dysfunction as diagnostic, preventive and curative tools in the field of cancer.

  9. Augmented telomerase activity, reduced telomere length and the presence of alternative lengthening of telomere in renal cell carcinoma: plausible predictive and diagnostic markers.

    Science.gov (United States)

    Pal, Deeksha; Sharma, Ujjawal; Khajuria, Ragini; Singh, Shrawan Kumar; Kakkar, Nandita; Prasad, Rajendra

    2015-05-15

    In this study, we analyzed 100 cases of renal cell carcinoma (RCC) for telomerase activity, telomere length and alternative lengthening of telomeres (ALT) using the TRAP assay, TeloTTAGGG assay kit and immunohistochemical analysis of ALT associated promyelocytic leukemia (PML) bodies respectively. A significantly higher (P=0.000) telomerase activity was observed in 81 cases of RCC which was correlated with clinicopathological features of tumor for instance, stage (P=0.008) and grades (P=0.000) but not with the subtypes of RCC (P = 0.355). Notwithstanding, no correlation was found between telomerase activity and subtypes of RCC. Strikingly, the telomere length was found to be significantly shorter in RCC (P=0.000) to that of corresponding normal renal tissues and it is well correlated with grades (P=0.016) but not with stages (P=0.202) and subtypes (P=0.669) of RCC. In this study, telomere length was also negatively correlated with the age of patients (r(2)=0.528; P=0.000) which supports the notion that it could be used as a marker for biological aging. ALT associated PML bodies containing PML protein was found in telomerase negative cases of RCC. It suggests the presence of an ALT pathway mechanism to maintain the telomere length in telomerase negative RCC tissues which was associated with high stages of RCC, suggesting a prevalent mechanism for telomere maintenance in high stages. In conclusion, the telomerase activity and telomere length can be used as a diagnostic as well as a predictive marker in RCC. The prevalence of ALT mechanism in high stages of RCC is warranted for the development of anti-ALT inhibitors along with telomerase inhibitor against RCC as a therapeutic approach. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Ku must load directly onto the chromosome end in order to mediate its telomeric functions.

    Directory of Open Access Journals (Sweden)

    Christopher R Lopez

    2011-08-01

    Full Text Available The Ku heterodimer associates with the Saccharomyces cerevisiae telomere, where it impacts several aspects of telomere structure and function. Although Ku avidly binds DNA ends via a preformed channel, its ability to associate with telomeres via this mechanism could be challenged by factors known to bind directly to the chromosome terminus. This has led to uncertainty as to whether Ku itself binds directly to telomeric ends and whether end association is crucial for Ku's telomeric functions. To address these questions, we constructed DNA end binding-defective Ku heterodimers by altering amino acid residues in Ku70 and Ku80 that were predicted to contact DNA. These mutants continued to associate with their known telomere-related partners, such as Sir4, a factor required for telomeric silencing, and TLC1, the RNA component of telomerase. Despite these interactions, we found that the Ku mutants had markedly reduced association with telomeric chromatin and null-like deficiencies for telomere end protection, length regulation, and silencing functions. In contrast to Ku null strains, the DNA end binding defective Ku mutants resulted in increased, rather than markedly decreased, imprecise end-joining proficiency at an induced double-strand break. This result further supports that it was the specific loss of Ku's telomere end binding that resulted in telomeric defects rather than global loss of Ku's functions. The extensive telomere defects observed in these mutants lead us to propose that Ku is an integral component of the terminal telomeric cap, where it promotes a specific architecture that is central to telomere function and maintenance.

  11. Ku must load directly onto the chromosome end in order to mediate its telomeric functions.

    Science.gov (United States)

    Lopez, Christopher R; Ribes-Zamora, Albert; Indiviglio, Sandra M; Williams, Christopher L; Haricharan, Svasti; Bertuch, Alison A

    2011-08-01

    The Ku heterodimer associates with the Saccharomyces cerevisiae telomere, where it impacts several aspects of telomere structure and function. Although Ku avidly binds DNA ends via a preformed channel, its ability to associate with telomeres via this mechanism could be challenged by factors known to bind directly to the chromosome terminus. This has led to uncertainty as to whether Ku itself binds directly to telomeric ends and whether end association is crucial for Ku's telomeric functions. To address these questions, we constructed DNA end binding-defective Ku heterodimers by altering amino acid residues in Ku70 and Ku80 that were predicted to contact DNA. These mutants continued to associate with their known telomere-related partners, such as Sir4, a factor required for telomeric silencing, and TLC1, the RNA component of telomerase. Despite these interactions, we found that the Ku mutants had markedly reduced association with telomeric chromatin and null-like deficiencies for telomere end protection, length regulation, and silencing functions. In contrast to Ku null strains, the DNA end binding defective Ku mutants resulted in increased, rather than markedly decreased, imprecise end-joining proficiency at an induced double-strand break. This result further supports that it was the specific loss of Ku's telomere end binding that resulted in telomeric defects rather than global loss of Ku's functions. The extensive telomere defects observed in these mutants lead us to propose that Ku is an integral component of the terminal telomeric cap, where it promotes a specific architecture that is central to telomere function and maintenance.

  12. Significantly lengthened telomere in granulosa cells from women with polycystic ovarian syndrome (PCOS).

    Science.gov (United States)

    Wei, Duo; Xie, Juanke; Yin, Baoli; Hao, Haoying; Song, Xiaobing; Liu, Qi; Zhang, Cuilian; Sun, Yingpu

    2017-07-01

    Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women at reproductive age. However, its etiology remains poorly understood. Recent studies indicated that telomere length was related to PCOS. However, the association between telomere length and PCOS has only been shown in leucocytes and remained controversial across different studies. To clarify the association between telomere length and PCOS, the current study interrogated telomere length not only in leucocytes, but also in follicular granulosa cells, which is essential for folliculogenesis and steroidogenesis. Seventy-five patients with PCOS and 81 controls with mechanical infertility undergoing their first in vitro fertilization cycle were enrolled. Their peripheral blood and granulosa cells were collected on the oocyte retrieval day. Telomere length of both leucocytes in the blood and granulosa cells was assayed by quantitative polymerase chain reaction. No significant difference was found in the leucocyte telomere length between controls and PCOS patients (0.99 ± 0.44 vs. 1.00 ± 0.38, p = 0.93). Interestingly, when comparing telomere length in granulosa cells between controls and PCOS subjects, significantly lengthened telomere length was found in PCOS subjects (1.00 ± 0.37 vs. 1.57±0.67, p < 0.0001). After adjustments for age and body mass index, the p value remained significant (p < 0.0001). This finding reinforced the association between telomere abnormalities and PCOS. Given the importance of telomere length in cellular proliferation, our findings provided novel insights into the pathophysiology of PCOS that abnormalities in telomere length possibly disturb folliculogenesis and subsequently result in PCOS.

  13. Yeast hnRNP-related proteins contribute to the maintenance of telomeres

    Energy Technology Data Exchange (ETDEWEB)

    Lee-Soety, Julia Y., E-mail: jlee04@sju.edu [Department of Biology, Saint Joseph' s University, PA 19131 (United States); Jones, Jennifer; MacGibeny, Margaret A.; Remaly, Erin C.; Daniels, Lynsey; Ito, Andrea; Jean, Jessica; Radecki, Hannah; Spencer, Shannon [Department of Biology, Saint Joseph' s University, PA 19131 (United States)

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer Yeast hnRNP-related proteins are able to prevent faster senescence in telomerase-null cells. Black-Right-Pointing-Pointer The conserved RRMs in Npl3 are important for telomere maintenance. Black-Right-Pointing-Pointer Human hnRNP A1 is unable to complement the lack of NPL3 in yeast. Black-Right-Pointing-Pointer Npl3 and Cbc2 may work as telomere capping proteins. -- Abstract: Telomeres protect the ends of linear chromosomes, which if eroded to a critical length can become uncapped and lead to replicative senescence. Telomerase maintains telomere length in some cells, but inappropriate expression facilitates the immortality of cancer cells. Recently, proteins involved in RNA processing and ribosome assembly, such as hnRNP (heterogeneous nuclear ribonucleoprotein) A1, have been found to participate in telomere maintenance in mammals. The Saccharomyces cerevisiae protein Npl3 shares significant amino acid sequence similarities with hnRNP A1. We found that deleting NPL3 accelerated the senescence of telomerase null cells. The highly conserved RNA recognition motifs (RRM) in Npl3 appear to be important for preventing faster senescence. Npl3 preferentially binds telomere sequences in vitro, suggesting that Npl3 may affect telomeres directly. Despite similarities between the two proteins, human hnRNP A1 is unable to complement the lack of Npl3 to rescue accelerated senescence in tlc1 npl3 cells. Deletion of CBC2, which encodes another hnRNP-related protein that associates with Npl3, also accelerates senescence. Potential mechanisms by which hnRNP-related proteins maintain telomeres are discussed.

  14. Telomere Shortening in Neurological Disorders: An Abundance of Unanswered Questions

    OpenAIRE

    Eitan, Erez; Hutchison, Emmette R.; Mattson, Mark P.

    2014-01-01

    Telomeres, ribonucleoprotein complexes that cap eukaryotic chromosomes, typically shorten in leukocytes with aging. Aging is a primary risk factor for neurodegenerative disease (ND), and a common assumption has arisen that leukocyte telomere length (LTL) can serve as a predictor of neurological disease. However, the evidence for shorter LTL in Alzheimer’s and Parkinson’s patients is inconsistent. The diverse causes of telomere shortening may explain variability in LTL between studies and indi...

  15. Telomere Length in Circulating Lymphocytes: Association with Chromosomal Aberrations

    Czech Academy of Sciences Publication Activity Database

    Hemminki, K.; Rachakonda, S.; Musak, L.; Vymetálková, Veronika; Halasová, E.; Forsti,, A.; Vodičková, Ludmila; Buchancová, J.; Vodička, Pavel; Kumar, R.

    2015-01-01

    Roč. 54, č. 3 (2015), s. 194-196 ISSN 1045-2257 Institutional support: RVO:68378041 Keywords : structural chromosome aberrations * healthy subjects * relative telomere length * genotoxicity * telomere biology Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.960, year: 2015

  16. A novel, simple and rapid nondenaturing FISH (ND-FISH) technique for the detection of plant telomeres. Potential used and possible target structures detected.

    Science.gov (United States)

    Cuadrado, Angeles; Golczyk, Hieronim; Jouve, Nicolás

    2009-01-01

    We report a new technique-nondenaturing FISH (ND-FISH)-for the rapid detection of plant telomeres without the need for prior denaturation of the chromosomes. In its development, two modified, synthetic oligonucleotides, 21 nt in length, fluorescently labelled at their 5' and 3' ends and complementary to either the cytidine-rich (C(3)TA(3)) or guanosine-rich (T(3)AG(3)) telomeric DNA strands, were used as probes. The high binding affinity of these probes and the short hybridization time required allows the visualization of plant telomeres in less than an hour. In tests, both probes gave strong signals visualized as double spots at both chromosome ends; this was true of both the mitotic and meiotic chromosomes of barley, wheat, rye, maize, Brachypodium distachyon and Rhoeo spathacea. They were also able to detect telomere motifs at certain intercalary sites in the chromosomes of R. spathacea. To investigate the nature of the target structures detected, the chromosomes were treated with RNase A and single strand-specific nuclease S1 before ND-FISH experiments. Signal formation was resistant to standard enzymatic treatment, but sensitive when much higher enzyme concentrations were used. The results are discussed in relation to current knowledge of telomere structure.

  17. HOT1 is a mammalian direct telomere repeat-binding protein contributing to telomerase recruitment

    NARCIS (Netherlands)

    Kappei, D.; Butter, F.; Benda, C.; Scheibe, M.; Draskovic, Irena; Stevense, M.; Novo, C.L.; Basquin, C.; Araki, M.; Araki, K.; Krastev, D.B.; Kittler, R.; Jessberger, R.; Londono-Vallejo, J.A.; Mann, M.; Buchholz, F.

    2013-01-01

    Telomeres are repetitive DNA structures that, together with the shelterin and the CST complex, protect the ends of chromosomes. Telomere shortening is mitigated in stem and cancer cells through the de novo addition of telomeric repeats by telomerase. Telomere elongation requires the delivery of the

  18. Leukocyte Telomere Length and Serum Levels of High-Molecular-Weight Adiponectin and Dehydroepiandrosterone-Sulfate Could Reflect Distinct Aspects of Longevity in Japanese Centenarians.

    Science.gov (United States)

    Aoki, Yuji; Aoki, Masato; Yamada, Kazuya

    2017-01-01

    Leukocyte telomere length and serum levels of high-molecular-weight adiponectin and dehydroepiandrosterone-sulfate (DHEA-S) were assessed in association with nutrition and performance status (PS) in Japanese centenarians. Twenty-three centenarians (five men, 18 women) were classified according to their PS 1 (nearly fully ambulatory, n = 2), 2 (in bed less than 50% of daytime, n = 10), 3 (in bed greater than 50%, n = 6), and 4 (completely bedridden, n = 5). Leukocyte telomere length was determined by the hybridization protection assay, and the adiponectin and DHEA-S levels were measured by chemiluminescent enzyme immunoassay. Among variables of PS, body mass index (BMI), albumin, adiponectin, DHEA-S, and telomere length, there were significant correlations between PS and albumin ( r = -.694, p r = .522, p r = -.574, p r = .530, p r = -.632, p < .01). It was indicated that the short leukocyte telomere was associated with poor PS and cancer development and that the adiponectin or DHEA-S was associated with adiposity or nutritional status. Despite a small number of subjects, these biomarkers seemed to reflect distinct aspects of longevity in Japanese centenarians.

  19. Compton suppression spectrometry for analysis of short-lived neutron activation products in foods

    International Nuclear Information System (INIS)

    Anderson, D.L.; Cunningham, W.C.

    2008-01-01

    Compton suppression spectrometry was used to analyze foods for elements with short-lived neutron activation products (half-lives of about 2 minutes to 1.5 days). Analysis conditions were optimized to provide quality assurance analyses for iodine in FDA's Total Diet Study. Iodine mass fractions (0.075 to 2.03 mg/kg) were measured in 19 of 42 foods analyzed, with limits of detection (LODs) ranging from 0.03 to 1.4 mg/kg, mostly depending on NaCl content. LODs were lowered by up to a factor of 2 for 16 elements. Suppression factors ranged from about 2 to 8 over the energy range 400 to 3200 keV. (author)

  20. A short leucocyte telomere length is associated with development of insulin resistance

    DEFF Research Database (Denmark)

    Verhulst, Simon; Dalgård, Christine; Labat, Carlos

    2016-01-01

    AIMS/HYPOTHESIS: A number of studies have shown that leucocyte telomere length (LTL) is inversely associated with insulin resistance and type 2 diabetes mellitus. The aim of the present longitudinal cohort study, utilising a twin design, was to assess whether shorter LTL predicts insulin resistance...... and insulin resistance over an average of 12 years were performed in a subset of the Registry consisting of 338 (184 monozygotic and 154 dizygotic) same-sex twin pairs. RESULTS: Age at baseline examination was 37.4 ± 9.6 (mean ± SD) years. Baseline insulin resistance was not associated with age......-dependent changes in LTL (attrition) over the follow-up period, whereas baseline LTL was associated with changes in insulin resistance during this period. The shorter the LTL at baseline, the more pronounced was the increase in insulin resistance over the follow-up period (p 

  1. Large-scale parent-child comparison confirms a strong paternal influence on telomere length.

    Science.gov (United States)

    Nordfjäll, Katarina; Svenson, Ulrika; Norrback, Karl-Fredrik; Adolfsson, Rolf; Roos, Göran

    2010-03-01

    Telomere length is documented to have a hereditary component, and both paternal and X-linked inheritance have been proposed. We investigated blood cell telomere length in 962 individuals with an age range between 0 and 102 years. Telomere length correlations were analyzed between parent-child pairs in different age groups and between grandparent-grandchild pairs. A highly significant correlation between the father's and the child's telomere length was observed (r=0.454, Pfather-son: r=0.465, Pfather-daughter: r=0.484, Pmothers, the correlations were weaker (mother-child: r=0.148, P=0.098; mother-son: r=0.080, P=0.561; mother-daughter: r=0.297, P=0.013). A positive telomere length correlation was also observed for grandparent-grandchild pairs (r=0.272, P=0.013). Our findings indicate that fathers contribute significantly stronger to the telomere length of the offspring compared with mothers (P=0.012), but we cannot exclude a maternal influence on the daughter's telomeres. Interestingly, the father-child correlations diminished with increasing age (P=0.022), suggesting that nonheritable factors have an impact on telomere length dynamics during life.

  2. Nature vs nurture: interplay between the genetic control of telomere length and environmental factors.

    Science.gov (United States)

    Harari, Yaniv; Romano, Gal-Hagit; Ungar, Lior; Kupiec, Martin

    2013-11-15

    Telomeres are nucleoprotein structures that cap the ends of the linear eukaryotic chromosomes, thus protecting their stability and integrity. They play important roles in DNA replication and repair and are central to our understanding of aging and cancer development. In rapidly dividing cells, telomere length is maintained by the activity of telomerase. About 400 TLM (telomere length maintenance) genes have been identified in yeast, as participants of an intricate homeostasis network that keeps telomere length constant. Two papers have recently shown that despite this extremely complex control, telomere length can be manipulated by external stimuli. These results have profound implications for our understanding of cellular homeostatic systems in general and of telomere length maintenance in particular. In addition, they point to the possibility of developing aging and cancer therapies based on telomere length manipulation.

  3. Gender and telomere length: Systematic review and meta-analysis☆

    Science.gov (United States)

    Gardner, Michael; Bann, David; Wiley, Laura; Cooper, Rachel; Hardy, Rebecca; Nitsch, Dorothea; Martin-Ruiz, Carmen; Shiels, Paul; Sayer, Avan Aihie; Barbieri, Michelangela; Bekaert, Sofie; Bischoff, Claus; Brooks-Wilson, Angela; Chen, Wei; Cooper, Cyrus; Christensen, Kaare; De Meyer, Tim; Deary, Ian; Der, Geoff; Roux, Ana Diez; Fitzpatrick, Annette; Hajat, Anjum; Halaschek-Wiener, Julius; Harris, Sarah; Hunt, Steven C.; Jagger, Carol; Jeon, Hyo-Sung; Kaplan, Robert; Kimura, Masayuki; Lansdorp, Peter; Li, Changyong; Maeda, Toyoki; Mangino, Massimo; Nawrot, Tim S.; Nilsson, Peter; Nordfjall, Katarina; Paolisso, Giuseppe; Ren, Fu; Riabowol, Karl; Robertson, Tony; Roos, Goran; Staessen, Jan A.; Spector, Tim; Tang, Nelson; Unryn, Brad; van der Harst, Pim; Woo, Jean; Xing, Chao; Yadegarfar, Mohammad E.; Park, Jae Yong; Young, Neal; Kuh, Diana; von Zglinicki, Thomas; Ben-Shlomo, Yoav

    2015-01-01

    Background It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. Methods We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression. Results Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p = 1.00) or cell type (p = 0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error. Conclusions Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required. PMID:24365661

  4. Cardiac telomere length in heart development, function, and disease.

    Science.gov (United States)

    Booth, S A; Charchar, F J

    2017-07-01

    Telomeres are repetitive nucleoprotein structures at chromosome ends, and a decrease in the number of these repeats, known as a reduction in telomere length (TL), triggers cellular senescence and apoptosis. Heart disease, the worldwide leading cause of death, often results from the loss of cardiac cells, which could be explained by decreases in TL. Due to the cell-specific regulation of TL, this review focuses on studies that have measured telomeres in heart cells and critically assesses the relationship between cardiac TL and heart function. There are several lines of evidence that have identified rapid changes in cardiac TL during the onset and progression of heart disease as well as at critical stages of development. There are also many factors, such as the loss of telomeric proteins, oxidative stress, and hypoxia, that decrease cardiac TL and heart function. In contrast, antioxidants, calorie restriction, and exercise can prevent both cardiac telomere attrition and the progression of heart disease. TL in the heart is also indicative of proliferative potential and could facilitate the identification of cells suitable for cardiac rejuvenation. Although these findings highlight the involvement of TL in heart function, there are important questions regarding the validity of animal models, as well as several confounding factors, that need to be considered when interpreting results and planning future research. With these in mind, elucidating the telomeric mechanisms involved in heart development and the transition to disease holds promise to prevent cardiac dysfunction and potentiate regeneration after injury. Copyright © 2017 the American Physiological Society.

  5. Telomere-independent functions of telomerase in nuclei, cytoplasm, and mitochondria

    Energy Technology Data Exchange (ETDEWEB)

    Chiodi, Ilaria; Mondello, Chiara, E-mail: mondello@igm.cnr.it [Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia (Italy)

    2012-09-28

    Telomerase canonical activity at telomeres prevents telomere shortening, allowing chromosome stability and cellular proliferation. To perform this task, the catalytic subunit (telomerase reverse transcriptase, TERT) of the enzyme works as a reverse transcriptase together with the telomerase RNA component (TERC), adding telomeric repeats to DNA molecule ends. Growing evidence indicates that, besides the telomeric-DNA synthesis activity, TERT has additional functions in tumor development and is involved in many different biological processes, among which cellular proliferation, gene expression regulation, and mitochondrial functionality. TERT has been shown to act independently of TERC in the Wnt-β-catenin signaling pathway, regulating the expression of Wnt target genes, which play a role in development and tumorigenesis. Moreover, TERT RNA-dependent RNA polymerase activity has been found, leading to the genesis of double-stranded RNAs that act as precursor of silencing RNAs. In mitochondria, a TERT TERC-independent reverse transcriptase activity has been described that could play a role in the protection of mitochondrial integrity. In this review, we will discuss some of the extra-telomeric functions of telomerase.

  6. Telomere length and age in humpback whales (Megaptera novaeangliae)

    NARCIS (Netherlands)

    Olsen, Morten Tange; Bérubé, Martine; Robbins, Jooke; Rew, Mary Beth; Palsboll, Per

    2009-01-01

    Telomeres are DNA sequences situated at the end of chromosomes that play a key role in maintaining chromosome integrity and are crucial for normal cell function. In vertebrates, telomeres tend to shorten with age, ultimately reaching a threshold believed to trigger cellular and organismal

  7. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence.

    Directory of Open Access Journals (Sweden)

    João F Passos

    2007-05-01

    Full Text Available Aging is an inherently stochastic process, and its hallmark is heterogeneity between organisms, cell types, and clonal populations, even in identical environments. The replicative lifespan of primary human cells is telomere dependent; however, its heterogeneity is not understood. We show that mitochondrial superoxide production increases with replicative age in human fibroblasts despite an adaptive UCP-2-dependent mitochondrial uncoupling. This mitochondrial dysfunction is accompanied by compromised [Ca(2+]i homeostasis and other indicators of a retrograde response in senescent cells. Replicative senescence of human fibroblasts is delayed by mild mitochondrial uncoupling. Uncoupling reduces mitochondrial superoxide generation, slows down telomere shortening, and delays formation of telomeric gamma-H2A.X foci. This indicates mitochondrial production of reactive oxygen species (ROS as one of the causes of replicative senescence. By sorting early senescent (SES cells from young proliferating fibroblast cultures, we show that SES cells have higher ROS levels, dysfunctional mitochondria, shorter telomeres, and telomeric gamma-H2A.X foci. We propose that mitochondrial ROS is a major determinant of telomere-dependent senescence at the single-cell level that is responsible for cell-to-cell variation in replicative lifespan.

  8. Regulation of Telomere Homeostasis during Epstein-Barr virus Infection and Immortalization.

    Science.gov (United States)

    Kamranvar, Siamak A; Masucci, Maria G

    2017-08-09

    The acquisition of unlimited proliferative potential is dependent on the activation of mechanisms for telomere maintenance, which counteracts telomere shortening and the consequent triggering of the DNA damage response, cell cycle arrest, and apoptosis. The capacity of Epstein Barr virus (EBV) to infect B-lymphocytes in vitro and transform the infected cells into autonomously proliferating immortal cell lines underlies the association of this human gamma-herpesvirus with a broad variety of lymphoid and epithelial cell malignancies. Current evidence suggests that both telomerase-dependent and -independent pathways of telomere elongation are activated in the infected cells during the early and late phases of virus-induced immortalization. Here we review the interaction of EBV with different components of the telomere maintenance machinery and the mechanisms by which the virus regulates telomere homeostasis in proliferating cells. We also discuss how these viral strategies may contribute to malignant transformation.

  9. 10 Hz Amplitude Modulated Sounds Induce Short-Term Tinnitus Suppression

    Directory of Open Access Journals (Sweden)

    Patrick Neff

    2017-05-01

    Full Text Available Objectives: Acoustic stimulation or sound therapy is proposed as a main treatment option for chronic subjective tinnitus. To further probe the field of acoustic stimulations for tinnitus therapy, this exploratory study compared 10 Hz amplitude modulated (AM sounds (two pure tones, noise, music, and frequency modulated (FM sounds and unmodulated sounds (pure tone, noise regarding their temporary suppression of tinnitus loudness. First, it was hypothesized that modulated sounds elicit larger temporary loudness suppression (residual inhibition than unmodulated sounds. Second, with manipulation of stimulus loudness and duration of the modulated sounds weaker or stronger effects of loudness suppression were expected, respectively.Methods: We recruited 29 participants with chronic tonal tinnitus from the multidisciplinary Tinnitus Clinic of the University of Regensburg. Participants underwent audiometric, psychometric and tinnitus pitch matching assessments followed by an acoustic stimulation experiment with a tinnitus loudness growth paradigm. In a first block participants were stimulated with all of the sounds for 3 min each and rated their subjective tinnitus loudness to the pre-stimulus loudness every 30 s after stimulus offset. The same procedure was deployed in the second block with the pure tone AM stimuli matched to the tinnitus frequency, manipulated in length (6 min, and loudness (reduced by 30 dB and linear fade out. Repeated measures mixed model analyses of variance (ANOVA were calculated to assess differences in loudness growth between the stimuli for each block separately.Results: First, we found that all sounds elicit a short-term suppression of tinnitus loudness (seconds to minutes with strongest suppression right after stimulus offset [F(6, 1331 = 3.74, p < 0.01]. Second, similar to previous findings we found that AM sounds near the tinnitus frequency produce significantly stronger tinnitus loudness suppression than noise [vs. Pink

  10. Impaired Telomere Maintenance and Decreased Canonical WNT Signaling but Normal Ribosome Biogenesis in Induced Pluripotent Stem Cells from X-Linked Dyskeratosis Congenita Patients.

    Directory of Open Access Journals (Sweden)

    Bai-Wei Gu

    Full Text Available Dyskeratosis congenita (DC is an inherited bone marrow failure syndrome characterized by the presence of short telomeres at presentation. Mutations in ten different genes, whose products are involved in the telomere maintenance pathway, have been shown to cause DC. The X-linked form is the most common form of the disease and is caused by mutations in the gene DKC1, encoding the protein dyskerin. Dyskerin is required for the assembly and stability of telomerase and is also involved in ribosomal RNA (rRNA processing where it converts specific uridines to pseudouridine. DC is thought to result from failure to maintain tissues, like blood, that are renewed by stem cell activity, but research into pathogenic mechanisms has been hampered by the difficulty of obtaining stem cells from patients. We reasoned that induced pluripotent stem (iPS cells from X-linked DC patients may provide information about the mechanisms involved. Here we describe the production of iPS cells from DC patients with DKC1 mutations Q31E, A353V and ΔL37. In addition we constructed "corrected" lines with a copy of the wild type dyskerin cDNA expressed from the AAVS1 safe harbor locus. We show that in iPS cells with DKC1 mutations telomere maintenance is compromised with short telomere lengths and decreased telomerase activity. The degree to which telomere lengths are affected by expression of telomerase during reprograming, or with ectopic expression of wild type dyskerin, is variable. The recurrent mutation A353V shows the most severe effect on telomere maintenance. A353V cells but not Q31E or ΔL37 cells, are refractory to correction by expression of wild type DKC1 cDNA. Because dyskerin is involved in both telomere maintenance and ribosome biogenesis it has been postulated that defective ribosome biogenesis and translation may contribute to the disease phenotype. Evidence from mouse and zebra fish models has supported the involvement of ribosome biogenesis but primary cells

  11. Impaired Telomere Maintenance and Decreased Canonical WNT Signaling but Normal Ribosome Biogenesis in Induced Pluripotent Stem Cells from X-Linked Dyskeratosis Congenita Patients.

    Science.gov (United States)

    Gu, Bai-Wei; Apicella, Marisa; Mills, Jason; Fan, Jian-Meng; Reeves, Dara A; French, Deborah; Podsakoff, Gregory M; Bessler, Monica; Mason, Philip J

    2015-01-01

    Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by the presence of short telomeres at presentation. Mutations in ten different genes, whose products are involved in the telomere maintenance pathway, have been shown to cause DC. The X-linked form is the most common form of the disease and is caused by mutations in the gene DKC1, encoding the protein dyskerin. Dyskerin is required for the assembly and stability of telomerase and is also involved in ribosomal RNA (rRNA) processing where it converts specific uridines to pseudouridine. DC is thought to result from failure to maintain tissues, like blood, that are renewed by stem cell activity, but research into pathogenic mechanisms has been hampered by the difficulty of obtaining stem cells from patients. We reasoned that induced pluripotent stem (iPS) cells from X-linked DC patients may provide information about the mechanisms involved. Here we describe the production of iPS cells from DC patients with DKC1 mutations Q31E, A353V and ΔL37. In addition we constructed "corrected" lines with a copy of the wild type dyskerin cDNA expressed from the AAVS1 safe harbor locus. We show that in iPS cells with DKC1 mutations telomere maintenance is compromised with short telomere lengths and decreased telomerase activity. The degree to which telomere lengths are affected by expression of telomerase during reprograming, or with ectopic expression of wild type dyskerin, is variable. The recurrent mutation A353V shows the most severe effect on telomere maintenance. A353V cells but not Q31E or ΔL37 cells, are refractory to correction by expression of wild type DKC1 cDNA. Because dyskerin is involved in both telomere maintenance and ribosome biogenesis it has been postulated that defective ribosome biogenesis and translation may contribute to the disease phenotype. Evidence from mouse and zebra fish models has supported the involvement of ribosome biogenesis but primary cells from human

  12. The Effect of Physical Activity agains the Telomere Length in the Leukocytes Cells of KONI Athletes

    Directory of Open Access Journals (Sweden)

    Endang Purwaningsih

    2017-07-01

    Full Text Available Telomeres are strands of non coding DNA at the ends of chromosomes that have the primary function to protect DNA from damage and maintain chromosomal stability. Physical exercise will increase the antioxidant activity can increase telomere proteins, lengthen telomeres and or protein networks associated with telomere so that the telomere remains long, or stopping telomere shortening. Telomere length was also associated with age. The purpose of the research was to determine telomere length of leukocyte cells in the KONI (Indonesian National Sports Committee athletes in Jakarta. The research method is descriptive, by measuring telomere length using quantitative PCR on leukocyte cells. Samples are KONI athletes from several sports, including men and women athletes, with ages between 15-20 years. Used a control group (not athletes is students of the Faculty of Medicine, University of YARSI. The results showed that there was no significant difference (p> 0.05 between telomere length group of athletes with the control group in both sexes. Similarly, telomere length between athlete male with female athletes also showed no significant difference (p> 0.05. It was concluded that physical exercise in athletes KONI at the age of 15- 20 years had no effect on telomere length in leukocytes. The results of this study provide information about the telomere length in Indonesian athletes at an early age.

  13. Age, sex, and telomere dynamics in a long-lived seabird with male-biased parental care.

    Directory of Open Access Journals (Sweden)

    Rebecca C Young

    Full Text Available The examination of telomere dynamics is a recent technique in ecology for assessing physiological state and age-related traits from individuals of unknown age. Telomeres shorten with age in most species and are expected to reflect physiological state, reproductive investment, and chronological age. Loss of telomere length is used as an indicator of biological aging, as this detrimental deterioration is associated with lowered survival. Lifespan dimorphism and more rapid senescence in the larger, shorter-lived sex are predicted in species with sexual size dimorphism, however, little is known about the effects of behavioral dimorphism on senescence and life history traits in species with sexual monomorphism. Here we compare telomere dynamics of thick-billed murres (Urialomvia, a species with male-biased parental care, in two ways: 1 cross-sectionally in birds of known-age (0-28 years from one colony and 2 longitudinally in birds from four colonies. Telomere dynamics are compared using three measures: the telomere restriction fragment (TRF, a lower window of TRF (TOE, and qPCR. All showed age-related shortening of telomeres, but the TRF measure also indicated that adult female murres have shorter telomere length than adult males, consistent with sex-specific patterns of ageing. Adult males had longer telomeres than adult females on all colonies examined, but chick telomere length did not differ by sex. Additionally, inter-annual telomere changes may be related to environmental conditions; birds from a potentially low quality colony lost telomeres, while those at more hospitable colonies maintained telomere length. We conclude that sex-specific patterns of telomere loss exist in the sexually monomorphic thick-billed murre but are likely to occur between fledging and recruitment. Longer telomeres in males may be related to their homogamous sex chromosomes (ZZ or to selection for longer life in the care-giving sex. Environmental conditions appeared to

  14. NEIL3 Repairs Telomere Damage during S Phase to Secure Chromosome Segregation at Mitosis

    Directory of Open Access Journals (Sweden)

    Jia Zhou

    2017-08-01

    Full Text Available Oxidative damage to telomere DNA compromises telomere integrity. We recently reported that the DNA glycosylase NEIL3 preferentially repairs oxidative lesions in telomere sequences in vitro. Here, we show that loss of NEIL3 causes anaphase DNA bridging because of telomere dysfunction. NEIL3 expression increases during S phase and reaches maximal levels in late S/G2. NEIL3 co-localizes with TRF2 and associates with telomeres during S phase, and this association increases upon oxidative stress. Mechanistic studies reveal that NEIL3 binds to single-stranded DNA via its intrinsically disordered C terminus in a telomere-sequence-independent manner. Moreover, NEIL3 is recruited to telomeres through its interaction with TRF1, and this interaction enhances the enzymatic activity of purified NEIL3. Finally, we show that NEIL3 interacts with AP Endonuclease 1 (APE1 and the long-patch base excision repair proteins PCNA and FEN1. Taken together, we propose that NEIL3 protects genome stability through targeted repair of oxidative damage in telomeres during S/G2 phase.

  15. Short wavelength limits of current shot noise suppression

    International Nuclear Information System (INIS)

    Nause, Ariel; Dyunin, Egor; Gover, Avraham

    2014-01-01

    Shot noise in electron beam was assumed to be one of the features beyond control of accelerator physics. Current results attained in experiments at Accelerator Test Facility in Brookhaven and Linac Coherent Light Source in Stanford suggest that the control of the shot noise in electron beam (and therefore of spontaneous radiation and Self Amplified Spontaneous Emission of Free Electron Lasers) is feasible at least in the visible range of the spectrum. Here, we present a general linear formulation for collective micro-dynamics of e-beam noise and its control. Specifically, we compare two schemes for current noise suppression: a quarter plasma wavelength drift section and a combined drift/dispersive (transverse magnetic field) section. We examine and compare their limits of applicability at short wavelengths via considerations of electron phase-spread and the related Landau damping effect

  16. Short wavelength limits of current shot noise suppression

    Energy Technology Data Exchange (ETDEWEB)

    Nause, Ariel, E-mail: arielnau@post.tau.ac.il [Faculty of Exact Sciences, Department of Physics, Tel Aviv University, Tel Aviv (Israel); Dyunin, Egor; Gover, Avraham [Faculty of Engineering, Department of Physical Electronics, Tel Aviv University, Tel Aviv (Israel)

    2014-08-15

    Shot noise in electron beam was assumed to be one of the features beyond control of accelerator physics. Current results attained in experiments at Accelerator Test Facility in Brookhaven and Linac Coherent Light Source in Stanford suggest that the control of the shot noise in electron beam (and therefore of spontaneous radiation and Self Amplified Spontaneous Emission of Free Electron Lasers) is feasible at least in the visible range of the spectrum. Here, we present a general linear formulation for collective micro-dynamics of e-beam noise and its control. Specifically, we compare two schemes for current noise suppression: a quarter plasma wavelength drift section and a combined drift/dispersive (transverse magnetic field) section. We examine and compare their limits of applicability at short wavelengths via considerations of electron phase-spread and the related Landau damping effect.

  17. Association between objectively measured physical activity, chronic stress and leukocyte telomere length.

    Science.gov (United States)

    von Känel, Roland; Bruwer, Erna J; Hamer, Mark; de Ridder, J Hans; Malan, Leoné

    2017-10-01

    Physical activity (PA) attenuates chronic stress and age-related and cardiovascular disease risks, whereby potentially slowing telomere shortening. We aimed to study the association between seven-day objectively measured habitual PA, chronic stress and leukocyte telomere length. Study participants were African (N.=96) and Caucasian (N.=107) school teachers of the Sympathetic activity and Ambulatory Blood Pressure in Africans study. All lifestyle characteristics (including PA) were objectively measured. The general health questionnaire and serum cortisol were assessed as psychological and physical measures of chronic stress. Leukocyte telomere length was measured using the quantitative real-time polymerase chain reaction. Africans had significantly shorter telomeres (Pstress or telomere length. However, more time spent with light intensity PA time was significantly and independently correlated with lower waist circumference (r=-0.21, P=0.004); in turn, greater waist circumference was significantly associated shorter telomeres (β=-0.17 [-0.30, -0.03], P=0.017). Habitual PA of different intensity was not directly associated with markers of chronic stress and leukocyte telomere length in this biethnic cohort. However, our findings suggest that light intensity PA could contribute to lowered age-related disease risk and healthy ageing by facilitating maintenance of a normal waist circumference.

  18. Modulation of telomere binding proteins: a future area of research for skin protection and anti-aging target.

    Science.gov (United States)

    Imbert, Isabelle; Botto, Jean-Marie; Farra, Claude D; Domloge, Nouha

    2012-06-01

    Telomere shortening is considered as one of the main characteristics of cellular aging by limiting cellular division. Besides the fundamental advances through the discoveries of telomere and telomerase, which were recognized by a Nobel Prize, telomere protection remains an essential area of research. Recently, it was evidenced that studying the cross-talks between the proteins associated with telomere should provide a better understanding of the mechanistic basis for telomere-associated aging phenotypes. In this review, we discuss the current knowledge on telomere shortening, telomerase activity, and the essential role of telomere binding proteins in telomere stabilization and telomere-end protection. This review highlights the capacity of telomere binding proteins to limit cellular senescence and to maintain skin tissue homeostasis, which is of key importance to reduce accelerated tissue aging. Future studies addressing telomere protection and limitation of DNA damage response in human skin should include investigations on telomere binding proteins. As little is known about the expression of telomere binding proteins in human skin and modulation of their expression with aging, it remains an interesting field of skin research and a key area for future skin protection and anti-aging developments. © 2012 Wiley Periodicals, Inc.

  19. Setting the Trajectory: Racial Disparities in Newborn Telomere Length

    Science.gov (United States)

    Drury, Stacy S.; Esteves, Kyle; Hatch, Virginia; Woodbury, Margaret; Borne, Sophie; Adamski, Alys; Theall, Katherine P.

    2015-01-01

    Objective To explore racial differences in newborn telomere length (TL) and the effect moderation of the sex of the infant while establishing the methodology for the use of newborn blood spots for telomere length analyses. Study design Pregnant mothers were recruited from the Greater New Orleans area. TL was determined using MMQ-PCR on DNA extracted from infant blood spots. Demographic data and other covariates were obtained via maternal report prior to infant birth. Birth outcome data were obtained from medical records and maternal report. Results Black infants weighed significantly less than white infants at birth, and had significantly longer TL than White infants (p=0.0134), with the strongest effect observed in Black female infants. No significant differences in gestational age were present. Conclusions Significant racial differences in TL were present at birth in this sample, even after controlling for a range of birth outcomes and demographic factors. As longer initial TL is predictive of more rapid TL attrition across the life course, these findings provide evidence that, even at birth, biological vulnerability to early life stress may differ by race and sex. PMID:25681203

  20. Large-scale parent–child comparison confirms a strong paternal influence on telomere length

    OpenAIRE

    Nordfjäll, Katarina; Svenson, Ulrika; Norrback, Karl-Fredrik; Adolfsson, Rolf; Roos, Göran

    2009-01-01

    Telomere length is documented to have a hereditary component, and both paternal and X-linked inheritance have been proposed. We investigated blood cell telomere length in 962 individuals with an age range between 0 and 102 years. Telomere length correlations were analyzed between parent–child pairs in different age groups and between grandparent–grandchild pairs. A highly significant correlation between the father's and the child's telomere length was observed (r=0.454, P

  1. Donor Telomere Length SAA

    Science.gov (United States)

    A new NCI study has found that, among patients with severe aplastic anemia who received a hematopoietic cell transplant from an unrelated donor, those whose donor white blood cells had longer telomeres had higher survival rates five-years after transplant

  2. Two faces of Solanaceae telomeres: a comparison between Nicotiana and Cestrum telomeres and telomere-binding proteins

    Czech Academy of Sciences Publication Activity Database

    Peška, Vratislav; Sýkorová, Eva; Fajkus, Jiří

    2008-01-01

    Roč. 122, 3-4 (2008), s. 380-387 ISSN 1424-8581 R&D Projects: GA AV ČR(CZ) IAA600040505; GA AV ČR(CZ) IAA500040801; GA MŠk(CZ) LC06004 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : POT1-like proteins * C-terminal OB domain * telomere-binding protein Subject RIV: BO - Biophysics Impact factor: 1.965, year: 2008

  3. High plasma folate is negatively associated with leukocyte telomere length in Framingham Offspring cohort.

    Science.gov (United States)

    Paul, Ligi; Jacques, Paul F; Aviv, Abraham; Vasan, Ramachandran S; D'Agostino, Ralph B; Levy, Daniel; Selhub, Jacob

    2015-03-01

    Shortening of telomeres, the protective structures at the ends of eukaryotic chromosomes, is associated with age-related pathologies. Telomere length is influenced by DNA integrity and DNA and histone methylation. Folate plays a role in providing precursors for nucleotides and methyl groups for methylation reactions and has the potential to influence telomere length. We determined the association between leukocyte telomere length and long-term plasma folate status (mean of 4 years) in Framingham Offspring Study (n = 1,044, females = 52.1 %, mean age 59 years) using data from samples collected before and after folic acid fortification. Leukocyte telomere length was determined by Southern analysis and fasting plasma folate concentration using microbiological assay. There was no significant positive association between long-term plasma folate and leukocyte telomere length among the Framingham Offspring Study participants perhaps due to their adequate folate status. While the leukocyte telomere length in the second quintile of plasma folate was longer than that in the first quintile, the difference was not statistically significant. The leukocyte telomere length of the individuals in the fifth quintile of plasma folate was shorter than that of those in the second quintile by 180 bp (P folate concentrations in the upper four quintiles of plasma folate (P for trend = 0.001). Multivitamin use was associated with shorter telomeres in this cohort (P = 0.015). High plasma folate status possibly resulting from high folic acid intake may interfere with the role of folate in maintaining telomere integrity.

  4. The influence of the telomere-telomerase system on diabetes mellitus and its vascular complications.

    Science.gov (United States)

    Qi Nan, Wu; Ling, Zhang; Bing, Chen

    2015-06-01

    The telomere-telomerase system plays an important role in the pathogenesis and disease progression of diabetes mellitus as well as in its vascular complications. Recent studies suggest that telomere shortening and abnormal telomerase activity occur in patients with diabetes mellitus, and targeting the telomere-telomerase system has become a prospective treatment for diabetes mellitus and its vascular complications. This review highlights the significance of the telomere-telomerase system and supports its role as a possible therapeutic target for patients with diabetes mellitus and its vascular complications Areas covered: This review covers the advances in understanding the telomere-telomerase system over the last 30 years and its significance in diabetes mellitus. In addition, it provides knowledge regarding the significance of the telomere-telomerase system in diabetes mellitus and its vascular complications as well as its role and mechanisms in oxidative stress, cell therapy and antioxidant activity Expert opinion: The telomere-telomerase system may be a potential therapeutic target that can protect against DNA damage and apoptosis in patients with diabetes mellitus and its vascular complications. DNA damage and apoptosis are associated with oxidative stress and are involved in the dysfunction of pancreatic β cells, insulin resistance, and its vascular complications. Abnormalities in the telomere-telomerase system may be associated with diabetes mellitus and its vascular complications. Therapies targeting telomere-telomerase system, telomerase reverse transcriptase transfection and alterative telomere lengthening must be identified before gene therapy can commence.

  5. Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Flávia S Donaires

    Full Text Available Telomeres are repetitive DNA sequences at linear chromosome termini, protecting chromosomes against end-to-end fusion and damage, providing chromosomal stability. Telomeres shorten with mitotic cellular division, but are maintained in cells with high proliferative capacity by telomerase. Loss-of-function mutations in telomere-maintenance genes are genetic risk factors for cirrhosis development in humans and murine models. Telomerase deficiency provokes accelerated telomere shortening and dysfunction, facilitating genomic instability and oncogenesis. Here we examined whether telomerase mutations and telomere shortening were associated with hepatocellular carcinoma (HCC secondary to cirrhosis. Telomere length of peripheral blood leukocytes was measured by Southern blot and qPCR in 120 patients with HCC associated with cirrhosis and 261 healthy subjects. HCC patients were screened for telomerase gene variants (in TERT and TERC by Sanger sequencing. Age-adjusted telomere length was comparable between HCC patients and healthy subjects by both Southern blot and qPCR. Four non-synonymous TERT heterozygous variants were identified in four unrelated patients, resulting in a significantly higher mutation carrier frequency (3.3% in patients as compared to controls (p = 0.02. Three of the four variants (T726M, A1062T, and V1090M were previously observed in patients with other telomere diseases (severe aplastic anemia, acute myeloid leukemia, and cirrhosis. A novel TERT variant, A243V, was identified in a 65-year-old male with advanced HCC and cirrhosis secondary to chronic hepatitis C virus (HCV and alcohol ingestion, but direct assay measurements in vitro did not detect modulation of telomerase enzymatic activity or processivity. In summary, constitutional variants resulting in amino acid changes in the telomerase reverse transcriptase were found in a small proportion of patients with cirrhosis-associated HCC.

  6. Mechanisms of breast cancer risk in shift workers: association of telomere shortening with the duration and intensity of night work.

    Science.gov (United States)

    Samulin Erdem, Johanna; Notø, Heidi Ødegaard; Skare, Øivind; Lie, Jenny-Anne S; Petersen-Øverleir, Marte; Reszka, Edyta; Pepłońska, Beata; Zienolddiny, Shanbeh

    2017-08-01

    Occupational factors such as shiftwork and especially night work that involves disruption of the circadian rhythm may contribute to increased breast cancer risk. Circadian disruption may also affect telomere length (TL). While short TL generally is associated with increased cancer risk, its association with breast cancer risk is inconclusive. We suggest that working schedules might be an important factor in assessment of effects of TL on breast cancer risk. Moreover, telomere shortening might be a potential mechanism for night work-related breast cancer. In this study, effects of shift work on TL and its association with breast cancer risk were investigated in a nested breast cancer case-control study of Norwegian nurses. TL was assessed by qPCR in DNA from 563 breast cancer patients and 619 controls. Here, we demonstrate that TL is affected by intensive night work schedules, as work with six consecutive night for a period of more than 5 years was associated with decreased telomere lengths (-3.18, 95% CI: -6.46 to -0.58, P = 0.016). Furthermore, telomere shortening is associated with increased breast cancer risk in workers with long periods of consecutive night shifts. Thus, nurses with longer telomere lengths had a lower risk for breast cancer if they had worked more than four (OR: 0.37, 95% CI: 0.16-0.79, P = 0.014) or five (OR: 0.31, 95% CI: 0.10-0.83, P = 0.029) consecutive night shifts for a period of 5 years or more. These data suggest that telomere shortening is associated with the duration and intensity of night work and may be a contributing factor for breast cancer risk among female shift workers. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  7. Telomere length in normal and neoplastic canine tissues.

    Science.gov (United States)

    Cadile, Casey D; Kitchell, Barbara E; Newman, Rebecca G; Biller, Barbara J; Hetler, Elizabeth R

    2007-12-01

    To determine the mean telomere restriction fragment (TRF) length in normal and neoplastic canine tissues. 57 solid-tissue tumor specimens collected from client-owned dogs, 40 samples of normal tissue collected from 12 clinically normal dogs, and blood samples collected from 4 healthy blood donor dogs. Tumor specimens were collected from client-owned dogs during diagnostic or therapeutic procedures at the University of Illinois Veterinary Medical Teaching Hospital, whereas 40 normal tissue samples were collected from 12 control dogs. Telomere restriction fragment length was determined by use of an assay kit. A histologic diagnosis was provided for each tumor by personnel at the Veterinary Diagnostic Laboratory at the University of Illinois. Mean of the mean TRF length for 44 normal samples was 19.0 kilobases (kb; range, 15.4 to 21.4 kb), and the mean of the mean TRF length for 57 malignant tumors was 19.0 kb (range, 12.9 to 23.5 kb). Although the mean of the mean TRF length for tumors and normal tissues was identical, tumor samples had more variability in TRF length. Telomerase, which represents the main mechanism by which cancer cells achieve immortality, is an attractive therapeutic target. The ability to measure telomere length is crucial to monitoring the efficacy of telomerase inhibition. In contrast to many other mammalian species, the length of canine telomeres and the rate of telomeric DNA loss are similar to those reported in humans, making dogs a compelling choice for use in the study of human anti-telomerase strategies.

  8. Non-erythroid alpha spectrin prevents telomere dysfunction after DNA interstrand cross-link damage

    OpenAIRE

    Zhang, Pan; Herbig, Utz; Coffman, Frederick; Lambert, Muriel W.

    2013-01-01

    Telomere integrity is critical for telomere function and genomic stability. We previously demonstrated that non-erythroid ?-spectrin (?IISp) is present in mammalian cell nuclei where it is important in repair of DNA interstrand cross-links (ICLs) and chromosome stability. We now demonstrate that ?IISp is also important for telomere maintenance after ICL damage. It localizes to telomeres in S phase after ICL damage where it has enhanced association with TRF1 and TRF2 and is required for recrui...

  9. Flap Endonuclease 1 Limits Telomere Fragility on the Leading Strand*

    Science.gov (United States)

    Teasley, Daniel C.; Parajuli, Shankar; Nguyen, Mai; Moore, Hayley R.; Alspach, Elise; Lock, Ying Jie; Honaker, Yuchi; Saharia, Abhishek; Piwnica-Worms, Helen; Stewart, Sheila A.

    2015-01-01

    The existence of redundant replication and repair systems that ensure genome stability underscores the importance of faithful DNA replication. Nowhere is this complexity more evident than in challenging DNA templates, including highly repetitive or transcribed sequences. Here, we demonstrate that flap endonuclease 1 (FEN1), a canonical lagging strand DNA replication protein, is required for normal, complete leading strand replication at telomeres. We find that the loss of FEN1 nuclease activity, but not DNA repair activities, results in leading strand-specific telomere fragility. Furthermore, we show that FEN1 depletion-induced telomere fragility is increased by RNA polymerase II inhibition and is rescued by ectopic RNase H1 expression. These data suggest that FEN1 limits leading strand-specific telomere fragility by processing RNA:DNA hybrid/flap intermediates that arise from co-directional collisions occurring between the replisome and RNA polymerase. Our data reveal the first molecular mechanism for leading strand-specific telomere fragility and the first known role for FEN1 in leading strand DNA replication. Because FEN1 mutations have been identified in human cancers, our findings raise the possibility that unresolved RNA:DNA hybrid structures contribute to the genomic instability associated with cancer. PMID:25922071

  10. Interaction of Berberine derivative with protein POT1 affect telomere function in cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Xiao, Nannan; Chen, Siqi; Ma, Yan; Qiu, Jun; Tan, Jia-Heng; Ou, Tian-Miao; Gu, Lian-Quan; Huang, Zhi-Shu [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, Waihuan East Road 132, Guangzhou 510006 (China); Li, Ding, E-mail: liding@mail.sysu.edu.cn [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, Waihuan East Road 132, Guangzhou 510006 (China)

    2012-03-16

    Highlights: Black-Right-Pointing-Pointer The protein POT1 plays an important role in telomere protection. Black-Right-Pointing-Pointer Functional POT1 was overexpressed in Escherichia coli for the first time, and purified. Black-Right-Pointing-Pointer Compound Sysu-00692 was found to be the first POT1-binding ligand. Black-Right-Pointing-Pointer Sysu-00692 could interfere with the binding activity of POT1 in vivo. Black-Right-Pointing-Pointer Sysu-00692 had inhibition on telomerase and cell proliferation. -- Abstract: The protein POT1 plays an important role in telomere protection, which is related with telomere elongation and cell immortality. The protein has been recognized as a promising drug target for cancer treatment. In the present study, we cloned, overexpressed in Escherichia coli for the first time, and purified recombinant human POT1. The protein was proved to be active through filter binding assay, FRET and CD experiments. In the initial screening for protein binding ligands using SPR, compound Sysu-00692 was found to bind well with the POT1, which was confirmed with EMSA. Its in vivo activity study showed that compound Sysu-00692 could interfere with the binding between human POT1 and the telomeric DNA through chromatin immunoprecipitation. Besides, the compound showed mild inhibition on telomerase and cell proliferation. As we know, compound Sysu-00692 is the first reported POT1-binding ligand, which could serve as a lead compound for further improvement. This work offered a potentially new approach for drug design for the treatment of cancers.

  11. The heritability of telomere length among the elderly and oldest-old

    DEFF Research Database (Denmark)

    Bischoff, Claus; Graakjaer, Jesper; Petersen, Hans Christian

    2005-01-01

    . Structural equation models revealed that a model including additive genetic effects and non-shared environment was the best fitting model and that telomere length was moderately heritable, with an estimate that was sensitive to the telomere length standardization procedure. Sex-specific analyses showed lower...... heritability in males, although not statistically significant, which is in line with our earlier finding of a sex difference in telomere dynamics among the elderly and oldest-old....

  12. Resolution of telomere associations by TRF1 cleavage in mouse embryonic stem cells

    NARCIS (Netherlands)

    Lisaingo, Kathleen; Uringa, Evert-Jan; Lansdorp, Peter M.

    2014-01-01

    Telomere associations have been observed during key cellular processes such as mitosis, meiosis, and carcinogenesis and must be resolved before cell division to prevent genome instability. Here we establish that telomeric repeat-binding factor 1 (TRF1), a core component of the telomere protein

  13. Beginning at the ends: telomeres and human disease [version 1; referees: 4 approved

    Directory of Open Access Journals (Sweden)

    Sharon A. Savage

    2018-05-01

    Full Text Available Studies of rare and common illnesses have led to remarkable progress in the understanding of the role of telomeres (nucleoprotein complexes at chromosome ends essential for chromosomal integrity in human disease. Telomere biology disorders encompass a growing spectrum of conditions caused by rare pathogenic germline variants in genes encoding essential aspects of telomere function. Dyskeratosis congenita, a disorder at the severe end of this spectrum, typically presents in childhood with the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia, accompanied by a very high risk of bone marrow failure, cancer, pulmonary fibrosis, and other medical problems. In contrast, the less severe end of the telomere biology disorder spectrum consists of middle-age or older adults with just one feature typically seen in dyskeratosis congenita, such as pulmonary fibrosis or bone marrow failure. In the common disease realm, large-scale molecular epidemiology studies have discovered novel associations between illnesses, such as cancer, heart disease, and mental health, and both telomere length and common genetic variants in telomere biology genes. This review highlights recent findings of telomere biology in human disease from both the rare and common disease perspectives. Multi-disciplinary collaborations between clinicians, basic scientists, and epidemiologist are essential as we seek to incorporate new telomere biology discoveries to improve health outcomes.

  14. Telomere shortening in hematopoietic stem cell transplantation: a potential mechanism for late graft failure?

    Science.gov (United States)

    Awaya, Norihiro; Baerlocher, Gabriela M; Manley, Thomas J; Sanders, Jean E; Mielcarek, Marco; Torok-Storb, Beverly; Lansdorp, Peter M

    2002-01-01

    Telomeres serve to maintain the structural integrity of chromosomes, yet each somatic cell division is associated with a decrease in telomere length. The cumulative decrease in telomere length can impose an upper limit for the number of cell divisions that can occur before a cell senesces. When studied in vitro with fibroblasts, this limit is referred to as the Hayflick limit and usually occurs after 40 to 80 cell doublings. In theory, a similar replicative potential in a hematopoietic stem cell could support hematopoiesis in a person for more than 100 years. However, stem cells differentiate, and the telomere length differs among chromosomes within a single cell, among cell types, and among age-matched individuals. This variation in telomere length raises the possibility that long-term hematopoiesis by transplanted stem cells could, depending on the telomere length of the engrafted stem cell and the proliferative demand to which it is subjected, reach a Hayflick limit during the life span of the patient. Although significant shortening of telomeres is reported to occur within the first year posttransplantation, as yet no evidence has indicated that this shortening is associated with marrow function. In this review, we summarize reports on telomere shortening in stem cell transplantation recipients and report 2 cases in which graft failure is associated with significant telomere shortening.

  15. Physical Activity and Telomere Biology: Exploring the Link with Aging-Related Disease Prevention

    Directory of Open Access Journals (Sweden)

    Andrew T. Ludlow

    2011-01-01

    Full Text Available Physical activity is associated with reduced risk of several age-related diseases as well as with increased longevity in both rodents and humans. Though these associations are well established, evidence of the molecular and cellular factors associated with reduced disease risk and increased longevity resulting from physical activity is sparse. A long-standing hypothesis of aging is the telomere hypothesis: as a cell divides, telomeres shorten resulting eventually in replicative senescence and an aged phenotype. Several reports have recently associated telomeres and telomere-related proteins to diseases associated with physical inactivity and aging including cardiovascular disease, insulin resistance, and hypertension. Interestingly several reports have also shown that longer telomeres are associated with higher physical activity levels, indicating a potential mechanistic link between physical activity, reduced age-related disease risk, and longevity. The primary purpose of this review is to discuss the potential importance of physical activity in telomere biology in the context of inactivity- and age-related diseases. A secondary purpose is to explore potential mechanisms and important avenues for future research in the field of telomeres and diseases associated with physical inactivity and aging.

  16. Utilizing Schottky barriers to suppress short-channel effects in organic transistors

    Science.gov (United States)

    Fernández, Anton F.; Zojer, Karin

    2017-10-01

    Transistors with short channel lengths exhibit profound deviations from the ideally expected behavior. One of the undesired short-channel effects is an enlarged OFF current that is associated with a premature turn on of the transistor. We present an efficient approach to suppress the OFF current, defined as the current at zero gate source bias, in short-channel organic transistors. We employ two-dimensional device simulations based on the drift-diffusion model to demonstrate that intentionally incorporating a Schottky barrier for injection enhances the ON-OFF ratio in both staggered and coplanar transistor architectures. The Schottky barrier is identified to directly counteract the origin of enlarged OFF currents: Short channels promote a drain-induced barrier lowering. The latter permits unhindered injection of charges even at reverse gate-source bias. An additional Schottky barrier hampers injection for such points of operations. We explain how it is possible to find the Schottky barrier of the smallest height necessary to exactly compensate for the premature turn on. This approach offers a substantial enhancement of the ON-OFF ratio. We show that this roots in the fact that such optimal barrier heights offer an excellent compromise between an OFF current diminished by orders of magnitude and an only slightly reduced ON current.

  17. Solution structure of telomere binding domain of AtTRB2 derived from Arabidopsis thaliana

    International Nuclear Information System (INIS)

    Yun, Ji-Hye; Lee, Won Kyung; Kim, Heeyoun; Kim, Eunhee; Cheong, Chaejoon; Cho, Myeon Haeng; Lee, Weontae

    2014-01-01

    Highlights: • We have determined solution structure of Myb domain of AtTRB2. • The Myb domain of AtTRB2 is located in the N-terminal region. • The Myb domain of AtTRB2 binds to plant telomeric DNA without fourth helix. • Helix 2 and 3 of the Myb domain of AtTRB2 are involved in DNA recognition. • AtTRB2 is a novel protein distinguished from other known plant TBP. - Abstract: Telomere homeostasis is regulated by telomere-associated proteins, and the Myb domain is well conserved for telomere binding. AtTRB2 is a member of the SMH (Single-Myb-Histone)-like family in Arabidopsis thaliana, having an N-terminal Myb domain, which is responsible for DNA binding. The Myb domain of AtTRB2 contains three α-helices and loops for DNA binding, which is unusual given that other plant telomere-binding proteins have an additional fourth helix that is essential for DNA binding. To understand the structural role for telomeric DNA binding of AtTRB2, we determined the solution structure of the Myb domain of AtTRB2 (AtTRB2 1–64 ) using nuclear magnetic resonance (NMR) spectroscopy. In addition, the inter-molecular interaction between AtTRB2 1–64 and telomeric DNA has been characterized by the electrophoretic mobility shift assay (EMSA) and NMR titration analyses for both plant (TTTAGGG)n and human (TTAGGG)n telomere sequences. Data revealed that Trp28, Arg29, and Val47 residues located in Helix 2 and Helix 3 are crucial for DNA binding, which are well conserved among other plant telomere binding proteins. We concluded that although AtTRB2 is devoid of the additional fourth helix in the Myb-extension domain, it is able to bind to plant telomeric repeat sequences as well as human telomeric repeat sequences

  18. RTEL1: an essential helicase for telomere maintenance and the regulation of homologous recombination.

    Science.gov (United States)

    Uringa, Evert-Jan; Youds, Jillian L; Lisaingo, Kathleen; Lansdorp, Peter M; Boulton, Simon J

    2011-03-01

    Telomere maintenance and DNA repair are crucial processes that protect the genome against instability. RTEL1, an essential iron-sulfur cluster-containing helicase, is a dominant factor that controls telomere length in mice and is required for telomere integrity. In addition, RTEL1 promotes synthesis-dependent strand annealing to direct DNA double-strand breaks into non-crossover outcomes during mitotic repair and in meiosis. Here, we review the role of RTEL1 in telomere maintenance and homologous recombination and discuss models linking RTEL1's enzymatic activity to its function in telomere maintenance and DNA repair.

  19. Chromosomal instability and telomere shortening in long-term culture of hematopoietic stem cells: insights from a cell culture model of RPS14 haploinsufficiency.

    Science.gov (United States)

    Thomay, K; Schienke, A; Vajen, B; Modlich, U; Schambach, A; Hofmann, W; Schlegelberger, B; Göhring, G

    2014-01-01

    The fate of cultivated primary hematopoietic stem cells (HSCs) with respect to genetic instability and telomere attrition has not yet been described in great detail. Thus, knowledge of the genetic constitution of HSCs is important when interpreting results of HSCs in culture. While establishing a cell culture model for myelodysplastic syndrome with a deletion in 5q by performing RPS14 knockdown, we found surprising data that may be of importance for any CD34+ cell culture experiments. We performed cytogenetic analyses and telomere length measurement on transduced CD34+ cells and untransduced control cells to observe the effects of long-term culturing. Initially, CD34+ cells had a normal median telomere length of about 12 kb and showed no signs of chromosomal instability. During follow-up, the median telomere length seemed to decrease and, simultaneously, increased chromosomal instability could be observed - in modified and control cells. One culture showed a clonal monosomy 7 - independent of prior RPS14 knockdown. During further culturing, it seemed that the telomeres re-elongated, and chromosomes stabilized, while TERT expression was not elevated. In summary, irrespective of our results of RPS14 knockdown in the long-term culture of CD34+ cells, it becomes clear that cell culture artefacts inducing telomere shortening and chromosomal instability have to be taken into account and regular cytogenetic analyses should always be performed. © 2013 S. Karger AG, Basel.

  20. The Role of the Telomere End Protection Complex in Telomere Main

    Science.gov (United States)

    2003-06-01

    identification of putative substrates of ATM kinase family members. J Biol Chem, 1999. 274(53): p. 37538-43. 9. Lei, M., E.R. Podell , P. Baumann, and T.R. Cech...DNA self-recognition in the structure of Pot1 bound to telomeric single-stranded DNA. Nature, 2003. 426(6963): p. 198-203. 10. Lei, M., E.R. Podell

  1. Telomere-Centromere-Driven Genomic Instability Contributes to Karyotype Evolution in a Mouse Model of Melanoma

    Directory of Open Access Journals (Sweden)

    Amanda Gonçalves dos Santos Silva

    2010-01-01

    Full Text Available Aneuploidy and chromosomal instability (CIN are hallmarks of most solid tumors. These alterations may result from inaccurate chromosomal segregation during mitosis, which can occur through several mechanisms including defective telomere metabolism, centrosome amplification, dysfunctional centromeres, and/or defective spindle checkpoint control. In this work, we used an in vitro murine melanoma model that uses a cellular adhesion blockade as a transforming factor to characterize telomeric and centromeric alterations that accompany melanocyte transformation. To study the timing of the occurrence of telomere shortening in this transformation model, we analyzed the profile of telomere length by quantitative fluorescent in situ hybridization and found that telomere length significantly decreased as additional rounds of cell adhesion blockages were performed. Together with it, an increase in telomere-free ends and complex karyotypic aberrations were also found, which include Robertsonian fusions in 100% of metaphases of the metastatic melanoma cells. These findings are in agreement with the idea that telomere length abnormalities seem to be one of the earliest genetic alterations acquired in the multistep process of malignant transformation and that telomere abnormalities result in telomere aggregation, breakage-bridge-fusion cycles, and CIN. Another remarkable feature of this model is the abundance of centromeric instability manifested as centromere fragments and centromeric fusions. Taken together, our results illustrate for this melanoma model CIN with a structural signature of centromere breakage and telomeric loss.

  2. Convergence of The Nobel Fields of Telomere Biology and DNA Repair.

    Science.gov (United States)

    Fouquerel, Elise; Opresko, Patricia L

    2017-01-01

    The fields of telomere biology and DNA repair have enjoyed a great deal of cross-fertilization and convergence in recent years. Telomeres function at chromosome ends to prevent them from being falsely recognized as chromosome breaks by the DNA damage response and repair machineries. Conversely, both canonical and nonconical functions of numerous DNA repair proteins have been found to be critical for preserving telomere structure and function. In 2009, Elizabeth Blackburn, Carol Greider and Jack Szostak were awarded the Nobel prize in Physiology or Medicine for the discovery of telomeres and telomerase. Four years later, pioneers in the field of DNA repair, Aziz Sancar, Tomas Lindahl and Paul Modrich were recognized for their seminal contributions by being awarded the Nobel Prize in Chemistry. This review is part of a special issue meant to celebrate this amazing achievement, and will focus in particular on the convergence of nucleotide excision repair and telomere biology, and will discuss the profound implications for human health. © 2016 The American Society of Photobiology.

  3. An experimental demonstration that early-life competitive disadvantage accelerates telomere loss.

    Science.gov (United States)

    Nettle, Daniel; Monaghan, Pat; Gillespie, Robert; Brilot, Ben; Bedford, Thomas; Bateson, Melissa

    2015-01-07

    Adverse experiences in early life can exert powerful delayed effects on adult survival and health. Telomere attrition is a potentially important mechanism in such effects. One source of early-life adversity is the stress caused by competitive disadvantage. Although previous avian experiments suggest that competitive disadvantage may accelerate telomere attrition, they do not clearly isolate the effects of competitive disadvantage from other sources of variation. Here, we present data from an experiment in European starlings (Sturnus vulgaris) that used cross-fostering to expose siblings to divergent early experience. Birds were assigned either to competitive advantage (being larger than their brood competitors) or competitive disadvantage (being smaller than their brood competitors) between days 3 and 12 post-hatching. Disadvantage did not affect weight gain, but it increased telomere attrition, leading to shorter telomere length in disadvantaged birds by day 12. There were no effects of disadvantage on oxidative damage as measured by plasma lipid peroxidation. We thus found strong evidence that early-life competitive disadvantage can accelerate telomere loss. This could lead to faster age-related deterioration and poorer health in later life.

  4. Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress--preliminary findings.

    Directory of Open Access Journals (Sweden)

    Owen M Wolkowitz

    2011-03-01

    Full Text Available Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of "accelerated aging" in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD, whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation.Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio and inflammation (IL-6. Analyses were controlled for age and sex.The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05. Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (≥9.2 years' cumulative duration was 281 base pairs shorter than that in controls (p<0.05, corresponding to approximately seven years of "accelerated cell aging." Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01 and in the controls (p<0.05 and with inflammation in the depressed subjects (p<0.05.These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening

  5. A stochastic model of cell replicative senescence based on telomere shortening, oxidative stress, and somatic mutations in nuclear and mitochondrial DNA.

    Science.gov (United States)

    Sozou, P D; Kirkwood, T B

    2001-12-21

    Human diploid fibroblast cells can divide for only a limited number of times in vitro, a phenomenon known as replicative senescence or the Hayflick limit. Variability in doubling potential is observed within a clone of cells, and between two sister cells arising from a single mitotic division. This strongly suggests that the process by which cells become senescent is intrinsically stochastic. Among the various biochemical mechanisms that have been proposed to explain replicative senescence, particular interest has been focussed on the role of telomere reduction. In the absence of telomerase--an enzyme switched off in normal diploid fibro-blasts-cells lose telomeric DNA at each cell division. According to the telomere hypothesis of cell senescence, cells eventually reach a critically short telomere length and cell cycle arrest follows. In support of this concept, forced expression of telomerase in normal fibroblasts appears to prevent cell senescence. Nevertheless, the telomere hypothesis in its basic form has some difficulty in explaining the marked stochastic variations seen in the replicative lifespans of individual cells within a culture, and there is strong empirical and theoretical support for the concept that other kinds of damage may contribute to cellular ageing. We describe a stochastic network model of cell senescence in which a primary role is played by telomere reduction but in which other mechanisms (oxidative stress linked particularly to mitochondrial damage, and nuclear somatic mutations) also contribute. The model gives simulation results that are in good agreement with published data on intra-clonal variability in cell doubling potential and permits an analysis of how the various elements of the stochastic network interact. Such integrative models may aid in developing new experimental approaches aimed at unravelling the intrinsic complexity of the mechanisms contributing to human cell ageing. Copyright 2001 Academic Press.

  6. TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA.

    Science.gov (United States)

    Flynn, Rachel Litman; Centore, Richard C; O'Sullivan, Roderick J; Rai, Rekha; Tse, Alice; Songyang, Zhou; Chang, Sandy; Karlseder, Jan; Zou, Lee

    2011-03-24

    Maintenance of telomeres requires both DNA replication and telomere 'capping' by shelterin. These two processes use two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomeres 1 (POT1). Although RPA and POT1 each have a critical role at telomeres, how they function in concert is not clear. POT1 ablation leads to activation of the ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase at telomeres, suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. Unexpectedly, we found that purified POT1 and its functional partner TPP1 are unable to prevent RPA binding to telomeric ssDNA efficiently. In cell extracts, we identified a novel activity that specifically displaces RPA, but not POT1, from telomeric ssDNA. Using purified protein, here we show that the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) recapitulates the RPA displacing activity. The RPA displacing activity is inhibited by the telomeric repeat-containing RNA (TERRA) in early S phase, but is then unleashed in late S phase when TERRA levels decline at telomeres. Interestingly, TERRA also promotes POT1 binding to telomeric ssDNA by removing hnRNPA1, suggesting that the re-accumulation of TERRA after S phase helps to complete the RPA-to-POT1 switch on telomeric ssDNA. Together, our data suggest that hnRNPA1, TERRA and POT1 act in concert to displace RPA from telomeric ssDNA after DNA replication, and promote telomere capping to preserve genomic integrity.

  7. Cigarette smoking and telomere length: A systematic review of 84 studies and meta-analysis.

    Science.gov (United States)

    Astuti, Yuliana; Wardhana, Ardyan; Watkins, Johnathan; Wulaningsih, Wahyu

    2017-10-01

    Cigarette smoking is a risk factor for ageing-related disease, but its association with biological ageing, indicated by telomere length, is unclear. We systematically reviewed evidence evaluating association between smoking status and telomere length. Searches were performed in MEDLINE (Ovid) and EMBASE (Ovid) databases, combining variation of keywords "smoking" and "telomere". Data was extracted for study characteristics and estimates for association between smoking and telomere length. Quality of studies was assessed with a risk of bias score, and publication bias was assessed with a funnel plot. I 2 test was used to observe heterogeneity. Meta-analysis was carried out to compare mean difference in telomere length by smoking status, and a dose-response approach was carried out for pack-years of smoking and telomere length. A sensitivity analysis was carried out to examine sources of heterogeneity. A total of 84 studies were included in the review, and 30 among them were included in our meta-analysis. Potential bias was addressed in half of included studies, and there was little evidence of small study bias. Telomere length was shorter among ever smokers compared to never smokers (summary standard mean difference [SMD]: -0.11 (95% CI -0.16 to -0.07)). Similarly, shorter telomere length was found among smokers compared to non-smokers, and among current smokers compared to never or former smokers. Dose-response meta-analysis suggested an inverse trend between pack-years of smoking and telomere length. However, heterogeneity among some analyses was observed. Shorter telomeres among ever smokers compared to those who never smoked may imply mechanisms linking tobacco smoke exposure to ageing-related disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Flap Endonuclease 1 Limits Telomere Fragility on the Leading Strand.

    Science.gov (United States)

    Teasley, Daniel C; Parajuli, Shankar; Nguyen, Mai; Moore, Hayley R; Alspach, Elise; Lock, Ying Jie; Honaker, Yuchi; Saharia, Abhishek; Piwnica-Worms, Helen; Stewart, Sheila A

    2015-06-12

    The existence of redundant replication and repair systems that ensure genome stability underscores the importance of faithful DNA replication. Nowhere is this complexity more evident than in challenging DNA templates, including highly repetitive or transcribed sequences. Here, we demonstrate that flap endonuclease 1 (FEN1), a canonical lagging strand DNA replication protein, is required for normal, complete leading strand replication at telomeres. We find that the loss of FEN1 nuclease activity, but not DNA repair activities, results in leading strand-specific telomere fragility. Furthermore, we show that FEN1 depletion-induced telomere fragility is increased by RNA polymerase II inhibition and is rescued by ectopic RNase H1 expression. These data suggest that FEN1 limits leading strand-specific telomere fragility by processing RNA:DNA hybrid/flap intermediates that arise from co-directional collisions occurring between the replisome and RNA polymerase. Our data reveal the first molecular mechanism for leading strand-specific telomere fragility and the first known role for FEN1 in leading strand DNA replication. Because FEN1 mutations have been identified in human cancers, our findings raise the possibility that unresolved RNA:DNA hybrid structures contribute to the genomic instability associated with cancer. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. RTEL1 contributes to DNA replication and repair and telomere maintenance.

    OpenAIRE

    Uringa, E.-J.; Lisaingo, K.; Pickett, H. A.; Brind'Amour, J.; Rohde, J.-H.; Zelensky, A.; Essers, J.; Lansdorp, P. M.

    2012-01-01

    textabstractTelomere maintenance and DNA repair are important processes that protect the genome against instability. mRtel1, an essential helicase, is a dominant factor setting telomere length in mice. In addition, mRtel1 is involved in DNA double-strand break repair. The role of mRtel1 in telomere maintenance and genome stability is poorly understood. Therefore we used mRtel1-deficient mouse embryonic stem cells to examine the function of mRtel1 in replication, DNA repair, recombination, and...

  10. Evidence that meiotic pairing starts at the telomeres: Molecular analysis of recombination in a family with a pericentric X chromosome inversion

    Energy Technology Data Exchange (ETDEWEB)

    Shashi, V.; Allinson, P.S.; Golden, W.L.; Kelly, T.E. [Univ. of Virginia, Charlottesville, VA (United States)

    1994-09-01

    Recent studies in yeast have shown that telomeres rather than centromeres lead in chromosome movement just prior to meiosis and may have a role in recombination. Cytological studies of meiosis in Drosophila and mice have shown that in pericentric inversion heterozygotes there is lack of loop formation, with recobmination seen only outside the inversion. In a family with Duchenne muscular dystrophy (DMD) we recognized that only affected males and carrier females had a pericentric X chromosome inversion (inv X(p11.4;q26)). Since the short arm inversion breakpoint was proximal to the DMD locus, it could not be implicated in the mutational event causing DMD. There was no history of infertility, recurrent miscarriages or liveborn unbalanced females to suggest there was recombination within the inversion. We studied 22 members over three generations to understand the pattern of meiotic recombination between the normal and the inverted X chromosome. In total, 17 meioses involving the inverted X chromosome in females were studied by cytogenetic analysis and 16 CA repeat polymorphisms along the length of the X chromosome. Results: (a) There was complete concordance between the segregation of the DMD mutation and the inverted X chromosome. (b) On DNA analysis, there was complete absence of recombination within the inverted segment. We also found no recombination at the DMD locus. Recombination was seen only at Xp22 and Xq27-28. (c) Recombination was seen in the same individual at both Xp22 and Xq27-28 without recombination otherwise. Conclusions: (1) Pericentric X inversions reduce the genetic map length of the chromosome, with the physical map length being normal. (2) Meiotic X chromosome pairing in this family is initiated at the telomeres. (3) Following telomeric pairing in pericentric X chromosome inversions, there is inhibition of recombination within the inversion and adjacent regions.

  11. [Methods of measuring telomere length and telomerase activity--practice and problems].

    Science.gov (United States)

    Saito, Y; Suda, T; Hatakeyama, K

    1998-05-01

    The development of a highly sensitive method for detection of telomerase activity, telomeric repeat amplification protocol (TRAP), has provided knowledge on telomerase activity in normal and cancer tissues. Subsequent several modifications have been achieved, including an introduction of the internal standard and hybridization protection technique that leads to simplicity and improvement of reproducibility and linearity of this method, and application of TRAP to in situ analysis to identify the cells responsible for telomerase activity. As for measurement of telomere length, fluorescence in situ hybridization technique appeared to give an information of telomere length on an individual chromosome in contrast to analysis of terminal restriction fragment, a conventional method which can express mean telomere length of all chromosomes. Further methodological improvement in this field is ongoing and showing a new sight on cell mortality and immortality.

  12. Direct comparison of flow-FISH and qPCR as diagnostic tests for telomere length measurement in humans.

    Directory of Open Access Journals (Sweden)

    Fernanda Gutierrez-Rodrigues

    Full Text Available Telomere length measurement is an essential test for the diagnosis of telomeropathies, which are caused by excessive telomere erosion. Commonly used methods are terminal restriction fragment (TRF analysis by Southern blot, fluorescence in situ hybridization coupled with flow cytometry (flow-FISH, and quantitative PCR (qPCR. Although these methods have been used in the clinic, they have not been comprehensively compared. Here, we directly compared the performance of flow-FISH and qPCR to measure leukocytes' telomere length of healthy individuals and patients evaluated for telomeropathies, using TRF as standard. TRF and flow-FISH showed good agreement and correlation in the analysis of healthy subjects (R(2 = 0.60; p<0.0001 and patients (R(2 = 0.51; p<0.0001. In contrast, the comparison between TRF and qPCR yielded modest correlation for the analysis of samples of healthy individuals (R(2 = 0.35; p<0.0001 and low correlation for patients (R(2 = 0.20; p = 0.001; Bland-Altman analysis showed poor agreement between the two methods for both patients and controls. Quantitative PCR and flow-FISH modestly correlated in the analysis of healthy individuals (R(2 = 0.33; p<0.0001 and did not correlate in the comparison of patients' samples (R(2 = 0.1, p = 0.08. Intra-assay coefficient of variation (CV was similar for flow-FISH (10.8 ± 7.1% and qPCR (9.5 ± 7.4%; p = 0.35, but the inter-assay CV was lower for flow-FISH (9.6 ± 7.6% vs. 16 ± 19.5%; p = 0.02. Bland-Altman analysis indicated that flow-FISH was more precise and reproducible than qPCR. Flow-FISH and qPCR were sensitive (both 100% and specific (93% and 89%, respectively to distinguish very short telomeres. However, qPCR sensitivity (40% and specificity (63% to detect telomeres below the tenth percentile were lower compared to flow-FISH (80% sensitivity and 85% specificity. In the clinical setting, flow-FISH was more accurate, reproducible, sensitive, and specific in the measurement of human

  13. Suppression of the initial transient in Monte Carlo criticality simulations; Suppression du regime transitoire initial des simulations Monte-Carlo de criticite

    Energy Technology Data Exchange (ETDEWEB)

    Richet, Y

    2006-12-15

    Criticality Monte Carlo calculations aim at estimating the effective multiplication factor (k-effective) for a fissile system through iterations simulating neutrons propagation (making a Markov chain). Arbitrary initialization of the neutron population can deeply bias the k-effective estimation, defined as the mean of the k-effective computed at each iteration. A simplified model of this cycle k-effective sequence is built, based on characteristics of industrial criticality Monte Carlo calculations. Statistical tests, inspired by Brownian bridge properties, are designed to discriminate stationarity of the cycle k-effective sequence. The initial detected transient is, then, suppressed in order to improve the estimation of the system k-effective. The different versions of this methodology are detailed and compared, firstly on a plan of numerical tests fitted on criticality Monte Carlo calculations, and, secondly on real criticality calculations. Eventually, the best methodologies observed in these tests are selected and allow to improve industrial Monte Carlo criticality calculations. (author)

  14. TRF1 and TRF2 use different mechanisms to find telomeric DNA but share a novel mechanism to search for protein partners at telomeres.

    Science.gov (United States)

    Lin, Jiangguo; Countryman, Preston; Buncher, Noah; Kaur, Parminder; E, Longjiang; Zhang, Yiyun; Gibson, Greg; You, Changjiang; Watkins, Simon C; Piehler, Jacob; Opresko, Patricia L; Kad, Neil M; Wang, Hong

    2014-02-01

    Human telomeres are maintained by the shelterin protein complex in which TRF1 and TRF2 bind directly to duplex telomeric DNA. How these proteins find telomeric sequences among a genome of billions of base pairs and how they find protein partners to form the shelterin complex remains uncertain. Using single-molecule fluorescence imaging of quantum dot-labeled TRF1 and TRF2, we study how these proteins locate TTAGGG repeats on DNA tightropes. By virtue of its basic domain TRF2 performs an extensive 1D search on nontelomeric DNA, whereas TRF1's 1D search is limited. Unlike the stable and static associations observed for other proteins at specific binding sites, TRF proteins possess reduced binding stability marked by transient binding (∼ 9-17 s) and slow 1D diffusion on specific telomeric regions. These slow diffusion constants yield activation energy barriers to sliding ∼ 2.8-3.6 κ(B)T greater than those for nontelomeric DNA. We propose that the TRF proteins use 1D sliding to find protein partners and assemble the shelterin complex, which in turn stabilizes the interaction with specific telomeric DNA. This 'tag-team proofreading' represents a more general mechanism to ensure a specific set of proteins interact with each other on long repetitive specific DNA sequences without requiring external energy sources.

  15. Leishmania replication protein A-1 binds in vivo single-stranded telomeric DNA

    International Nuclear Information System (INIS)

    Neto, J.L. Siqueira; Lira, C.B.B.; Giardini, M.A.; Khater, L.; Perez, A.M.; Peroni, L.A.; Reis, J.R.R. dos; Freitas-Junior, L.H.; Ramos, C.H.I.; Cano, M.I.N.

    2007-01-01

    Replication protein A (RPA) is a highly conserved heterotrimeric single-stranded DNA-binding protein involved in different events of DNA metabolism. In yeast, subunits 1 (RPA-1) and 2 (RPA-2) work also as telomerase recruiters and, in humans, the complex unfolds G-quartet structures formed by the 3' G-rich telomeric strand. In most eukaryotes, RPA-1 and RPA-2 bind DNA using multiple OB fold domains. In trypanosomatids, including Leishmania, RPA-1 has a canonical OB fold and a truncated RFA-1 structural domain. In Leishmania amazonensis, RPA-1 alone can form a complex in vitro with the telomeric G-rich strand. In this work, we show that LaRPA-1 is a nuclear protein that associates in vivo with Leishmania telomeres. We mapped the boundaries of the OB fold DNA-binding domain using deletion mutants. Since Leishmania and other trypanosomatids lack homologues of known telomere end binding proteins, our results raise questions about the function of RPA-1 in parasite telomeres

  16. Shwachman-Diamond Syndrome Protein SBDS Maintains Human Telomeres by Regulating Telomerase Recruitment

    Directory of Open Access Journals (Sweden)

    Yi Liu

    2018-02-01

    Full Text Available Shwachman-Diamond syndrome (SDS is a rare pediatric disease characterized by various systemic disorders, including hematopoietic dysfunction. The mutation of Shwachman-Bodian-Diamond syndrome (SBDS gene has been proposed to be a major causative reason for SDS. Although SBDS patients were reported to have shorter telomere length in granulocytes, the underlying mechanism is still unclear. Here we provide data to elucidate the role of SBDS in telomere protection. We demonstrate that SBDS deficiency leads to telomere shortening. We found that overexpression of disease-associated SBDS mutants or knockdown of SBDS hampered the recruitment of telomerase onto telomeres, while the overall reverse transcriptase activity of telomerase remained unaffected. Moreover, we show that SBDS could specifically bind to TPP1 during the S phase of cell cycle, likely functioning as a stabilizer for TPP1-telomerase interaction. Our findings suggest that SBDS is a telomere-protecting protein that participates in regulating telomerase recruitment.

  17. Solution structure of telomere binding domain of AtTRB2 derived from Arabidopsis thaliana

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Ji-Hye [Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Lee, Won Kyung [Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Kim, Heeyoun [Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Kim, Eunhee; Cheong, Chaejoon [Magnetic Resonance Team, Korea Basic Science Institute (KBSI), Ochang, Chungbuk 363-883 (Korea, Republic of); Cho, Myeon Haeng [Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Lee, Weontae, E-mail: wlee@spin.yonsei.ac.kr [Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2014-09-26

    Highlights: • We have determined solution structure of Myb domain of AtTRB2. • The Myb domain of AtTRB2 is located in the N-terminal region. • The Myb domain of AtTRB2 binds to plant telomeric DNA without fourth helix. • Helix 2 and 3 of the Myb domain of AtTRB2 are involved in DNA recognition. • AtTRB2 is a novel protein distinguished from other known plant TBP. - Abstract: Telomere homeostasis is regulated by telomere-associated proteins, and the Myb domain is well conserved for telomere binding. AtTRB2 is a member of the SMH (Single-Myb-Histone)-like family in Arabidopsis thaliana, having an N-terminal Myb domain, which is responsible for DNA binding. The Myb domain of AtTRB2 contains three α-helices and loops for DNA binding, which is unusual given that other plant telomere-binding proteins have an additional fourth helix that is essential for DNA binding. To understand the structural role for telomeric DNA binding of AtTRB2, we determined the solution structure of the Myb domain of AtTRB2 (AtTRB2{sub 1–64}) using nuclear magnetic resonance (NMR) spectroscopy. In addition, the inter-molecular interaction between AtTRB2{sub 1–64} and telomeric DNA has been characterized by the electrophoretic mobility shift assay (EMSA) and NMR titration analyses for both plant (TTTAGGG)n and human (TTAGGG)n telomere sequences. Data revealed that Trp28, Arg29, and Val47 residues located in Helix 2 and Helix 3 are crucial for DNA binding, which are well conserved among other plant telomere binding proteins. We concluded that although AtTRB2 is devoid of the additional fourth helix in the Myb-extension domain, it is able to bind to plant telomeric repeat sequences as well as human telomeric repeat sequences.

  18. RTEL1: an essential helicase for telomere maintenance and the regulation of homologous recombination

    OpenAIRE

    Uringa, Evert-Jan; Youds, Jillian L.; Lisaingo, Kathleen; Lansdorp, Peter M.; Boulton, Simon J.

    2010-01-01

    Telomere maintenance and DNA repair are crucial processes that protect the genome against instability. RTEL1, an essential iron–sulfur cluster-containing helicase, is a dominant factor that controls telomere length in mice and is required for telomere integrity. In addition, RTEL1 promotes synthesis-dependent strand annealing to direct DNA double-strand breaks into non-crossover outcomes during mitotic repair and in meiosis. Here, we review the role of RTEL1 in telomere maintenance and homolo...

  19. Blood and dried blood spot telomere length measurement by qPCR: assay considerations.

    Directory of Open Access Journals (Sweden)

    DeAnna L Zanet

    Full Text Available Measurement of telomere length is crucial for the study of telomere maintenance and its role in molecular pathophysiology of diseases and in aging. Several methods are used to measure telomere length, the choice of which usually depends on the type and size of sample to be assayed, as well as cost and throughput considerations. The goal of this study was to investigate the factors that may influence the reliability of qPCR-based relative telomere length measurements in whole blood. Day to day intra-individual variability, types of blood anticoagulant, sample storage conditions, processing and site of blood draw were investigated. Two qPCR-based methods to measure telomere length (monoplex vs. multiplex were also investigated and showed a strong correlation between them. Freezing and thawing of the blood and storage of the blood at 4°C for up to 4 days did not affect telomere length values. Telomere lengths in dried blood spots were significantly higher than both whole blood and peripheral mononuclear blood cells, and were highly correlated with both. We found that telomere length measurements were significantly higher in dried blood spots collected directly from fingertip prick compared to dried blood spots prepared with anticoagulated whole blood collected from the finger, and non-blotted whole blood taken from both finger and arm venipuncture. This suggests that DNA from cells blotted on paper is not equivalent to that collected from venipuncture whole blood, and caution should be taken when comparing between blood sample types.

  20. Short-Term Caloric Restriction Suppresses Cardiac Oxidative Stress and Hypertrophy Caused by Chronic Pressure Overload.

    Science.gov (United States)

    Kobara, Miyuki; Furumori-Yukiya, Akiko; Kitamura, Miho; Matsumura, Mihoko; Ohigashi, Makoto; Toba, Hiroe; Nakata, Tetsuo

    2015-08-01

    Caloric restriction (CR) prevents senescent changes, in which reactive oxygen species (ROS) have a critical role. Left ventricular (LV) hypertrophy is a risk factor for cardiovascular diseases. We examined whether CR alters cardiac redox state and hypertrophy from chronic pressure overload. Male c57BL6 mice were subjected to ascending aortic constriction (AAC) with ad libitum caloric intake (AL + AAC group) or 40% restricted caloric intake (CR + AAC group). CR was initiated 2 weeks before AAC and was continued for 4 weeks. Two weeks after constriction, AAC increased LV wall thickness, impaired transmitral flow velocity, and augmented myocyte hypertrophy and fibrosis, in association with enhancement of BNP and collagen III expressions in the AL + AAC group. In the AL + AAC group, oxidative stress in cardiac tissue and mitochondria were enhanced, and NADPH oxidase activity and mitochondrial ROS production were elevated. These changes were significantly attenuated in the CR + AAC group. Additionally, in antioxidant systems, myocardial glutathione peroxidase and superoxide dismutase activities were enhanced in the CR + AAC group. Chronic pressure overload increased cardiac oxidative damage, in association with cardiac hypertrophy and fibrosis. Short-term CR suppressed oxidative stress and improved cardiac function, suggesting that short-term CR could be a useful strategy to prevent pressure overload-induced cardiac injury. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. n-3 Fatty Acid Supplementation and Leukocyte Telomere Length in Patients with Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Anne Barden

    2016-03-01

    Full Text Available DNA telomere shortening associates with the age-related increase cardiovascular disease (CVD risk. Reducing oxidative stress, could modify telomere erosion during cell replication, and CVD risk in patients with chronic kidney disease (CKD. The effect of n-3 fatty acids and coenzyme Q10 (CoQ on telomere length was studied in a double-blind placebo-controlled trial in CKD. Eighty-five CKD patients were randomized to: n-3 fatty acids (4 g; CoQ (200 mg; both supplements; or control (4 g olive oil, daily for 8 weeks. Telomere length was measured in neutrophils and peripheral blood mononuclear cells (PBMC at baseline and 8 weeks, with and without correction for cell counts. Main and interactive effects of n-3 fatty acids and CoQ on telomere length were assessed adjusting for baseline values. F2-isoprostanes were measured as markers of oxidative stress. There was no effect of n-3 fatty acids or CoQ on neutrophil or PBMC telomere length. However, telomere length corrected for neutrophil count was increased after n-3 fatty acids (p = 0.015. Post-intervention plasma F2-isoprostanes were negative predictors of post-intervention telomere length corrected for neutrophil count (p = 0.025.The effect of n-3 fatty acids to increased telomere length corrected for neutrophil count may relate to reduced oxidative stress and increased clearance of neutrophils with shorter telomeres from the circulation. This may be a novel mechanism of modifying CVD risk in CKD patients.

  2. Association of cadmium and arsenic exposure with salivary telomere length in adolescents in Terai, Nepal

    Energy Technology Data Exchange (ETDEWEB)

    Fillman, Toki, E-mail: tokif@humeco.m.u-tokyo.ac.jp [Department of Human Ecology, School of International Health, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-Ku, Tokyo, 113-0033 (Japan); Shimizu-Furusawa, Hana, E-mail: hana-shimizu@umin.ac.jp [Department of Human Ecology, School of International Health, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-Ku, Tokyo, 113-0033 (Japan); Ng, Chris Fook Sheng, E-mail: chrisng-tky@umin.ac.jp [Department of Pediatric Infectious Diseases, Institute of Tropical Medicine, Nagasaki University, Nagasaki (Japan); Parajuli, Rajendra Prasad, E-mail: rp.parajuli@mcgill.ca [Basu Laboratory, CINE Building, Macdonald Campus, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec (Canada); Watanabe, Chiho, E-mail: chiho@humeco.m.u-tokyo.ac.jp [Department of Human Ecology, School of International Health, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-Ku, Tokyo, 113-0033 (Japan)

    2016-08-15

    Background: Cadmium and arsenic are ubiquitous metals commonly found in the environment which can harm human health. A growing body of research shows telomere length as a potential biomarker of future disease risk. Few studies have examined the effects of metals on telomere length and none have focused on adolescents. Objectives: In this study, the impact of cadmium and arsenic on salivary telomere length was studied in adolescents in Terai, Nepal. Methods: Adolescents aged 12–16 years old (n=351)were recruited where questionnaire interviews and both saliva and urine collection took place. Telomere length was determined by quantitative polymerase chain reaction using DNA extracted from saliva. Urinary cadmium and arsenic concentration were measured by inductively coupled plasma mass spectrometry. Multivariable linear regression was used to examine associations between urinary metals and salivary telomere length. Results: The geometric means and standard deviations of cadmium and arsenic were 0.33±0.33 μg/g creatinine and 196.0±301.1 μg/g creatinine, respectively. Urinary cadmium concentration was negatively associated with salivary telomere length after adjustment for confounders (β=−0.24, 95% CI −0.42,−0.07). Arsenic showed positive associations with telomere length but did not reach statistical significance. Conclusions: This is the first study to demonstrate that cadmium may shorten adolescent telomeres, even at exposure levels that may be considered low. These results agree with prior experimental and adult epidemiological studies, and also help identify the mechanism of DNA damage by cadmium. This study expanded current evidence on the harmful effects of cadmium exposure on telomere length even to adolescents. - Highlights: • This is the first study examining metal exposure on telomere length in adolescents. • Urinary cadmium levels were similar to non-industrially polluted levels in Asia. • Urinary arsenic levels were as high as groundwater

  3. Association of cadmium and arsenic exposure with salivary telomere length in adolescents in Terai, Nepal

    International Nuclear Information System (INIS)

    Fillman, Toki; Shimizu-Furusawa, Hana; Ng, Chris Fook Sheng; Parajuli, Rajendra Prasad; Watanabe, Chiho

    2016-01-01

    Background: Cadmium and arsenic are ubiquitous metals commonly found in the environment which can harm human health. A growing body of research shows telomere length as a potential biomarker of future disease risk. Few studies have examined the effects of metals on telomere length and none have focused on adolescents. Objectives: In this study, the impact of cadmium and arsenic on salivary telomere length was studied in adolescents in Terai, Nepal. Methods: Adolescents aged 12–16 years old (n=351)were recruited where questionnaire interviews and both saliva and urine collection took place. Telomere length was determined by quantitative polymerase chain reaction using DNA extracted from saliva. Urinary cadmium and arsenic concentration were measured by inductively coupled plasma mass spectrometry. Multivariable linear regression was used to examine associations between urinary metals and salivary telomere length. Results: The geometric means and standard deviations of cadmium and arsenic were 0.33±0.33 μg/g creatinine and 196.0±301.1 μg/g creatinine, respectively. Urinary cadmium concentration was negatively associated with salivary telomere length after adjustment for confounders (β=−0.24, 95% CI −0.42,−0.07). Arsenic showed positive associations with telomere length but did not reach statistical significance. Conclusions: This is the first study to demonstrate that cadmium may shorten adolescent telomeres, even at exposure levels that may be considered low. These results agree with prior experimental and adult epidemiological studies, and also help identify the mechanism of DNA damage by cadmium. This study expanded current evidence on the harmful effects of cadmium exposure on telomere length even to adolescents. - Highlights: • This is the first study examining metal exposure on telomere length in adolescents. • Urinary cadmium levels were similar to non-industrially polluted levels in Asia. • Urinary arsenic levels were as high as groundwater

  4. The fission yeast heterochromatin protein Rik1 is required for telomere clustering during meiosis

    DEFF Research Database (Denmark)

    Tuzon, Creighton T; Borgstrøm, Britta; Weilguny, Dietmar

    2004-01-01

    Telomeres share the ability to silence nearby transcription with heterochromatin, but the requirement of heterochromatin proteins for most telomere functions is unknown. The fission yeast Rik1 protein is required for heterochromatin formation at centromeres and the mating-type locus, as it recrui...... meiosis. However, Rik1 is dispensable for the protective roles of telomeres in preventing chromosome end-fusion. Thus, a Swi6-independent heterochromatin function distinct from that at centromeres and the mating-type locus operates at telomeres during sexual differentiation....

  5. Therapeutic opportunities: Telomere maintenance in inducible pluripotent stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Gourronc, Francoise A. [Department of Microbiology, University of Iowa (United States); Klingelhutz, Aloysius J., E-mail: al-klingelhutz@uiowa.edu [Department of Microbiology, University of Iowa (United States)

    2012-02-01

    It has been demonstrated that exogenous expression of a combination of transcription factors can reprogram differentiated cells such as fibroblasts and keratinocytes into what have been termed induced pluripotent stem (iPS) cells. These iPS cells are capable of differentiating into all the tissue lineages when placed in the right environment and, in the case of mouse cells, can generate chimeric mice and be transmitted through the germline. Safer and more efficient methods of reprogramming are rapidly being developed. Clearly, iPS cells present a number of exciting possibilities, including disease modeling and therapy. A major question is whether the nuclei of iPS cells are truly rejuvenated or whether they might retain some of the marks of aging from the cells from which they were derived. One measure of cellular aging is the telomere. In this regard, recent studies have demonstrated that telomeres in iPS cells may be rejuvenated. They are not only elongated by reactivated telomerase but they are also epigenetically modified to be similar but not identical to embryonic stem cells. Upon differentiation, the derivative cells turn down telomerase, the telomeres begin to shorten again, and the telomeres and the genome are returned to an epigenetic state that is similar to normal differentiated somatic cells. While these preliminary telomere findings are promising, the overall genomic integrity of reprogrammed cells may still be problematic and further studies are needed to examine the safety and feasibility of using iPS cells in regenerative medicine applications.

  6. Therapeutic opportunities: Telomere maintenance in inducible pluripotent stem cells

    International Nuclear Information System (INIS)

    Gourronc, Francoise A.; Klingelhutz, Aloysius J.

    2012-01-01

    It has been demonstrated that exogenous expression of a combination of transcription factors can reprogram differentiated cells such as fibroblasts and keratinocytes into what have been termed induced pluripotent stem (iPS) cells. These iPS cells are capable of differentiating into all the tissue lineages when placed in the right environment and, in the case of mouse cells, can generate chimeric mice and be transmitted through the germline. Safer and more efficient methods of reprogramming are rapidly being developed. Clearly, iPS cells present a number of exciting possibilities, including disease modeling and therapy. A major question is whether the nuclei of iPS cells are truly rejuvenated or whether they might retain some of the marks of aging from the cells from which they were derived. One measure of cellular aging is the telomere. In this regard, recent studies have demonstrated that telomeres in iPS cells may be rejuvenated. They are not only elongated by reactivated telomerase but they are also epigenetically modified to be similar but not identical to embryonic stem cells. Upon differentiation, the derivative cells turn down telomerase, the telomeres begin to shorten again, and the telomeres and the genome are returned to an epigenetic state that is similar to normal differentiated somatic cells. While these preliminary telomere findings are promising, the overall genomic integrity of reprogrammed cells may still be problematic and further studies are needed to examine the safety and feasibility of using iPS cells in regenerative medicine applications.

  7. Interstitial telomere-like repeats in the Arabidopsis thaliana genome.

    Science.gov (United States)

    Uchida, Wakana; Matsunaga, Sachihiro; Sugiyama, Ryuji; Kawano, Shigeyuki

    2002-02-01

    Eukaryotic chromosomal ends are protected by telomeres, which are thought to play an important role in ensuring the complete replication of chromosomes. On the other hand, non-functional telomere-like repeats in the interchromosomal regions (interstitial telomeric repeats; ITRs) have been reported in several eukaryotes. In this study, we identified eight ITRs in the Arabidopsis thaliana genome, each consisting of complete and degenerate 300- to 1200-bp sequences. The ITRs were grouped into three classes (class IA-B, class II, and class IIIA-E) based on the degeneracy of the telomeric repeats in ITRs. The telomeric repeats of the two ITRs in class I were conserved for the most part, whereas the single ITR in class II, and the five ITRs in class III were relatively degenerated. In addition, degenerate ITRs were surrounded by common sequences that shared 70-100% homology to each other; these are named ITR-adjacent sequences (IAS). Although the genomic regions around ITRs in class I lacked IAS, those around ITRs in class II contained IAS (IASa), and those around five ITRs in class III had nine types of IAS (IASb, c, d, e, f, g, h, i, and j). Ten IAS types in classes II and III showed no significant homology to each other. The chromosomal locations of ITRs and IAS were not category-related, but most of them were adjacent to, or part of, a centromere. These results show that the A. thaliana genome has undergone chromosomal rearrangements, such as end-fusions and segmental duplications.

  8. Early life adversity and telomere length: a meta-analysis.

    Science.gov (United States)

    Ridout, K K; Levandowski, M; Ridout, S J; Gantz, L; Goonan, K; Palermo, D; Price, L H; Tyrka, A R

    2018-04-01

    Early adversity, in the form of abuse, neglect, socioeconomic status and other adverse experiences, is associated with poor physical and mental health outcomes. To understand the biologic mechanisms underlying these associations, studies have evaluated the relationship between early adversity and telomere length, a marker of cellular senescence. Such results have varied in regard to the size and significance of this relationship. Using meta-analytic techniques, we aimed to clarify the relationship between early adversity and telomere length while exploring factors affecting the association, including adversity type, timing and study design. A comprehensive search in July 2016 of PubMed/MEDLINE, PsycINFO and Web of Science identified 2462 studies. Multiple reviewers appraised studies for inclusion or exclusion using a priori criteria; 3.9% met inclusion criteria. Data were extracted into a structured form; the Newcastle-Ottawa Scale assessed study quality, validity and bias. Forty-one studies (N=30 773) met inclusion criteria. Early adversity and telomere length were significantly associated (Cohen's d effect size=-0.35; 95% CI, -0.46 to -0.24; P<0.0001). Sensitivity analyses revealed no outlier effects. Adversity type and timing significantly impacted the association with telomere length (P<0.0001 and P=0.0025, respectively). Subgroup and meta-regression analyses revealed that medication use, medical or psychiatric conditions, case-control vs longitudinal study design, methodological factors, age and smoking significantly affected the relationship. Comprehensive evaluations of adversity demonstrated more extensive telomere length changes. These results suggest that early adversity may have long-lasting physiological consequences contributing to disease risk and biological aging.

  9. Work-related exhaustion and telomere length: a population-based study.

    Directory of Open Access Journals (Sweden)

    Kirsi Ahola

    Full Text Available Psychological stress is suggested to accelerate the rate of biological aging. We investigated whether work-related exhaustion, an indicator of prolonged work stress, is associated with accelerated biological aging, as indicated by shorter leukocyte telomeres, that is, the DNA-protein complexes that cap chromosomal ends in cells.We used data from a representative sample of the Finnish working-age population, the Health 2000 Study. Our sample consisted of 2911 men and women aged 30-64. Work-related exhaustion was assessed using the Maslach Burnout Inventory--General Survey. We determined relative leukocyte telomere length using a quantitative real-time polymerase chain reaction (PCR -based method.After adjustment for age and sex, individuals with severe exhaustion had leukocyte telomeres on average 0.043 relative units shorter (standard error of the mean 0.016 than those with no exhaustion (p = 0.009. The association between exhaustion and relative telomere length remained significant after additional adjustment for marital and socioeconomic status, smoking, body mass index, and morbidities (adjusted difference 0.044 relative units, standard error of the mean 0.017, p = 0.008.These data suggest that work-related exhaustion is related to the acceleration of the rate of biological aging. This hypothesis awaits confirmation in a prospective study measuring changes in relative telomere length over time.

  10. Influence of exposure to pesticides on telomere length in tobacco farmers: A biology system approach

    Energy Technology Data Exchange (ETDEWEB)

    Kahl, Vivian Francília Silva [Laboratory of Genetic Toxicology, PPGBioSaúde and PPGGTA, Lutheran University of Brazil (ULBRA), Canoas, RS (Brazil); Silva, Juliana da, E-mail: juliana.silva@ulbra.br [Laboratory of Genetic Toxicology, PPGBioSaúde and PPGGTA, Lutheran University of Brazil (ULBRA), Canoas, RS (Brazil); Rabaioli da Silva, Fernanda, E-mail: fernanda.silva@unilasalle.edu.br [Master’s Degree in Environmental Impact Evaluation, Centro Universitário La Salle, Canoas, RS (Brazil)

    2016-09-15

    Highlights: • Exposure to pesticides in tobacco fields is related to shorten telomere length. • The molecular mechanism of pesticide on telomere length is not fully understood. • Pesticides inhibit ubiquitin proteasome system. • Nicotine activates ubiquitin proteasome system. • Pesticides and nicotine regulate telomere length. - Abstract: Various pesticides in the form of mixtures must be used to keep tobacco crops pest-free. Recent studies have shown a link between occupational exposure to pesticides in tobacco crops and increased damage to the DNA, mononuclei, nuclear buds and binucleated cells in buccal cells as well as micronuclei in lymphocytes. Furthermore, pesticides used specifically for tobacco crops shorten telomere length (TL) significantly. However, the molecular mechanism of pesticide action on telomere length is not fully understood. Our study evaluated the interaction between a complex mixture of chemical compounds (tobacco cultivation pesticides plus nicotine) and proteins associated with maintaining TL, as well as the biological processes involved in this exposure by System Biology tools to provide insight regarding the influence of pesticide exposure on TL maintenance in tobacco farmers. Our analysis showed that one cluster was associated with TL proteins that act in bioprocesses such as (i) telomere maintenance via telomere lengthening; (ii) senescence; (iii) age-dependent telomere shortening; (iv) DNA repair (v) cellular response to stress and (vi) regulation of proteasome ubiquitin-dependent protein catabolic process. We also describe how pesticides and nicotine regulate telomere length. In addition, pesticides inhibit the ubiquitin proteasome system (UPS) and consequently increase proteins of the shelterin complex, avoiding the access of telomerase in telomere and, nicotine activates UPS mechanisms and promotes the degradation of human telomerase reverse transcriptase (hTERT), decreasing telomerase activity.

  11. Influence of exposure to pesticides on telomere length in tobacco farmers: A biology system approach

    International Nuclear Information System (INIS)

    Kahl, Vivian Francília Silva; Silva, Juliana da; Rabaioli da Silva, Fernanda

    2016-01-01

    Highlights: • Exposure to pesticides in tobacco fields is related to shorten telomere length. • The molecular mechanism of pesticide on telomere length is not fully understood. • Pesticides inhibit ubiquitin proteasome system. • Nicotine activates ubiquitin proteasome system. • Pesticides and nicotine regulate telomere length. - Abstract: Various pesticides in the form of mixtures must be used to keep tobacco crops pest-free. Recent studies have shown a link between occupational exposure to pesticides in tobacco crops and increased damage to the DNA, mononuclei, nuclear buds and binucleated cells in buccal cells as well as micronuclei in lymphocytes. Furthermore, pesticides used specifically for tobacco crops shorten telomere length (TL) significantly. However, the molecular mechanism of pesticide action on telomere length is not fully understood. Our study evaluated the interaction between a complex mixture of chemical compounds (tobacco cultivation pesticides plus nicotine) and proteins associated with maintaining TL, as well as the biological processes involved in this exposure by System Biology tools to provide insight regarding the influence of pesticide exposure on TL maintenance in tobacco farmers. Our analysis showed that one cluster was associated with TL proteins that act in bioprocesses such as (i) telomere maintenance via telomere lengthening; (ii) senescence; (iii) age-dependent telomere shortening; (iv) DNA repair (v) cellular response to stress and (vi) regulation of proteasome ubiquitin-dependent protein catabolic process. We also describe how pesticides and nicotine regulate telomere length. In addition, pesticides inhibit the ubiquitin proteasome system (UPS) and consequently increase proteins of the shelterin complex, avoiding the access of telomerase in telomere and, nicotine activates UPS mechanisms and promotes the degradation of human telomerase reverse transcriptase (hTERT), decreasing telomerase activity.

  12. Healthy lifestyle and leukocyte telomere length in U.S. women.

    Directory of Open Access Journals (Sweden)

    Qi Sun

    Full Text Available Whether a healthy lifestyle may be associated with longer telomere length is largely unknown.To examine healthy lifestyle practices, which are primary prevention measures against major age-related chronic diseases, in relation to leukocyte telomere length.Cross-sectional analysis in the Nurses' Health Study (NHS.The population consisted of 5,862 women who participated in multiple prospective case-control studies within the NHS cohort. Z scores of leukocyte telomere length were derived within each case-control study. Based on prior work, we defined low-risk or healthy categories for five major modifiable factors assessed in 1988 or 1990: non-current smoking, maintaining a healthy body weight (body mass index in 18.5-24.9 kg/m(2, engaging in regular moderate or vigorous physical activities (≥150 minutes/week, drinking alcohol in moderation (1 drink/week to <2 drinks/day, and eating a healthy diet (Alternate Healthy Eating Index score in top 50%. We calculated difference (% of the z scores contrasting low-risk groups with reference groups to evaluate the association of interest.Although none of the individual low-risk factors was significantly associated with larger leukocyte telomere length z scores, we observed a significant, positive relationship between the number of low-risk factors and the z scores. In comparison with women who had zero low-risk factors (1.9% of the total population and were, therefore, considered the least healthy group, the leukocyte telomere length z scores were 16.4%, 22.1%, 28.7%, 22.6%, and 31.2% (P for trend = 0.015 higher for women who had 1 to 5 low-risk factors, respectively.Adherence to a healthy lifestyle, defined by major modifiable risk factors, was associated with longer telomere length in leukocytes.

  13. Systematic correlation of environmental exposure and physiological and self-reported behaviour factors with leukocyte telomere length.

    Science.gov (United States)

    Patel, Chirag J; Manrai, Arjun K; Corona, Erik; Kohane, Isaac S

    2017-02-01

    It is hypothesized that environmental exposures and behaviour influence telomere length, an indicator of cellular ageing. We systematically associated 461 indicators of environmental exposures, physiology and self-reported behaviour with telomere length in data from the US National Health and Nutrition Examination Survey (NHANES) in 1999-2002. Further, we tested whether factors identified in the NHANES participants are also correlated with gene expression of telomere length modifying genes. We correlated 461 environmental exposures, behaviours and clinical variables with telomere length, using survey-weighted linear regression, adjusting for sex, age, age squared, race/ethnicity, poverty level, education and born outside the USA, and estimated the false discovery rate to adjust for multiple hypotheses. We conducted a secondary analysis to investigate the correlation between identified environmental variables and gene expression levels of telomere-associated genes in publicly available gene expression samples. After correlating 461 variables with telomere length, we found 22 variables significantly associated with telomere length after adjustment for multiple hypotheses. Of these varaibales, 14 were associated with longer telomeres, including biomarkers of polychlorinated biphenyls([PCBs; 0.1 to 0.2 standard deviation (SD) increase for 1 SD increase in PCB level, P  environmental exposures and chronic disease-related risk factors may play a role in telomere length. Our secondary analysis found no evidence of association between PCBs/smoking and gene expression of telomere-associated genes. All correlations between exposures, behaviours and clinical factors and changes in telomere length will require further investigation regarding biological influence of exposure. © The Author 2016. Published by Oxford University Press on behalf of the International Epidemiological Association

  14. Telomere length in alcohol dependence: A role for impulsive choice and childhood maltreatment.

    Science.gov (United States)

    Kang, Jee In; Hwang, Syung Shick; Choi, Jong Rak; Lee, Seung-Tae; Kim, Jieun; Hwang, In Sik; Kim, Hae Won; Kim, Chan-Hyung; Kim, Se Joo

    2017-09-01

    Telomere shortening, a marker of cellular aging, has been considered to be linked with psychosocial stress as well as with chronic alcohol consumption, possibly mediated by oxidative stress and inflammatory response. Recent findings suggested that early life adversity on telomere dynamics may be related to impulsive choice. To further our understanding of the association of impulsive choice and childhood trauma on telomere length, we examined whether delayed discounting and childhood trauma or their interaction is related to leukocyte telomere length, while controlling for multiple potential confounding variables, in patients with alcohol dependence who are considered to have higher impulsive choice and shorter telomere length. We recruited 253 male patients with chronic alcohol dependence. All participants performed the delay discounting task, and the area under curve was used as a measure of delay discounting. Steeper delay discounting represents more impulsive choices. The modified Parent-Child Conflict Tactics Scale was used to measure childhood maltreatment. In addition, confounding factors, including socio-demographic characteristics, the Alcohol Use Disorders Identification Test, the Buss-Perry Aggression Questionnaire, the Resilience Quotient, the Beck Depression Inventory, and the Beck Anxiety Inventory, were also assessed. Hierarchical regression analyses showed a significant main effect of delay discounting (β=0.161, t=2.640, p=0.009), and an interaction effect between delay discounting and childhood maltreatment on leukocyte telomere length (β=0.173, t=2.138, p=0.034). In subsequent analyses stratified by childhood maltreatment, patients with alcohol dependence and high childhood trauma showed a significant relationship between delay discounting and leukocyte telomere length (β=0.279, t=3.183, p=0.002), while those with low trauma showed no association between them. Our findings suggest that higher impulsive choice is associated with shorter telomere

  15. Telomere erosion varies during in vitro aging of normal human fibroblasts from young and adult donors.

    Science.gov (United States)

    Figueroa, R; Lindenmaier, H; Hergenhahn, M; Nielsen, K V; Boukamp, P

    2000-06-01

    The life span of normal fibroblasts in vitro (Hayflick limit) depends on donor age, and telomere shortening has been proposed as a potential mechanism. By quantitative fluorescence in situ hybridization and Southern blot analysis, we show progressive telomere loss to about 5 kb mean telomere restriction fragment length in fibroblasts from two adult donors within 40 population doublings, whereas in fibroblasts from two infant donors, telomere erosion is reduced, leaving a mean telomere restriction fragment length of approximately 7 kb at senescence (after approximately 60 population doublings). Aging of fibroblasts from both infant and adult donors was not accompanied by chromosomal abnormalities but was correlated with increased telomere repeat-binding factor 2 expression at both the protein and transcriptional level.

  16. Utility of telomere length measurements for age determination of humpback whales

    NARCIS (Netherlands)

    Olsen, Morten T.; Robbins, Jooke; Bérubé, Martine; Rew, Mary Beth; Palsboll, Per

    2014-01-01

    This study examines the applicability of telomere length measurements by quantitative PCR as a tool for minimally invasive age determination of free-ranging cetaceans. We analysed telomere length in skin samples from 28 North Atlantic humpback whales (Megaptera novaeangliae), ranging from 0 to 26

  17. Strand exchange of telomeric DNA catalyzed by the Werner syndrome protein (WRN) is specifically stimulated by TRF2

    Science.gov (United States)

    Edwards, Deanna N.; Orren, David K.; Machwe, Amrita

    2014-01-01

    Werner syndrome (WS), caused by loss of function of the RecQ helicase WRN, is a hereditary disease characterized by premature aging and elevated cancer incidence. WRN has DNA binding, exonuclease, ATPase, helicase and strand annealing activities, suggesting possible roles in recombination-related processes. Evidence indicates that WRN deficiency causes telomeric abnormalities that likely underlie early onset of aging phenotypes in WS. Furthermore, TRF2, a protein essential for telomere protection, interacts with WRN and influences its basic helicase and exonuclease activities. However, these studies provided little insight into WRN's specific function at telomeres. Here, we explored the possibility that WRN and TRF2 cooperate during telomeric recombination processes. Our results indicate that TRF2, through its interactions with both WRN and telomeric DNA, stimulates WRN-mediated strand exchange specifically between telomeric substrates; TRF2's basic domain is particularly important for this stimulation. Although TRF1 binds telomeric DNA with similar affinity, it has minimal effects on WRN-mediated strand exchange of telomeric DNA. Moreover, TRF2 is displaced from telomeric DNA by WRN, independent of its ATPase and helicase activities. Together, these results suggest that TRF2 and WRN act coordinately during telomeric recombination processes, consistent with certain telomeric abnormalities associated with alteration of WRN function. PMID:24880691

  18. Depressive and anxiety disorders and short leukocyte telomere length: mediating effects of metabolic stress and lifestyle factors.

    Science.gov (United States)

    Révész, D; Verhoeven, J E; Milaneschi, Y; Penninx, B W J H

    2016-08-01

    Depressive and anxiety disorders are associated with shorter leukocyte telomere length (LTL), an indicator of cellular aging. It is, however, unknown which pathways underlie this association. This study examined the extent to which lifestyle factors and physiological changes such as inflammatory or metabolic alterations mediate the relationship. We applied mediation analysis techniques to data from 2750 participants of the Netherlands Study of Depression and Anxiety. LTL was assessed using quantitative polymerase chain reaction. Independent variables were current depressive (30-item Inventory of Depressive Symptoms - Self Report) and anxiety (21-item Beck's Anxiety Inventory) symptoms and presence of a depressive or anxiety disorder diagnosis based on DSM-IV; mediator variables included physiological stress systems, metabolic syndrome components and lifestyle factors. Short LTL was associated with higher symptom severity (B = -2.4, p = 0.002) and current psychiatric diagnosis (B = -63.3, p = 0.024). C-reactive protein, interleukin-6, waist circumference, triglycerides, high-density lipoprotein cholesterol and cigarette smoking were significant mediators in the relationship between psychopathology and LTL. When all significant mediators were included in one model, the effect sizes of the relationships between LTL and symptom severity and current diagnosis were reduced by 36.7 and 32.7%, respectively, and the remaining direct effects were no longer significant. Pro-inflammatory cytokines, metabolic alterations and cigarette smoking are important mediators of the association between depressive and anxiety disorders and LTL. This calls for future research on intervention programs that take into account lifestyle changes in mental health care settings.

  19. The protein network surrounding the human telomere repeat binding factors TRF1, TRF2, and POT1.

    Directory of Open Access Journals (Sweden)

    Richard J Giannone

    2010-08-01

    Full Text Available Telomere integrity (including telomere length and capping is critical in overall genomic stability. Telomere repeat binding factors and their associated proteins play vital roles in telomere length regulation and end protection. In this study, we explore the protein network surrounding telomere repeat binding factors, TRF1, TRF2, and POT1 using dual-tag affinity purification in combination with multidimensional protein identification technology liquid chromatography--tandem mass spectrometry (MudPIT LC-MS/MS. After control subtraction and data filtering, we found that TRF2 and POT1 co-purified all six members of the telomere protein complex, while TRF1 identified five of six components at frequencies that lend evidence towards the currently accepted telomere architecture. Many of the known TRF1 or TRF2 interacting proteins were also identified. Moreover, putative associating partners identified for each of the three core components fell into functional categories such as DNA damage repair, ubiquitination, chromosome cohesion, chromatin modification/remodeling, DNA replication, cell cycle and transcription regulation, nucleotide metabolism, RNA processing, and nuclear transport. These putative protein-protein associations may participate in different biological processes at telomeres or, intriguingly, outside telomeres.

  20. Different requirements of functional telomeres in neural stem cells and terminally differentiated neurons.

    Science.gov (United States)

    Lobanova, Anastasia; She, Robert; Pieraut, Simon; Clapp, Charlie; Maximov, Anton; Denchi, Eros Lazzerini

    2017-04-01

    Telomeres have been studied extensively in peripheral tissues, but their relevance in the nervous system remains poorly understood. Here, we examine the roles of telomeres at distinct stages of murine brain development by using lineage-specific genetic ablation of TRF2, an essential component of the shelterin complex that protects chromosome ends from the DNA damage response machinery. We found that functional telomeres are required for embryonic and adult neurogenesis, but their uncapping has surprisingly no detectable consequences on terminally differentiated neurons. Conditional knockout of TRF2 in post-mitotic immature neurons had virtually no detectable effect on circuit assembly, neuronal gene expression, and the behavior of adult animals despite triggering massive end-to-end chromosome fusions across the brain. These results suggest that telomeres are dispensable in terminally differentiated neurons and provide mechanistic insight into cognitive abnormalities associated with aberrant telomere length in humans. © 2017 Lobanova et al.; Published by Cold Spring Harbor Laboratory Press.

  1. Exploring the link between depression and accelerated cellular aging: telomeres hold the key

    Directory of Open Access Journals (Sweden)

    Yu R

    2015-12-01

    Full Text Available Ruby Yu, Jean Woo Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China Abstract: Accumulating evidence suggests that telomeres may be a marker for biological aging and telomere length may be affected by multifactorial influences, including cumulative exposure to depression. Associations with telomere length have been reported for major depressive disorder, lifetime duration of depression, higher depression severity, and history of depression. The exact underling mechanisms for these associations have yet to be fully elucidated; however, oxidative stress, chronic inflammation, dysregulated hypothalamus-pituitary-adrenal axis, and altered cortisol levels may be important biochemical mediators. These mediators could also be influenced by psychological stress, unhealthy lifestyle behaviors, or other potential factors, such as childhood abuse, post-traumatic stress disorder, and anxiety that are commonly associated with depression. As such, stress reduction and lifestyle interventions that may affect the telomere maintenance system should be considered for individuals with depression.Keywords: depression, telomere length, biomarkers, cellular ageing

  2. If the cap fits, wear it: an overview of telomeric structures over evolution.

    Science.gov (United States)

    Fulcher, Nick; Derboven, Elisa; Valuchova, Sona; Riha, Karel

    2014-03-01

    Genome organization into linear chromosomes likely represents an important evolutionary innovation that has permitted the development of the sexual life cycle; this process has consequently advanced nuclear expansion and increased complexity of eukaryotic genomes. Chromosome linearity, however, poses a major challenge to the internal cellular machinery. The need to efficiently recognize and repair DNA double-strand breaks that occur as a consequence of DNA damage presents a constant threat to native chromosome ends known as telomeres. In this review, we present a comparative survey of various solutions to the end protection problem, maintaining an emphasis on DNA structure. This begins with telomeric structures derived from a subset of prokaryotes, mitochondria, and viruses, and will progress into the typical telomere structure exhibited by higher organisms containing TTAGG-like tandem sequences. We next examine non-canonical telomeres from Drosophila melanogaster, which comprise arrays of retrotransposons. Finally, we discuss telomeric structures in evolution and possible switches between canonical and non-canonical solutions to chromosome end protection.

  3. Investigation of telomere length and psychological stress in rape victims.

    Science.gov (United States)

    Malan, Stefanie; Hemmings, Sian; Kidd, Martin; Martin, Lindi; Seedat, Soraya

    2011-12-21

    Women are at an increased risk of depression and other mental health problems following rape. Various etiological factors for depression, including predisposing genetic factors, have been identified. Telomeres are repetitive nucleoprotein structures located at chromosomal ends that protect them from premature degradation. Telomeres reduce in length with each cell division, resulting in cellular senescence and apoptosis. Relative quantification of telomeric repeats using qPCR was performed to investigate whether shorter relative leukocyte telomere length (LTL) in a cohort of 64 rape victims was associated with resilience, the development of rape trauma-related major depressive disorder (MDD) or the development of posttraumatic stress disorder (PTSD) after 3 months. Out of the 64 participants, 23 participants were diagnosed with MDD at baseline and 31 after 3 months. Nine participants were diagnosed with PTSD (MDD and PTSD specifically related to the trauma). No significant associations were observed between relative LTL and resilience or the development of MDD at either baseline or after 3 months in this cohort. However, a marginally significant association was evident between relative LTL and PTSD status. The significant association between relative LTL and PTSD suggests that shorter relative LTL might have acted as a predisposing factor in the development of PTSD after a severely traumatic event. The results of this study indicate that telomere shortening may be an important marker of PTSD risk, with implications for early intervention and timely treatment, and as such warrant replication in a larger cohort. © 2011 Wiley Periodicals, Inc.

  4. Accumulative effects of indoor air pollution exposure on leukocyte telomere length among non-smokers

    International Nuclear Information System (INIS)

    Lin, Nan; Mu, Xinlin; Wang, Guilian; Ren, Yu'ang; Su, Shu; Li, Zhiwen; Wang, Bin; Tao, Shu

    2017-01-01

    Indoor air pollution is an important environmental factor that contributes to the burden of various diseases. Long-term exposure to ambient air pollution is associated with telomere shortening. However, the association between chronic indoor air pollution from household fuel combustion and leukocyte telomere length has not been studied. In our study, 137 cancer-free non-smokers were recruited. Their exposure levels to indoor air pollution from 1985 to 2014 were assessed using a face-to-face interview questionnaire, and leukocyte telomere length (LTL) was measured using a monochrome multiplex quantitative PCR method. Accumulative exposure to solid fuel usage for cooking was negatively correlated with LTL. The LTL of residents who were exposed to solid fuel combustion for three decades (LTL = 0.70 ± 0.17) was significantly shorter than that of other populations. In addition, education and occupation were related to both exposure to solid fuel and LTL. Sociodemographic factors may play a mediating role in the correlation between leukocyte telomere length and environmental exposure to indoor air pollution. In conclusion, long-term exposure to indoor air pollution may cause LTL dysfunction. - Highlights: • This is the first study to investigate a clear association between indoor air pollution and leukocyte telomere length. • Chronic exposure to household solid fuel combustion and leukocyte telomere length presented a negative correlation. • Shortest leukocyte telomere length belonged to population cooking for longest time. • Education and occupation were remarkably associated with leukocyte telomere length via relating with indoor air pollution. - Long-term exposure to household solid fuel combustion is negatively associated with LTL.

  5. Semantic and phonological contributions to short-term repetition and long-term cued sentence recall.

    Science.gov (United States)

    Meltzer, Jed A; Rose, Nathan S; Deschamps, Tiffany; Leigh, Rosie C; Panamsky, Lilia; Silberberg, Alexandra; Madani, Noushin; Links, Kira A

    2016-02-01

    The function of verbal short-term memory is supported not only by the phonological loop, but also by semantic resources that may operate on both short and long time scales. Elucidation of the neural underpinnings of these mechanisms requires effective behavioral manipulations that can selectively engage them. We developed a novel cued sentence recall paradigm to assess the effects of two factors on sentence recall accuracy at short-term and long-term stages. Participants initially repeated auditory sentences immediately following a 14-s retention period. After this task was complete, long-term memory for each sentence was probed by a two-word recall cue. The sentences were either concrete (high imageability) or abstract (low imageability), and the initial 14-s retention period was filled with either an undemanding finger-tapping task or a more engaging articulatory suppression task (Exp. 1, counting backward by threes; Exp. 2, repeating a four-syllable nonword). Recall was always better for the concrete sentences. Articulatory suppression reduced accuracy in short-term recall, especially for abstract sentences, but the sentences initially recalled following articulatory suppression were retained better at the subsequent cued-recall test, suggesting that the engagement of semantic mechanisms for short-term retention promoted encoding of the sentence meaning into long-term memory. These results provide a basis for using sentence imageability and subsequent memory performance as probes of semantic engagement in short-term memory for sentences.

  6. The roles of telomeres and telomerase in cellular immortalization and the development of cancer.

    Science.gov (United States)

    Klingelhutz, A J

    1999-01-01

    Normal human cells have a limited lifespan in culture called the Hayflick limit. Recent studies have indicated that telomere shortening is one of the important meters utilized by cells to determine the Hayflick limit, and that activation of a mechanism to maintain telomere length is essential for cells to become immortal. It is generally believed that cells must have a means to maintain telomeres in order to progress to malignancy. Most cancers do this by activating an enzyme called telomerase which adds telomeric repeats to the telomere ends. Recently, expression of this enzyme has been shown to extend the lifespan of cells. This review discusses the research that led to the discovery of telomerase, the characteristics of telomerase complex, and how recent and future advances in the telomerase field may lead to better diagnostic and treatment protocols for many different cancer types.

  7. High phobic anxiety is related to lower leukocyte telomere length in women.

    Directory of Open Access Journals (Sweden)

    Olivia I Okereke

    Full Text Available Chronic psychological distress has been linked to shorter telomeres, an indication of accelerated aging. Yet, little is known about relations of anxiety to telomeres. We examined whether a typically chronic form of anxiety--phobic anxiety--is related to telomere length.Relative telomere lengths (RTLs in peripheral blood leukocytes were measured by quantitative real-time polymerase chain reaction among 5,243 women (aged 42-69 years who: were participants in the Nurses' Health Study; were controls in prior case-control studies of telomeres and disease, or randomly selected healthy participants in a cognitive function sub-study; had completed the Crown-Crisp phobic index proximal to blood collection. Adjusted least-squares mean RTLs (z-scores were calculated across phobic categories. Higher phobic anxiety was generally associated with lower RTLs (age-adjusted p-trend = 0.09; this association was similar after adjustment for confounders--paternal age-at-birth, smoking, body mass index (BMI and physical activity (p-trend = 0.15. Notably, a threshold was identified. Among women with Crown-Crisp<6 points, the multivariable-adjusted least-squares mean RTL z-score = 0.02 standard units; however, among the most phobic women (Crown-Crisp ≥ 6, the multivariable-adjusted least-squares mean RTL z-score = -0.09 standard units (mean difference = -0.10 standard units; p = 0.02. The magnitude of this difference was comparable to that for women 6 years apart in age. Finally, effect modification by BMI, smoking and paternal age was observed: associations were stronger among highly phobic women with BMI ≥ 25 kg/m(2, without smoking history, or born to fathers aged ≥ 40 years.In this large, cross-sectional study high phobic anxiety was associated with shorter telomeres. These results point toward prospective investigations relating anxiety to telomere length change.

  8. Association between childhood trauma and accelerated telomere erosion in adulthood: A meta-analytic study.

    Science.gov (United States)

    Li, Zongchang; He, Ying; Wang, Dong; Tang, Jingsong; Chen, Xiaogang

    2017-10-01

    Childhood trauma has long-term sequelae on health status and contributes to numbers of somatic and mental disorders in later life. Findings from experimental studies in animals suggest that telomere erosion may be a mediator of this relationship. However, results from human studies are heterogeneous. To address these inconsistencies, we performed a meta-analysis regarding the association between childhood trauma and telomere length in adulthood. Articles were identified by systematically searching the Medline, EMBASE and Web of Science databases. Twenty four studies, which include twenty six sample sets and 30,919 participants, met the inclusion criteria for meta-analyses. This meta-analyses revealed that individuals experienced childhood trauma have accelerated telomere erosion in adulthood, with a small effect size (r = -0.05, 95% CI = -0.08-0.03, p childhood trauma revealed a trend in difference between groups (Q = 5.24, p = 0.07). Analyses for individual trauma types revealed a significant association between childhood separation and telomere erosion (r = -0.09, p childhood trauma and accelerated telomere erosion in adulthood, and further revealed that different trauma types have various impacts on telomere. Additional research on the mechanism that links the individual types of childhood trauma with telomere is needed in the future. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. CTC1-STN1 coordinates G- and C-strand synthesis to regulate telomere length.

    Science.gov (United States)

    Gu, Peili; Jia, Shuting; Takasugi, Taylor; Smith, Eric; Nandakumar, Jayakrishnan; Hendrickson, Eric; Chang, Sandy

    2018-05-17

    Coats plus (CP) is a rare autosomal recessive disorder caused by mutations in CTC1, a component of the CST (CTC1, STN1, and TEN1) complex important for telomere length maintenance. The molecular basis of how CP mutations impact upon telomere length remains unclear. The CP CTC1 L1142H mutation has been previously shown to disrupt telomere maintenance. In this study, we used CRISPR/Cas9 to engineer this mutation into both alleles of HCT116 and RPE cells to demonstrate that CTC1:STN1 interaction is required to repress telomerase activity. CTC1 L1142H interacts poorly with STN1, leading to telomerase-mediated telomere elongation. Impaired interaction between CTC1 L1142H :STN1 and DNA Pol-α results in increased telomerase recruitment to telomeres and further telomere elongation, revealing that C:S binding to DNA Pol-α is required to fully repress telomerase activity. CP CTC1 mutants that fail to interact with DNA Pol-α resulted in loss of C-strand maintenance and catastrophic telomere shortening. Our findings place the CST complex as an important regulator of both G-strand extensions by telomerase and C-strand synthesis by DNA Pol-α. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  10. Endogenous and ectopic expression of telomere regulating genes in chicken embryonic fibroblasts

    International Nuclear Information System (INIS)

    Michailidis, Georgios; Saretzki, Gabriele; Hall, Judith

    2005-01-01

    In this study, we compared the endogenous expression of genes encoding telomere regulating proteins in cultured chicken embryonic fibroblasts (CEFs) and 10-day-old chicken embryos. CEFs maintained in vitro senesced and senescence was accompanied by reduced telomere length, telomerase activity, and expression of the chicken (c) TRF1 gene. There was no change in TRF2 gene expression although the major TRF2 transcript identified in 10-day-old chicken embryos encoded a truncated TRF2 protein (TRF2'), containing an N-terminal dimerisation domain but lacking a myb-related DNA binding domain and nuclear localisation signal. Senescence of the CEFs in vitro was associated with the loss of the TRF2' transcript, indicative of a novel function for the encoded protein. Senescence was also coupled with decreased expression of RAD51, but increased RAD52 expression. These data support that RAD51 independent recombination mechanisms do not function in vitro to maintain chicken telomeres. To attempt to rescue the CEFs from replicative senescence, we stably transfected passage 3 CEFs with the human telomerase reverse transcriptase (hTERT) catalytic subunit. While hTERT expression was detected in the stable transfectants neither telomerase activity nor the stabilisation of telomere length was observed, and the transfectant cells senesced at the same passage number as the untransfected cells. These data indicate that the human TERT is incompatible with the avian telomere maintenance apparatus and suggest the functioning of a species specific telomere system in the avian

  11. Sex-dependent effects of nutrition on telomere dynamics in zebra finches (Taeniopygia guttata)

    OpenAIRE

    Noguera, Jose C.; Metcalfe, Neil B.; Boner, Winnie; Monaghan, Pat

    2015-01-01

    At a cellular level, oxidative stress is known to increase telomere attrition, and hence cellular senescence and risk of disease. It has been proposed that dietary micronutrients play an important role in telomere protection due to their antioxidant properties. We experimentally manipulated dietary micronutrients during early life in zebra finches (Taeniopygia guttata). We found no effects of micronutrient intake on telomere loss during chick growth. However, females given a diet high in micr...

  12. Telomere dysfunction and cell survival: roles for distinctTIN2-containing complexes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sahn-Ho; Davalos, Albert R.; Heo, Seok-Jin; Rodier, Francis; Beausejour, Christian; Kaminker, Patrick; Campisi, Judith

    2006-11-07

    Telomeres are maintained by three DNA binding proteins, TRF1, TRF2 and POT1, and several associated factors. One factor, TIN2, binds TRF1 and TRF2 directly and POT1 indirectly. These and two other proteins form a soluble complex that may be the core telomere-maintenance complex. It is not clear whether subcomplexes exist or function in vivo. Here, we provide evidence for two TIN2 subcomplexes with distinct functions in human cells. TIN2 ablation by RNA interference caused telomere uncapping and p53-independent cell death in all cells tested. However, we isolated two TIN2 complexes from cell lysates, each selectively sensitive to a TIN2 mutant (TIN2-13, TIN2-15C). In cells with wild-type p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere uncapping and eventual growth arrest. In cells lacking p53 function, TIN215C more than TIN2-13 caused genomic instability and cell death. Thus, TIN2 subcomplexes likely have distinct functions in telomere maintenance, and may provide selective targets for eliminating cells with mutant p53.

  13. Formation of radiation induced chromosome aberrations: involvement of telomeric sequences and telomerase

    International Nuclear Information System (INIS)

    Pirzio, L.

    2004-07-01

    As telomeres are crucial for chromosome integrity; we investigated the role played by telomeric sequences in the formation and in the transmission of radio-induced chromosome rearrangements in human cells. Starting from interstitial telomeric sequences (ITS) as putative region of breakage, we showed that the radiation sensitivity is not equally distributed along chromosomes and. is not affected by ITS. On the contrary, plasmid integration sites are prone to radio-induced breaks, suggesting a possible integration at sites already characterized by fragility. However plasmids do not preferentially insert at radio-induced breaks in human cells immortalized by telomerase. These cells showed remarkable karyotype stability even after irradiation, suggesting a role of telomerase in the genome maintenance despite functional telomeres. Finally, we showed that the presence of more breaks in a cell favors the repair, leading to an increase of transmissible rearrangements. (author)

  14. Sexual intimacy in couples is associated with longer telomere length.

    Science.gov (United States)

    Cabeza de Baca, Tomás; Epel, Elissa S; Robles, Theodore F; Coccia, Michael; Gilbert, Amanda; Puterman, Eli; Prather, Aric A

    2017-07-01

    High-quality relationships have been shown to be beneficial for physical and mental health. This study examined overall relationship satisfaction and perceived stress as well as daily reports of partner support, partner conflict, and physical intimacy obtained over the course of one week in a sample of 129 high and low stress mothers. Telomere length was examined in whole blood, as well as the two cell subpopulations: peripheral blood mononuclear cells (PBMCs) and granulocytes. Telomerase activity was measured in PBMCs. Analyses revealed no statistically significant associations of telomere length with current relationship satisfaction, daily support or conflict, or perceived stress. In contrast, women who reported any sexual intimacy during the course of the week had significantly longer telomeres measured in whole blood and PBMCs, but not in granulocytes. These relationships held covarying for age, body mass index, perceived stress, the relationship indices, and caregiver status. Sexual intimacy was not significantly related to PBMC telomerase activity. These data provide preliminary data that sexual intimacy is associated with longer telomere length. Future studies investigating these associations are warranted. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Telomere elongation in immortal human cells without detectable telomerase activity.

    Science.gov (United States)

    Bryan, T M; Englezou, A; Gupta, J; Bacchetti, S; Reddel, R R

    1995-09-01

    Immortalization of human cells is often associated with reactivation of telomerase, a ribonucleoprotein enzyme that adds TTAGGG repeats onto telomeres and compensates for their shortening. We examined whether telomerase activation is necessary for immortalization. All normal human fibroblasts tested were negative for telomerase activity. Thirteen out of 13 DNA tumor virus-transformed cell cultures were also negative in the pre-crisis (i.e. non-immortalized) stage. Of 35 immortalized cell lines, 20 had telomerase activity as expected, but 15 had no detectable telomerase. The 15 telomerase-negative immortalized cell lines all had very long and heterogeneous telomeres of up to 50 kb. Hybrids between telomerase-negative and telomerase-positive cells senesced. Two senescent hybrids demonstrated telomerase activity, indicating that activation of telomerase is not sufficient for immortalization. Some hybrid clones subsequently recommenced proliferation and became immortalized either with or without telomerase activity. Those without telomerase activity also had very long and heterogeneous telomeres. Taken together, these data suggest that the presence of lengthened or stabilized telomeres is necessary for immortalization, and that this may be achieved either by the reactivation of telomerase or by a novel and as yet unidentified mechanism.

  16. Telomere- and Telomerase-Associated Proteins and Their Functions in the Plant Cell

    Czech Academy of Sciences Publication Activity Database

    Schrumpfová, P.; Schorová, Š.; Fajkus, Jiří

    2016-01-01

    Roč. 7, č. 851 (2016) ISSN 1664-462X R&D Projects: GA ČR(CZ) GA13-06943S Institutional support: RVO:68081707 Keywords : telomere * telomerase * telomeric proteins Subject RIV: BO - Biophysics Impact factor: 4.298, year: 2016

  17. Telomere length in Chernobyl accident recovery workers in the late period after the disaster

    International Nuclear Information System (INIS)

    Reste, Jelena; Zvagule, Tija; Kurjane, Natalja; Eglite, Maija; Zvigule, Gunda; Berzina, Dace; Plonis, Juris; Miklasevics, Edvins; Gabruseva, Natalija

    2014-01-01

    The outcome of the Chernobyl nuclear power plant (CNPP) accident was that a huge number of people were exposed to ionizing radiation. Previous studies of CNPP clean-up workers from Latvia revealed a high occurrence of age-associated degenerative diseases and cancer in young adults, as well as a high mortality as a result of cardiovascular disorders at age 45–54 years. DNA tandem repeats that cap chromosome ends, known as telomeres, are sensitive to oxidative damage and exposure to ionizing radiation. Telomeres are important in aging processes and carcinogenesis. The aim of this study was to investigate the long-term effect of protracted ionizing radiation exposure on telomere length in CNPP clean-up workers. Relative telomere length (RTL) was measured in peripheral blood leukocytes of 595 CNPP clean-up workers and 236 gender- and age-matched controls using real-time quantitative polymerase chain reaction (q-PCR). Close attention was paid to participation year and tasks performed during the worker's stay in Chernobyl, health status, and RTL differences between subgroups. Telomere shortening was not found in CNPP clean-up workers; on the contrary, their RTL was slightly greater than in controls (P = 0.001). Longer telomeres were found in people who worked during 1986, in those undertaking 'dirty' tasks (digging and deactivation), and in people with cancer. Shorter telomeres appeared frequently in those with cataract, osteoporosis, atherosclerosis, or coronary heart disease. We conclude that the longer telomeres revealed in people more heavily exposed to ionizing radiation probably indicate activation of telomerase as a chromosome healing mechanism following damage, and reflect defects in telomerase regulation that could potentiate carcinogenesis. (author)

  18. Telomere shortening in the colonic mucosa of patients with ulcerative colitis.

    Science.gov (United States)

    Kinouchi, Y; Hiwatashi, N; Chida, M; Nagashima, F; Takagi, S; Maekawa, H; Toyota, T

    1998-06-01

    Telomere length in human somatic cells gradually decreases with the number of cell divisions and is regarded as a marker of somatic cell turnover. Mucosal cells of the affected colon show rapid turnover in individuals with active ulcerative colitis (UC). Telomere length was determined by Southern blot analysis of terminal restriction fragments (TRFs) from the colonic mucosa of 17 patients with UC in remission, two of whom showed dysplasia, and 17 control subjects without colitis. For each individual, mean TRF length was compared between rectal mucosa and unaffected cecal mucosa. The mean TRF length of the rectal mucosa was significantly less than that of cecal mucosa in UC patients (7.87 +/- 0.36kb versus 8.77 +/- 0.21 kb; P = 0.0015, Wilcoxon signed rank test), whereas no significant difference was detected in the control subjects. The extent of telomere shortening was 10.6 +/- 3.35% in UC patients, compared with 0.8 +/- 0.64% in noncolitis controls (P = 0.0024, Mann-Whitney U-test). Four UC patients, two of whom had dysplasia, showed telomere shortening of more than 20% in the rectal mucosa. These observations suggest that telomere shortening in the colonic mucosa of individuals with UC may represent the history of mucosal inflammation during disease of long duration, and that it may contribute to aneuploidy in UC.

  19. Telomeric repeat-containing RNA (TERRA) related to polycystic ovary syndrome (PCOS).

    Science.gov (United States)

    Wang, Caiqin; Shen, Fengxian; Zhu, Yuning; Fang, Yuying; Lu, Shiming

    2017-04-01

    Telomeric repeat-containing RNA (TERRA) participates in the regulation of telomere length, and leucocyte telomere length (LTL) plays an important role in the pathophysiology of polycystic ovary syndrome (PCOS), but little is known about the role of TERRA in PCOS. To evaluate the role of TERRA and peripheral blood LTL in PCOS. Forty women with PCOS and 35 healthy women without PCOS were recruited. A prospective case-control study was performed. RNA fluorescence in situ hybridization (FISH) was used to detect TERRA expression in peripheral blood leucocyte. Quantitative PCR was used to measure TERRA expression and the mean LTL in the PCOS and control groups. We analysed the association between related clinical parameters and the age-adjusted ratio of the telomere repeat length (T/S ratio) or TERRA. Telomeric repeat-containing RNA was expressed in human peripheral blood leucocytes, and the signal was abolished after culture with RNase A. The age-adjusted LTLs were significantly longer in the PCOS group than in the control group (P PCOS group than in the control group (P PCOS group (r = 0·532, P = 0·002; r = -0·477, P = 0·017). We found TERRA expression in human peripheral blood leucocytes, and LTLs were positively associated with PCOS. TERRA and testosterone play an important role in the LTL regulation in PCOS. © 2016 John Wiley & Sons Ltd.

  20. Leukocyte Telomere Length and Cognitive Function in Older Adults

    Directory of Open Access Journals (Sweden)

    Emily Frith

    2018-04-01

    Full Text Available We evaluated the specific association between leukocyte telomere length and cognitive function among a national sample of the broader U.S. older adult population. Data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES were used to identify 1,722 adults, between 60-85 years, with complete data on selected study variables. DNA was extracted from whole blood via the LTL assay, which is administered using quantitative polymerase chain reaction to measure telomere length relative to standard reference DNA (T/S ratio. Average telomere length was recorded, with two to three assays performed to control for individual variability. The DSST (Digit Symbol Substitution Test was used to assess participant executive cognitive functioning tasks of pairing and free recall. Individuals were excluded if they had been diagnosed with coronary artery disease, congestive heart failure, heart attack or stroke at the baseline assessment. Leukocyte telomere length was associated with higher cognitive performance, independent of gender, race-ethnicity, physical activity status, body mass index and other covariates. In this sample, there was a strong association between LTL and cognition; for every 1 T/S ratio increase in LTL, there was a corresponding 9.9 unit increase in the DSST (β = 9.9; 95% CI: 5.6-14.2; P [JCBPR 2018; 7(1.000: 14-18

  1. Longitudinal changes in telomere length and associated genetic parameters in dairy cattle analysed using random regression models.

    Directory of Open Access Journals (Sweden)

    Luise A Seeker

    Full Text Available Telomeres cap the ends of linear chromosomes and shorten with age in many organisms. In humans short telomeres have been linked to morbidity and mortality. With the accumulation of longitudinal datasets the focus shifts from investigating telomere length (TL to exploring TL change within individuals over time. Some studies indicate that the speed of telomere attrition is predictive of future disease. The objectives of the present study were to 1 characterize the change in bovine relative leukocyte TL (RLTL across the lifetime in Holstein Friesian dairy cattle, 2 estimate genetic parameters of RLTL over time and 3 investigate the association of differences in individual RLTL profiles with productive lifespan. RLTL measurements were analysed using Legendre polynomials in a random regression model to describe TL profiles and genetic variance over age. The analyses were based on 1,328 repeated RLTL measurements of 308 female Holstein Friesian dairy cattle. A quadratic Legendre polynomial was fitted to the fixed effect of age in months and to the random effect of the animal identity. Changes in RLTL, heritability and within-trait genetic correlation along the age trajectory were calculated and illustrated. At a population level, the relationship between RLTL and age was described by a positive quadratic function. Individuals varied significantly regarding the direction and amount of RLTL change over life. The heritability of RLTL ranged from 0.36 to 0.47 (SE = 0.05-0.08 and remained statistically unchanged over time. The genetic correlation of RLTL at birth with measurements later in life decreased with the time interval between samplings from near unity to 0.69, indicating that TL later in life might be regulated by different genes than TL early in life. Even though animals differed in their RLTL profiles significantly, those differences were not correlated with productive lifespan (p = 0.954.

  2. Three-dimensional telomere architecture of esophageal squamous cell carcinoma: comparison of tumor and normal epithelial cells.

    Science.gov (United States)

    Sunpaweravong, S; Sunpaweravong, P; Sathitruangsak, C; Mai, S

    2016-05-01

    Telomeres are repetitive nucleotide sequences (TTAGGG)n located at the ends of chromosomes that function to preserve chromosomal integrity and prevent terminal end-to-end fusions. Telomere loss or dysfunction results in breakage-bridge-fusion cycles, aneuploidy, gene amplification and chromosomal rearrangements, which can lead to genomic instability and promote carcinogenesis. Evaluating the hypothesis that changes in telomeres contribute to the development of esophageal squamous cell carcinoma (ESCC) and to determine whether there are differences between young and old patients, we compared the three-dimensional (3D) nuclear telomere architecture in ESCC tumor cells with that of normal epithelial cells obtained from the same patient. Patients were equally divided by age into two groups, one comprising those less than 45 years of age and the other consisting of those over 80 years of age. Tumor and normal epithelial cells located at least 10 cm from the border of the tumor were biopsied in ESCC patients. Hematoxylin and eosin staining was performed for each sample to confirm and identify the cancer and normal epithelial cells. This study was based on quantitative 3D fluorescence in situ hybridization (Q-FISH), 3D imaging and 3D analysis of paraffin-embedded slides. The 3D telomere architecture data were computer analyzed using 100 nuclei per slide. The following were the main parameters compared: the number of signals (number of telomeres), signal intensity (telomere length), number of telomere aggregates, and nuclear volume. Tumor and normal epithelial samples from 16 patients were compared. The normal epithelial cells had more telomere signals and higher intensities than the tumor cells, with P-values of P architecture and found no statistically significant differences in any parameter tested between the young and old patients in either the tumor or epithelial cells. The 3D nuclear telomeric signature was able to detect differences in telomere architecture

  3. Telomere length is longer in women with late maternal age

    DEFF Research Database (Denmark)

    Fagan, Erin; Sun, Fangui; Bae, Harold

    2017-01-01

    OBJECTIVE:: Maternal age at birth of last child has been associated with maternal longevity. The aim of this study was to determine whether older women with a history of late maternal age at last childbirth had a longer leukocyte telomere length than those with maternal age at last childbirth of 29...... died, but were at least 70 years old, were studied. Logistic regression models using generalized estimating equations were used to determine the association between tertiles of telomere length and maternal age at last childbirth, adjusting for covariates. RESULTS:: Age at birth of the last child...... in the first tertile. CONCLUSIONS:: These findings show an association between longer leukocyte telomere length and a later maternal age at birth of last child, suggesting that extended maternal age at last childbirth may be a marker for longevity....

  4. Age-related sex differences in body condition and telomere dynamics of red-sided garter snakes

    Science.gov (United States)

    Rollings, Nicky; Uhrig, Emily J.; Krohmer, Randolph W.; Waye, Heather L.; Mason, Robert T.; Olsson, Mats; Whittington, Camilla M.

    2017-01-01

    Life-history strategies vary dramatically between the sexes, which may drive divergence in sex-specific senescence and mortality rates. Telomeres are tandem nucleotide repeats that protect the ends of chromosomes from erosion during cell division. Telomeres have been implicated in senescence and mortality because they tend to shorten with stress, growth and age. We investigated age-specific telomere length in female and male red-sided garter snakes, Thamnophis sirtalis parietalis. We hypothesized that age-specific telomere length would differ between males and females given their divergent reproductive strategies. Male garter snakes emerge from hibernation with high levels of corticosterone, which facilitates energy mobilization to fuel mate-searching, courtship and mating behaviours during a two to four week aphagous breeding period at the den site. Conversely, females remain at the dens for only about 4 days and seem to invest more energy in growth and cellular maintenance, as they usually reproduce biennially. As male investment in reproduction involves a yearly bout of physiologically stressful activities, while females prioritize self-maintenance, we predicted male snakes would experience more age-specific telomere loss than females. We investigated this prediction using skeletochronology to determine the ages of individuals and qPCR to determine telomere length in a cross-sectional study. For both sexes, telomere length was positively related to body condition. Telomere length decreased with age in male garter snakes, but remained stable in female snakes. There was no correlation between telomere length and growth in either sex, suggesting that our results are a consequence of divergent selection on life histories of males and females. Different selection on the sexes may be the physiological consequence of the sexual dimorphism and mating system dynamics displayed by this species. PMID:28381620

  5. Age-related sex differences in body condition and telomere dynamics of red-sided garter snakes.

    Science.gov (United States)

    Rollings, Nicky; Uhrig, Emily J; Krohmer, Randolph W; Waye, Heather L; Mason, Robert T; Olsson, Mats; Whittington, Camilla M; Friesen, Christopher R

    2017-04-12

    Life-history strategies vary dramatically between the sexes, which may drive divergence in sex-specific senescence and mortality rates. Telomeres are tandem nucleotide repeats that protect the ends of chromosomes from erosion during cell division. Telomeres have been implicated in senescence and mortality because they tend to shorten with stress, growth and age. We investigated age-specific telomere length in female and male red-sided garter snakes, Thamnophis sirtalis parietalis We hypothesized that age-specific telomere length would differ between males and females given their divergent reproductive strategies. Male garter snakes emerge from hibernation with high levels of corticosterone, which facilitates energy mobilization to fuel mate-searching, courtship and mating behaviours during a two to four week aphagous breeding period at the den site. Conversely, females remain at the dens for only about 4 days and seem to invest more energy in growth and cellular maintenance, as they usually reproduce biennially. As male investment in reproduction involves a yearly bout of physiologically stressful activities, while females prioritize self-maintenance, we predicted male snakes would experience more age-specific telomere loss than females. We investigated this prediction using skeletochronology to determine the ages of individuals and qPCR to determine telomere length in a cross-sectional study. For both sexes, telomere length was positively related to body condition. Telomere length decreased with age in male garter snakes, but remained stable in female snakes. There was no correlation between telomere length and growth in either sex, suggesting that our results are a consequence of divergent selection on life histories of males and females. Different selection on the sexes may be the physiological consequence of the sexual dimorphism and mating system dynamics displayed by this species. © 2017 The Author(s).

  6. Structural Insight into the interaction of Flavonoids with Human Telomeric Sequence

    Science.gov (United States)

    Tawani, Arpita; Kumar, Amit

    2015-01-01

    Flavonoids are a group of naturally available compounds that are an attractive source for drug discovery. Their potential to act as anti-tumourigenic and anti-proliferative agents has been reported previously but is not yet fully understood. Targeting human telomeric G-quadruplex DNA could be one of the mechanisms by which these flavonoids exert anticancer activity. We have performed detailed biophysical studies for the interaction of four representative flavonoids, Luteolin, Quercetin, Rutin and Genistein, with the human telomeric G-quadruplex sequence tetramolecular d-(T2AG3T) (Tel7). In addition, we used NMR spectroscopy to derive the first model for the complex formed between Quercetin and G-quadruplex sequence. The model showed that Quercetin stabilises the G-quadruplex structure and does not open the G-tetrad. It interacts with the telomeric sequence through π-stacking at two sites: between T1pT2 and between G6pT7. Based on our findings, we suggest that Quercetin could be a potent candidate for targeting the telomere and thus, act as a potent anti-cancer agent. PMID:26627543

  7. Examining a scaled dynamical system of telomere shortening

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    Cyrenne, Benoit M.; Gooding, Robert J.

    2015-02-01

    A model of telomere dynamics is proposed and examined. Our model, which extends a previously introduced model that incorporates stem cells as progenitors of new cells, imposes the Hayflick limit, the maximum number of cell divisions that are possible. This new model leads to cell populations for which the average telomere length is not necessarily a monotonically decreasing function of time, in contrast to previously published models. We provide a phase diagram indicating where such results would be expected via the introduction of scaled populations, rate constants and time. The application of this model to available leukocyte baboon data is discussed.

  8. NBS1 plays a synergistic role with telomerase in the maintenance of telomeres in Arabidopsis thaliana

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    Najdekrova Lucie

    2012-09-01

    Full Text Available Abstract Background Telomeres, as elaborate nucleo-protein complexes, ensure chromosomal stability. When impaired, the ends of linear chromosomes can be recognised by cellular repair mechanisms as double-strand DNA breaks and can be healed by non-homologous-end-joining activities to produce dicentric chromosomes. During cell divisions, particularly during anaphase, dicentrics can break, thus producing naked chromosome tips susceptible to additional unwanted chromosome fusion. Many telomere-building protein complexes are associated with telomeres to ensure their proper capping function. It has been found however, that a number of repair complexes also contribute to telomere stability. Results We used Arabidopsis thaliana to study the possible functions of the DNA repair subunit, NBS1, in telomere homeostasis using knockout nbs1 mutants. The results showed that although NBS1-deficient plants were viable, lacked any sign of developmental aberration and produced fertile seeds through many generations upon self-fertilisation, plants also missing the functional telomerase (double mutants, rapidly, within three generations, displayed severe developmental defects. Cytogenetic inspection of cycling somatic cells revealed a very early onset of massive genome instability. Molecular methods used for examining the length of telomeres in double homozygous mutants detected much faster telomere shortening than in plants deficient in telomerase gene alone. Conclusions Our findings suggest that NBS1 acts in concert with telomerase and plays a profound role in plant telomere renewal.

  9. NBS1 plays a synergistic role with telomerase in the maintenance of telomeres in Arabidopsis thaliana.

    Science.gov (United States)

    Najdekrova, Lucie; Siroky, Jiri

    2012-09-17

    Telomeres, as elaborate nucleo-protein complexes, ensure chromosomal stability. When impaired, the ends of linear chromosomes can be recognised by cellular repair mechanisms as double-strand DNA breaks and can be healed by non-homologous-end-joining activities to produce dicentric chromosomes. During cell divisions, particularly during anaphase, dicentrics can break, thus producing naked chromosome tips susceptible to additional unwanted chromosome fusion. Many telomere-building protein complexes are associated with telomeres to ensure their proper capping function. It has been found however, that a number of repair complexes also contribute to telomere stability. We used Arabidopsis thaliana to study the possible functions of the DNA repair subunit, NBS1, in telomere homeostasis using knockout nbs1 mutants. The results showed that although NBS1-deficient plants were viable, lacked any sign of developmental aberration and produced fertile seeds through many generations upon self-fertilisation, plants also missing the functional telomerase (double mutants), rapidly, within three generations, displayed severe developmental defects. Cytogenetic inspection of cycling somatic cells revealed a very early onset of massive genome instability. Molecular methods used for examining the length of telomeres in double homozygous mutants detected much faster telomere shortening than in plants deficient in telomerase gene alone. Our findings suggest that NBS1 acts in concert with telomerase and plays a profound role in plant telomere renewal.

  10. Neighborhood Disadvantage and Telomere Length: Results from the Fragile Families Study

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    Douglas S. Massey

    2018-04-01

    Full Text Available Telomeres are repetitive nucleotide sequences located at the ends of chromosomes that protect genetic material. We use data from the Fragile Families and Child Wellbeing Study to analyze the relationship between exposure to spatially concentrated disadvantage and telomere length for white and black mothers. We find that neighborhood disadvantage is associated with shorter telomere length for mothers of both races. This finding highlights a potential mechanism through which the unique spatially concentrated disadvantage faced by African Americans contributes to racial health disparities. We conclude that equalizing the health and socioeconomic status of black and white Americans will be very difficult without reducing levels of residential segregation in the United States.

  11. Leucocyte telomere length and risk of type 2 diabetes mellitus: new prospective cohort study and literature-based meta-analysis.

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    Peter Willeit

    Full Text Available Short telomeres have been linked to various age-related diseases. We aimed to assess the association of telomere length with incident type 2 diabetes mellitus (T2DM in prospective cohort studies.Leucocyte relative telomere length (RTL was measured using quantitative polymerase chain reaction in 684 participants of the prospective population-based Bruneck Study (1995 baseline, with repeat RTL measurements performed in 2005 (n = 558 and 2010 (n = 479. Hazard ratios for T2DM were calculated across quartiles of baseline RTL using Cox regression models adjusted for age, sex, body-mass index, smoking, socio-economic status, physical activity, alcohol consumption, high-density lipoprotein cholesterol, log high-sensitivity C-reactive protein, and waist-hip ratio. Separate analyses corrected hazard ratios for within-person variability using multivariate regression calibration of repeated measurements. To contextualise findings, we systematically sought PubMed, Web of Science and EMBASE for relevant articles and pooled results using random-effects meta-analysis.Over 15 years of follow-up, 44 out of 606 participants free of diabetes at baseline developed incident T2DM. The adjusted hazard ratio for T2DM comparing the bottom vs. the top quartile of baseline RTL (i.e. shortest vs. longest was 2.00 (95% confidence interval: 0.90 to 4.49; P = 0.091, and 2.31 comparing the bottom quartile vs. the remainder (1.21 to 4.41; P = 0.011. The corresponding hazard ratios corrected for within-person RTL variability were 3.22 (1.27 to 8.14; P = 0.014 and 2.86 (1.45 to 5.65; P = 0.003. In a random-effects meta-analysis of three prospective cohort studies involving 6,991 participants and 2,011 incident T2DM events, the pooled relative risk was 1.31 (1.07 to 1.60; P = 0.010; I2 = 69%.Low RTL is independently associated with the risk of incident T2DM. To avoid regression dilution biases in observed associations of RTL with disease risk, future studies should implement

  12. Telomere length in Chernobyl accident recovery workers in the late period after the disaster.

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    Reste, Jelena; Zvigule, Gunda; Zvagule, Tija; Kurjane, Natalja; Eglite, Maija; Gabruseva, Natalija; Berzina, Dace; Plonis, Juris; Miklasevics, Edvins

    2014-11-01

    The outcome of the Chernobyl nuclear power plant (CNPP) accident was that a huge number of people were exposed to ionizing radiation. Previous studies of CNPP clean-up workers from Latvia revealed a high occurrence of age-associated degenerative diseases and cancer in young adults, as well as a high mortality as a result of cardiovascular disorders at age 45-54 years. DNA tandem repeats that cap chromosome ends, known as telomeres, are sensitive to oxidative damage and exposure to ionizing radiation. Telomeres are important in aging processes and carcinogenesis. The aim of this study was to investigate the long-term effect of protracted ionizing radiation exposure on telomere length in CNPP clean-up workers. Relative telomere length (RTL) was measured in peripheral blood leukocytes of 595 CNPP clean-up workers and 236 gender- and age-matched controls using real-time quantitative polymerase chain reaction (q-PCR). Close attention was paid to participation year and tasks performed during the worker's stay in Chernobyl, health status, and RTL differences between subgroups. Telomere shortening was not found in CNPP clean-up workers; on the contrary, their RTL was slightly greater than in controls (P = 0.001). Longer telomeres were found in people who worked during 1986, in those undertaking 'dirty' tasks (digging and deactivation), and in people with cancer. Shorter telomeres appeared frequently in those with cataract, osteoporosis, atherosclerosis, or coronary heart disease. We conclude that the longer telomeres revealed in people more heavily exposed to ionizing radiation probably indicate activation of telomerase as a chromosome healing mechanism following damage, and reflect defects in telomerase regulation that could potentiate carcinogenesis. © The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  13. Systematic and Cell Type-Specific Telomere Length Changes in Subsets of Lymphocytes

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    Jue Lin

    2016-01-01

    Full Text Available Telomeres, the protective DNA-protein complexes at the ends of linear chromosomes, are important for genome stability. Leukocyte or peripheral blood mononuclear cell (PBMC telomere length is a potential biomarker for human aging that integrates genetic, environmental, and lifestyle factors and is associated with mortality and risks for major diseases. However, only a limited number of studies have examined longitudinal changes of telomere length and few have reported data on sorted circulating immune cells. We examined the average telomere length (TL in CD4+, CD8+CD28+, and CD8+CD28− T cells, B cells, and PBMCs, cross-sectionally and longitudinally, in a cohort of premenopausal women. We report that TL changes over 18 months were correlated among these three T cell types within the same participant. Additionally, PBMC TL change was also correlated with those of all three T cell types, and B cells. The rate of shortening for B cells was significantly greater than for the three T cell types. CD8+CD28− cells, despite having the shortest TL, showed significantly more rapid attrition when compared to CD8+CD28+ T cells. These results suggest systematically coordinated, yet cell type-specific responses to factors and pathways contribute to telomere length regulation.

  14. Reversibility of Defective Hematopoiesis Caused by Telomere Shortening in Telomerase Knockout Mice.

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    Aparna Raval

    Full Text Available Telomere shortening is common in bone marrow failure syndromes such as dyskeratosis congenita (DC, aplastic anemia (AA and myelodysplastic syndromes (MDS. However, improved knowledge of the lineage-specific consequences of telomere erosion and restoration of telomere length in hematopoietic progenitors is required to advance therapeutic approaches. We have employed a reversible murine model of telomerase deficiency to compare the dependence of erythroid and myeloid lineage differentiation on telomerase activity. Fifth generation Tert-/- (G5 Tert-/- mice with shortened telomeres have significant anemia, decreased erythroblasts and reduced hematopoietic stem cell (HSC populations associated with neutrophilia and increased myelopoiesis. Intracellular multiparameter analysis by mass cytometry showed significantly reduced cell proliferation and increased sensitivity to activation of DNA damage checkpoints in erythroid progenitors and in erythroid-biased CD150hi HSC, but not in myeloid progenitors. Strikingly, Cre-inducible reactivation of telomerase activity restored hematopoietic stem and progenitor cell (HSPC proliferation, normalized the DNA damage response, and improved red cell production and hemoglobin levels. These data establish a direct link between the loss of TERT activity, telomere shortening and defective erythropoiesis and suggest that novel strategies to restore telomerase function may have an important role in the treatment of the resulting anemia.

  15. Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma

    International Nuclear Information System (INIS)

    Lin, Shih-Wen; Wang, Guo-Qing; Wei, Wen-Qiang; Lu, Ning; Taylor, Philip R; Qiao, You-Lin; Dawsey, Sanford M; Abnet, Christian C; Freedman, Neal D; Murphy, Gwen; Risques, Rosana; Prunkard, Donna; Rabinovitch, Peter; Pan, Qin-Jing; Roth, Mark J

    2013-01-01

    Esophageal cancer is the sixth leading cause of cancer death worldwide; current early detection screening tests are inadequate. Esophageal balloon cytology successfully retrieves exfoliated and scraped superficial esophageal epithelial cells, but cytologic reading of these cells has poor sensitivity and specificity for detecting esophageal squamous dysplasia (ESD), the precursor lesion of esophageal squamous cell carcinoma (ESCC). Measuring telomere length, a marker for chromosomal instability, may improve the utility of balloon cytology for detecting ESD and early ESCC. We examined balloon cytology specimens from 89 asymptomatic cases of ESD (37 low-grade and 52 high-grade) and 92 age- and sex-matched normal controls from an esophageal cancer early detection screening study. All subjects also underwent endoscopy and biopsy, and ESD was diagnosed histopathologically. DNA was extracted from the balloon cytology cells, and telomere length was measured by quantitative PCR. A receiver operating characteristic (ROC) curve was plotted for telomere length as a diagnostic marker for high-grade dysplasia. Telomere lengths were comparable among the low- and high-grade dysplasia cases and controls, with means of 0.96, 0.96, and 0.92, respectively. The area under the ROC curve was 0.55 for telomere length as a diagnostic marker for high-grade dysplasia. Further adjustment for subject characteristics, including sex, age, smoking, drinking, hypertension, and body mass index did not improve the use of telomere length as a marker for ESD. Telomere length of esophageal balloon cytology cells was not associated with ESCC precursor lesions. Therefore, telomere length shows little promise as an early detection marker for ESCC in esophageal balloon samples

  16. Telomeres, telomerase and oral cancer (Review).

    Science.gov (United States)

    Sebastian, Sinto; Grammatica, Luciano; Paradiso, Angelo

    2005-12-01

    Oral squamous cell carcinoma (oral cancer) and many squamous cell carcinomas of the head and neck arise as a consequence of multiple molecular events induced by the effects of various carcinogens related to tobacco use, environmental factors, and viruses in some instances (e.g., mucosal oncogenic human papillomaviruses), against a background of inheritable resistance or susceptibility. Consequent genetic damage affects many chromosomes and genes, and it is the accumulation of these changes that appears to lead to carcinoma. Telomere maintenance by telomerase or, in its absence, alternative lengthening of telomeres protect this acquired altered genetic information ensuring immortality without losing eukaryotic linear DNA; when this does not occur DNA is lost and end-replication problems arise. Telomerase is reactivated in 80-90% of cancers thus attracting the attention of pathologists and clinicians who have explored its use as a target for anticancer therapy and to develop better diagnostic and prognostic markers. In the last few years, valuable research from various laboratories has provided major insights into telomerase and telomeres leading to their use as diagnostic and prognostic markers in several types of cancer. Moreover, many strategies have emerged which inhibit this complex enzyme for anticancer therapy and are one step ahead of clinical trials. This review explains the basic biology and the clinical implications of telomerase-based diagnosis and prognosis, the prospects for its use in anticancer therapy, and the limitations it presents in the context of oral cancer.

  17. Quantitative fluorescence in situ hybridization measurement of telomere length in skin with/without sun exposure or actinic keratosis.

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    Ikeda, Hiroyuki; Aida, Junko; Hatamochi, Atsushi; Hamasaki, Yoichiro; Izumiyama-Shimomura, Naotaka; Nakamura, Ken-Ichi; Ishikawa, Naoshi; Poon, Steven S; Fujiwara, Mutsunori; Tomita, Ken-Ichiro; Hiraishi, Naoki; Kuroiwa, Mie; Matsuura, Masaaki; Sanada, Yukihiro; Kawano, Youichi; Arai, Tomio; Takubo, Kaiyo

    2014-03-01

    Chromosomal and genomic instability due to telomere dysfunction is known to play an important role in carcinogenesis. To study telomere shortening in the epidermis surrounding actinic keratosis, we measured telomere lengths of basal, parabasal, and suprabasal cells in epidermis with actinic keratosis (actinic keratosis group, n = 18) and without actinic keratosis (sun-protected, n = 15, and sun-exposed, n = 13 groups) and in actinic keratosis itself as well as in dermal fibroblasts in the 3 groups, using quantitative fluorescence in situ hybridization. Among the 3 cell types, telomeres of basal cells were not always the longest, suggesting that tissue stem cells are not necessarily located among basal cells. Telomeres of basal cells in the sun-exposed group were shorter than those in the sun-protected group. Telomeres in the background of actinic keratosis and in actinic keratosis itself and those of fibroblasts in actinic keratosis were significantly shorter than those in the controls. Our findings demonstrate that sun exposure induces telomere shortening and that actinic keratosis arises from epidermis with shorter telomeres despite the absence of any histologic atypia. © 2014.

  18. RPA prevents G-rich structure formation at lagging-strand telomeres to allow maintenance of chromosome ends.

    Science.gov (United States)

    Audry, Julien; Maestroni, Laetitia; Delagoutte, Emmanuelle; Gauthier, Tiphaine; Nakamura, Toru M; Gachet, Yannick; Saintomé, Carole; Géli, Vincent; Coulon, Stéphane

    2015-07-14

    Replication protein A (RPA) is a highly conserved heterotrimeric single-stranded DNA-binding protein involved in DNA replication, recombination, and repair. In fission yeast, the Rpa1-D223Y mutation provokes telomere shortening. Here, we show that this mutation impairs lagging-strand telomere replication and leads to the accumulation of secondary structures and recruitment of the homologous recombination factor Rad52. The presence of these secondary DNA structures correlates with reduced association of shelterin subunits Pot1 and Ccq1 at telomeres. Strikingly, heterologous expression of the budding yeast Pif1 known to efficiently unwind G-quadruplex rescues all the telomeric defects of the D223Y cells. Furthermore, in vitro data show that the identical D to Y mutation in human RPA specifically affects its ability to bind G-quadruplex. We propose that RPA prevents the formation of G-quadruplex structures at lagging-strand telomeres to promote shelterin association and facilitate telomerase action at telomeres. © 2015 The Authors.

  19. Fission yeast shelterin regulates DNA polymerases and Rad3(ATR kinase to limit telomere extension.

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    Ya-Ting Chang

    2013-11-01

    Full Text Available Studies in fission yeast have previously identified evolutionarily conserved shelterin and Stn1-Ten1 complexes, and established Rad3(ATR/Tel1(ATM-dependent phosphorylation of the shelterin subunit Ccq1 at Thr93 as the critical post-translational modification for telomerase recruitment to telomeres. Furthermore, shelterin subunits Poz1, Rap1 and Taz1 have been identified as negative regulators of Thr93 phosphorylation and telomerase recruitment. However, it remained unclear how telomere maintenance is dynamically regulated during the cell cycle. Thus, we investigated how loss of Poz1, Rap1 and Taz1 affects cell cycle regulation of Ccq1 Thr93 phosphorylation and telomere association of telomerase (Trt1(TERT, DNA polymerases, Replication Protein A (RPA complex, Rad3(ATR-Rad26(ATRIP checkpoint kinase complex, Tel1(ATM kinase, shelterin subunits (Tpz1, Ccq1 and Poz1 and Stn1. We further investigated how telomere shortening, caused by trt1Δ or catalytically dead Trt1-D743A, affects cell cycle-regulated telomere association of telomerase and DNA polymerases. These analyses established that fission yeast shelterin maintains telomere length homeostasis by coordinating the differential arrival of leading (Polε and lagging (Polα strand DNA polymerases at telomeres to modulate Rad3(ATR association, Ccq1 Thr93 phosphorylation and telomerase recruitment.

  20. Disordering of human telomeric G-quadruplex with novel antiproliferative anthrathiophenedione.

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    Dmitry Kaluzhny

    Full Text Available Linear heteroareneanthracenediones have been shown to interfere with DNA functions, thereby causing death of human tumor cells and their drug resistant counterparts. Here we report the interaction of our novel antiproliferative agent 4,11-bis[(2-{[acetimido]amino}ethylamino]anthra[2,3-b]thiophene-5,10-dione with telomeric DNA structures studied by isothermal titration calorimetry, circular dichroism and UV absorption spectroscopy. New compound demonstrated a high affinity (K(ass∼10⁶ M⁻¹ for human telomeric antiparallel quadruplex d(TTAGGG₄ and duplex d(TTAGGG₄∶d(CCCTAA₄. Importantly, a ∼100-fold higher affinity was determined for the ligand binding to an unordered oligonucleotide d(TTAGGG TTAGAG TTAGGG TTAGGG unable to form quadruplex structures. Moreover, in the presence of Na+ the compound caused dramatic conformational perturbation of the telomeric G-quadruplex, namely, almost complete disordering of G-quartets. Disorganization of a portion of G-quartets in the presence of K+ was also detected. Molecular dynamics simulations were performed to illustrate how the binding of one molecule of the ligand might disrupt the G-quartet adjacent to the diagonal loop of telomeric G-quadruplex. Our results provide evidence for a non-trivial mode of alteration of G-quadruplex structure by tentative antiproliferative drugs.

  1. dAdd1 and dXNP prevent genome instability by maintaining HP1a localization at Drosophila telomeres.

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    Chavez, Joselyn; Murillo-Maldonado, Juan Manuel; Bahena, Vanessa; Cruz, Ana Karina; Castañeda-Sortibrán, América; Rodriguez-Arnaiz, Rosario; Zurita, Mario; Valadez-Graham, Viviana

    2017-12-01

    Telomeres are important contributors to genome stability, as they prevent linear chromosome end degradation and contribute to the avoidance of telomeric fusions. An important component of the telomeres is the heterochromatin protein 1a (HP1a). Mutations in Su(var)205, the gene encoding HP1a in Drosophila, result in telomeric fusions, retrotransposon regulation loss and larger telomeres, leading to chromosome instability. Previously, it was found that several proteins physically interact with HP1a, including dXNP and dAdd1 (orthologues to the mammalian ATRX gene). In this study, we found that mutations in the genes encoding the dXNP and dAdd1 proteins affect chromosome stability, causing chromosomal aberrations, including telomeric defects, similar to those observed in Su(var)205 mutants. In somatic cells, we observed that dXNP and dAdd1 participate in the silencing of the telomeric HTT array of retrotransposons, preventing anomalous retrotransposon transcription and integration. Furthermore, the lack of dAdd1 results in the loss of HP1a from the telomeric regions without affecting other chromosomal HP1a binding sites; mutations in dxnp also affected HP1a localization but not at all telomeres, suggesting a specialized role for dAdd1 and dXNP proteins in locating HP1a at the tips of the chromosomes. These results place dAdd1 as an essential regulator of HP1a localization and function in the telomere heterochromatic domain.

  2. Effects of brood size manipulation and common origin on phenotype and telomere length in nestling collared flycatchers

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    Voillemot Marie

    2012-08-01

    Full Text Available Abstract Background Evidence is accumulating that telomere length is a good predictor of life expectancy, especially early in life, thus calling for determining the factors that affect telomere length at this stage. Here, we investigated the relative influence of early growth conditions and origin (genetics and early maternal effects on telomere length of collared flycatchers (Ficedula albicollis at fledging. We experimentally transferred hatchlings among brood triplets to create reduced, control (i.e. unchanged final nestling number and enlarged broods. Results Although our treatment significantly affected body mass at fledging, we found no evidence that increased sibling competition affected nestling tarsus length and telomere length. However, mixed models showed that brood triplets explained a significant part of the variance in body mass (18% and telomere length (19%, but not tarsus length (13%, emphasizing that unmanipulated early environmental factors influenced telomere length. These models also revealed low, but significant, heritability of telomere length (h2 = 0.09. For comparison, the heritability of nestling body mass and tarsus length was 0.36 and 0.39, respectively, which was in the range of previously published estimates for those two traits in this species. Conclusion Those findings in a wild bird population demonstrate that telomere length at the end of the growth period is weakly, but significantly, determined by genetic and/or maternal factors taking place before hatching. However, we found no evidence that the brood size manipulation experiment, and by extension the early growth conditions, influenced nestling telomere length. The weak heritability of telomere length suggests a close association with fitness in natural populations.

  3. Development of software and modification of Q-FISH protocol for estimation of individual telomere length in immunopathology.

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    Barkovskaya, M Sh; Bogomolov, A G; Knauer, N Yu; Rubtsov, N B; Kozlov, V A

    2017-04-01

    Telomere length is an important indicator of proliferative cell history and potential. Decreasing telomere length in the cells of an immune system can indicate immune aging in immune-mediated and chronic inflammatory diseases. Quantitative fluorescent in situ hybridization (Q-FISH) of a labeled (C 3 TA[Formula: see text] peptide nucleic acid probe onto fixed metaphase cells followed by digital image microscopy allows the evaluation of telomere length in the arms of individual chromosomes. Computer-assisted analysis of microscopic images can provide quantitative information on the number of telomeric repeats in individual telomeres. We developed new software to estimate telomere length. The MeTeLen software contains new options that can be used to solve some Q-FISH and microscopy problems, including correction of irregular light effects and elimination of background fluorescence. The identification and description of chromosomes and chromosome regions are essential to the Q-FISH technique. To improve the quality of cytogenetic analysis after Q-FISH, we optimized the temperature and time of DNA-denaturation to get better DAPI-banding of metaphase chromosomes. MeTeLen was tested by comparing telomere length estimations for sister chromatids, background fluorescence estimations, and correction of nonuniform light effects. The application of the developed software for analysis of telomere length in patients with rheumatoid arthritis was demonstrated.

  4. Age and Heat Stress as Determinants of Telomere Length in a Long-Lived Fish, the Siberian Sturgeon.

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    Simide, Rémy; Angelier, Frédéric; Gaillard, Sandrine; Stier, Antoine

    2016-01-01

    Telomeres shorten at each cell division due to the end-replication problem but also in response to oxidative stress. Consequently, telomeres shorten with age in many endotherms, and this shortening is accelerated under stressful environmental conditions. Data in ectotherm vertebrates remain scarce so far, so our goal was to review existing data for fish and to test the influence of age and stress on telomere length in a very long-lived fish, the Siberian sturgeon (Acipenser baerii). Our review of the literature revealed age-related telomere shortening in approximately half of the published studies. In the Siberian sturgeon, we found a significant telomere shortening with age, both at the intraindividual level using red blood cells (-12.5% in 16 mo) and at the interindividual level using cross-sectional samples of fin over an age range of 8 yr. We also found that heat stress (30°C) significantly reduced telomere length by 15.0% after only 1 mo of exposure. Our results highlight that both age and stressful environmental conditions might be important determinants of telomere length in fish.

  5. Systematic Analysis of the DNA Damage Response Network in Telomere Defective Budding Yeast

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    Eva-Maria Holstein

    2017-07-01

    Full Text Available Functional telomeres are critically important to eukaryotic genetic stability. Scores of proteins and pathways are known to affect telomere function. Here, we report a series of related genome-wide genetic interaction screens performed on budding yeast cells with acute or chronic telomere defects. Genetic interactions were examined in cells defective in Cdc13 and Stn1, affecting two components of CST, a single stranded DNA (ssDNA binding complex that binds telomeric DNA. For comparison, genetic interactions were also examined in cells with defects in Rfa3, affecting the major ssDNA binding protein, RPA, which has overlapping functions with CST at telomeres. In more complex experiments, genetic interactions were measured in cells lacking EXO1 or RAD9, affecting different aspects of the DNA damage response, and containing a cdc13-1 induced telomere defect. Comparing fitness profiles across these data sets helps build a picture of the specific responses to different types of dysfunctional telomeres. The experiments show that each context reveals different genetic interactions, consistent with the idea that each genetic defect causes distinct molecular defects. To help others engage with the large volumes of data, the data are made available via two interactive web-based tools: Profilyzer and DIXY. One particularly striking genetic interaction observed was that the chk1∆ mutation improved fitness of cdc13-1 exo1∆ cells more than other checkpoint mutations (ddc1∆, rad9∆, rad17∆, and rad24∆, whereas, in cdc13-1 cells, the effects of all checkpoint mutations were similar. We show that this can be explained by Chk1 stimulating resection—a new function for Chk1 in the eukaryotic DNA damage response network.

  6. Telomeric repeat factor 1 protein levels correlates with telomere length in colorectal cancer Los niveles proteicos del factor de repetición telomérico 1 se correlacionan con la longitud del telómero en el cáncer colorrectal

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    Cristina Valls-Bautista

    2012-11-01

    Full Text Available Background: colorectal cancer is the third cancer cause of death in Spain. It is important to investigate new tumoral markers for early diagnosis, disease monitoring and prevention strategies. Telomeres protect the chromosome from degradation by nucleases and end-to-end fusion. The progressive loss of the telomeric ends of chromosomes is an important mechanism in the timing of human cellular aging. Telomeric Repeat Factor 1 (TRF1 is a protein that binds at telomere ends. Purpose: to measure the concentrations of TRF1 and the relationships among telomere length, telomerase activity, and TRF1 levels in tumor and normal colorectal mucosa. Method: from normal and tumoral samples of 83 patients who underwent surgery for colorectal cancer we analyzed TRF1 protein concentration by Western Blot, telomerase activity, by the fluorescent-telomeric repeat amplification protocol assay and telomere length by Southern Blot. Results: high levels of TRF1 were observed in 68.7% of tumor samples, while the majority of normal samples (59% showed negative or weak TRF1 concentrations. Among the tumor samples, telomere length was significantly associated with TRF1 protein levels (p = 0.023. Conclusions: a relationship was found between telomere length and TRF1 abundance protein in tumor samples, which means that TRF1 is an important factor in the tumor progression and maybe a diagnostic factor.

  7. RAD51 and RTEL1 compensate telomere loss in the absence of telomerase.

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    Olivier, Margaux; Charbonnel, Cyril; Amiard, Simon; White, Charles I; Gallego, Maria E

    2018-03-16

    Replicative erosion of telomeres is naturally compensated by telomerase and studies in yeast and vertebrates show that homologous recombination can compensate for the absence of telomerase. We show that RAD51 protein, which catalyzes the key strand-invasion step of homologous recombination, is localized at Arabidopsis telomeres in absence of telomerase. Blocking the strand-transfer activity of the RAD51 in telomerase mutant plants results in a strikingly earlier onset of developmental defects, accompanied by increased numbers of end-to-end chromosome fusions. Imposing replication stress through knockout of RNaseH2 increases numbers of chromosome fusions and reduces the survival of these plants deficient for telomerase and homologous recombination. This finding suggests that RAD51-dependent homologous recombination acts as an essential backup to the telomerase for compensation of replicative telomere loss to ensure genome stability. Furthermore, we show that this positive role of RAD51 in telomere stability is dependent on the RTEL1 helicase. We propose that a RAD51 dependent break-induced replication process is activated in cells lacking telomerase activity, with RTEL1 responsible for D-loop dissolution after telomere replication.

  8. Chalcone-imidazolone conjugates induce apoptosis through DNA damage pathway by affecting telomeres

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    Kamal Ahmed

    2011-04-01

    Full Text Available Abstract Background Breast cancer is one of the most prevalent cancers in the world and more than one million women are diagnosed leading to 410,000 deaths every year. In our previous studies new chalcone-imidazolone conjugates were prepared and evaluated for their anticancer activity in a panel of 53 human tumor cell lines and the lead compounds identified were 6 and 8. This prompted us to investigate the mechanism of apoptotic event. Results Involvement of pro-apoptotic protein (Bax, active caspase-9 and cleavage of retinoblastoma protein was studied. Interestingly, the compounds caused upregulation of p21, check point proteins (Chk1, Chk2 and as well as their phosphorylated forms which are known to regulate the DNA damage pathway. Increased p53BP1 foci by immunolocalisation studies and TRF1 suggested the possible involvement of telomere and associated proteins in the apoptotic event. The telomeric protein such as TRF2 which is an important target for anticancer therapy against human breast cancer was extensively studied along with proteins involved in proper functioning of telomeres. Conclusions The apoptotic proteins such as Bax, active caspase-9 and cleaved RB are up-regulated in the compound treated cells revealing the apoptotic nature of the compounds. Down regulation of TRF2 and upregulation of the TRF1 as well as telomerase assay indicated the decrease in telomeric length revealing telomeric dysfunction and thereby controlling the rapid rate of cell proliferation. In summary, chalcone-imidazolone conjugates displayed significant DNA damage activity particularly at telomeres and caused both apoptosis and senescence-like growth arrest which suggested that these compounds have potential activity against breast carcinoma.

  9. Shorter preschool, leukocyte telomere length is associated with obesity at age 9 in Latino children

    DEFF Research Database (Denmark)

    Kjaer, Thora Wesenberg; Faurholt-Jepsen, D; Mehta, K M

    2018-01-01

    The aim of this study was to determine the potential role of leukocyte telomere length as a biomarker for development of childhood obesity in a low-income Latino population. A birth cohort of Latino children (N = 201) in San Francisco (recruited May 2006-May 2007) was followed until age 9...... and assessed annually for obesity and dietary intake. Leukocyte telomere length was measured at 4 and 5 years (n = 102) and assessed as a predictor for obesity at age 9, adjusting for known risk factors. Furthermore, leukocyte telomere length at age 4 and 5 was evaluated as a possible mediator...... of the relationship between excessive sugar-sweetened beverage consumption and obesity at age 9. Shorter leukocyte telomere length in preschoolers was associated with obesity at age 9 (adjusted odds ratio 0.35, 95% confidence interval 0.13-0.94) after adjustment for known risk factors. Telomere length mediated 11...

  10. Magellanic penguin telomeres do not shorten with age with increased reproductive effort, investment, and basal corticosterone.

    Science.gov (United States)

    Cerchiara, Jack A; Risques, Rosa Ana; Prunkard, Donna; Smith, Jeffrey R; Kane, Olivia J; Boersma, P Dee

    2017-08-01

    All species should invest in systems that enhance longevity; however, a fundamental adult life-history trade-off exists between the metabolic resources allocated to maintenance and those allocated to reproduction. Long-lived species will invest more in reproduction than in somatic maintenance as they age. We investigated this trade-off by analyzing correlations among telomere length, reproductive effort and output, and basal corticosterone in Magellanic penguins ( Spheniscus magellanicus ). Telomeres shorten with age in most species studied to date, and may affect adult survival. High basal corticosterone is indicative of stressful conditions. Corticosterone, and stress, has been linked to telomere shortening in other species. Magellanic penguins are a particularly good model organism for this question as they are an unusually long-lived species, exceeding their mass-adjusted predicted lifespan by 26%. Contrary to our hypothesis, we found adults aged 5 years to over 24 years of age had similar telomere lengths. Telomeres of adults did not shorten over a 3-year period, regardless of the age of the individual. Neither telomere length, nor the rate at which the telomeres changed over these 3 years, correlated with breeding frequency or investment. Older females also produced larger volume clutches until approximately 15 years old and larger eggs produced heavier fledglings. Furthermore, reproductive success ( chicks fledged/eggs laid ) is maintained as females aged. Basal corticosterone, however, was not correlated with telomere length in adults and suggests that low basal corticosterone may play a role in the telomere maintenance we observed. Basal corticosterone also declined during the breeding season and was positively correlated with the age of adult penguins. This higher basal corticosterone in older individuals, and consistent reproductive success, supports the prediction that Magellanic penguins invest more in reproduction as they age. Our results

  11. Shorter telomeres in peripheral blood mononuclear cells from older persons with sarcopenia: results from an exploratory study

    Directory of Open Access Journals (Sweden)

    Emanuele eMarzetti

    2014-08-01

    Full Text Available Background. Telomere shortening in peripheral blood mononuclear cells (PBMCs has been associated with biological age and several chronic degenerative diseases. However, the relationship between telomere length and sarcopenia, a hallmark of the aging process, is unknown. The aim of the present study was therefore to determine whether PBMC telomeres obtained from sarcopenic older persons were shorter relative to non-sarcopenic peers. We further explored if PBMC telomere length was associated with frailty, a major clinical correlate of sarcopenia.Methods. Analyses were conducted in 142 persons aged >/= 65 years referred to a geriatric outpatient clinic (University Hospital. The presence of sarcopenia was established according to the European Working Group on Sarcopenia in Older People criteria, with bioelectrical impedance analysis used for muscle mass estimation. The frailty status was determined by both the Fried’s criteria (physical frailty, PF and a modified Rockwood’s frailty index (FI. Telomere length was measured in PBMCs by quantitative real-time polymerase chain reaction according to the Telomere/Single copy gene ratio (T/S method.Results. Among 142 outpatients (mean age 75.0 ± 6.5 years, 59.2% women, sarcopenia was diagnosed in 23 individuals (19.3%. The PF phenotype was detected in 74 participants (52.1%. The average FI score was 0.46 ± 0.17. PBMC telomeres were shorter in sarcopenic subjects (T/S = 0.21; 95% CI: 0.18 – 0.24 relative to non-sarcopenic individuals (T/S = 0.26; 95%: CI: 0.24 – 0.28; p = 0.01, independent of age, gender, smoking habit, or comorbidity. No significant associations were determined between telomere length and either PF or FI.Conclusion. PBMC telomere length, expressed as T/S values, is shorter in older outpatients with sarcopenia. The cross-sectional assessment of PBMC telomere length is not sufficient at capturing the complex, multidimensional syndrome of frailty.

  12. High tobacco consumption is causally associated with increased all-cause mortality in a general population sample of 55 568 individuals, but not with short telomeres

    DEFF Research Database (Denmark)

    Rode, Line; Bojesen, Stig E; Weischer, Maren

    2014-01-01

    ,568 individuals including 32,823 ever smokers from the Danish general population, of whom 3430 died during 10 years of follow-up. All had telomere length measured, detailed information on smoking history, and CHRNA3 rs1051730 genotype, which is associated with tobacco consumption, determined. In a Mendelian...... randomization study, we conducted observational, genetic, and mediation analyses. RESULTS: First, tobacco consumption was 21.1 pack-years in non-carriers, 22.8 in heterozygotes and 24.8 in homozygotes (P-trend....12 [95% confidence interval (CI): 1.09, 1.15] per doubling in tobacco consumption. In Mendelian randomization analysis, the hazard ratio was 1.08 (1.02, 1.14) per minor CHRNA3 allele in ever smokers. Third, in observational analysis telomeres shortened with -13 base pairs (-18, -8) per doubling...

  13. A calmodulin-like protein (LCALA) is a new Leishmania amazonensis candidate for telomere end-binding protein.

    Science.gov (United States)

    Morea, Edna G O; Viviescas, Maria Alejandra; Fernandes, Carlos A H; Matioli, Fabio F; Lira, Cristina B B; Fernandez, Maribel F; Moraes, Barbara S; da Silva, Marcelo S; Storti, Camila B; Fontes, Marcos R M; Cano, Maria Isabel N

    2017-11-01

    Leishmania spp. telomeres are composed of 5'-TTAGGG-3' repeats associated with proteins. We have previously identified LaRbp38 and LaRPA-1 as proteins that bind the G-rich telomeric strand. At that time, we had also partially characterized a protein: DNA complex, named LaGT1, but we could not identify its protein component. Using protein-DNA interaction and competition assays, we confirmed that LaGT1 is highly specific to the G-rich telomeric single-stranded DNA. Three protein bands, with LaGT1 activity, were isolated from affinity-purified protein extracts in-gel digested, and sequenced de novo using mass spectrometry analysis. In silico analysis of the digested peptide identified them as a putative calmodulin with sequences identical to the T. cruzi calmodulin. In the Leishmania genome, the calmodulin ortholog is present in three identical copies. We cloned and sequenced one of the gene copies, named it LCalA, and obtained the recombinant protein. Multiple sequence alignment and molecular modeling showed that LCalA shares homology to most eukaryotes calmodulin. In addition, we demonstrated that LCalA is nuclear, partially co-localizes with telomeres and binds in vivo the G-rich telomeric strand. Recombinant LCalA can bind specifically and with relative affinity to the G-rich telomeric single-strand and to a 3'G-overhang, and DNA binding is calcium dependent. We have described a novel candidate component of Leishmania telomeres, LCalA, a nuclear calmodulin that binds the G-rich telomeric strand with high specificity and relative affinity, in a calcium-dependent manner. LCalA is the first reported calmodulin that binds in vivo telomeric DNA. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Influence of exposure to pesticides on telomere length in tobacco farmers: A biology system approach.

    Science.gov (United States)

    Kahl, Vivian Francília Silva; da Silva, Juliana; da Silva, Fernanda Rabaioli

    Various pesticides in the form of mixtures must be used to keep tobacco crops pest-free. Recent studies have shown a link between occupational exposure to pesticides in tobacco crops and increased damage to the DNA, mononuclei, nuclear buds and binucleated cells in buccal cells as well as micronuclei in lymphocytes. Furthermore, pesticides used specifically for tobacco crops shorten telomere length (TL) significantly. However, the molecular mechanism of pesticide action on telomere length is not fully understood. Our study evaluated the interaction between a complex mixture of chemical compounds (tobacco cultivation pesticides plus nicotine) and proteins associated with maintaining TL, as well as the biological processes involved in this exposure by System Biology tools to provide insight regarding the influence of pesticide exposure on TL maintenance in tobacco farmers. Our analysis showed that one cluster was associated with TL proteins that act in bioprocesses such as (i) telomere maintenance via telomere lengthening; (ii) senescence; (iii) age-dependent telomere shortening; (iv) DNA repair (v) cellular response to stress and (vi) regulation of proteasome ubiquitin-dependent protein catabolic process. We also describe how pesticides and nicotine regulate telomere length. In addition, pesticides inhibit the ubiquitin proteasome system (UPS) and consequently increase proteins of the shelterin complex, avoiding the access of telomerase in telomere and, nicotine activates UPS mechanisms and promotes the degradation of human telomerase reverse transcriptase (hTERT), decreasing telomerase activity. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Short initial length quench on CICC of ITER TF coils

    Energy Technology Data Exchange (ETDEWEB)

    Nicollet, S.; Ciazynski, D.; Duchateau, J.-L.; Lacroix, B. [CEA, IRFM, F-13108 Saint-Paul-lez-Durance (France); Bessette, D.; Rodriguez-Mateos, F. [ITER Organization, Route de Vinon sur Verdon, 13115 Saint Paul Lez Durance (France); Coatanea-Gouachet, M. [ELC Engineering, 350 chemin du Verladet, F-13290 Les Milles (France); Gauthier, F. [Soditech Ingenierie, 4 bis allée des Gabians, ZI La Frayère, 06150 Cannes (France)

    2014-01-29

    Previous quench studies performed for the International Thermonuclear Experimental Reactor (ITER) Toroidal Field (TF) Coils have led to identify two extreme families of quench: first 'severe' quenches over long initial lengths in high magnetic field, and second smooth quenches over short initial lengths in low field region. Detailed analyses and results on smooth quench propagation and detectability on one TF Cable In Conduit Conductor (CICC) with a lower propagation velocity are presented here. The influence of the initial quench energy is shown and results of computations with either a Fast Discharge (FD) of the magnet or without (failure of the voltage quench detection system) are reported. The influence of the central spiral of the conductor on the propagation velocity is also detailed. In the cases of a regularly triggered FD, the hot spot temperature criterion of 150 K (with helium and jacket) is fulfilled for an initial quench length of 1 m, whereas this criterion is exceed (Tmax ≈ 200 K) for an extremely short length of 5 cm. These analyses were carried out using both the Supermagnet(trade mark, serif) and Venecia codes and the comparisons of the results are also discussed.

  16. Short initial length quench on CICC of ITER TF coils

    International Nuclear Information System (INIS)

    Nicollet, S.; Ciazynski, D.; Duchateau, J.-L.; Lacroix, B.; Bessette, D.; Rodriguez-Mateos, F.; Coatanea-Gouachet, M.; Gauthier, F.

    2014-01-01

    Previous quench studies performed for the International Thermonuclear Experimental Reactor (ITER) Toroidal Field (TF) Coils have led to identify two extreme families of quench: first 'severe' quenches over long initial lengths in high magnetic field, and second smooth quenches over short initial lengths in low field region. Detailed analyses and results on smooth quench propagation and detectability on one TF Cable In Conduit Conductor (CICC) with a lower propagation velocity are presented here. The influence of the initial quench energy is shown and results of computations with either a Fast Discharge (FD) of the magnet or without (failure of the voltage quench detection system) are reported. The influence of the central spiral of the conductor on the propagation velocity is also detailed. In the cases of a regularly triggered FD, the hot spot temperature criterion of 150 K (with helium and jacket) is fulfilled for an initial quench length of 1 m, whereas this criterion is exceed (Tmax ≈ 200 K) for an extremely short length of 5 cm. These analyses were carried out using both the Supermagnet(trade mark, serif) and Venecia codes and the comparisons of the results are also discussed

  17. End-joining inhibition at telomeres requires the translocase and polySUMO-dependent ubiquitin ligase Uls1.

    Science.gov (United States)

    Lescasse, Rachel; Pobiega, Sabrina; Callebaut, Isabelle; Marcand, Stéphane

    2013-03-20

    In eukaryotes, permanent inhibition of the non-homologous end joining (NHEJ) repair pathway at telomeres ensures that chromosome ends do not fuse. In budding yeast, binding of Rap1 to telomere repeats establishes NHEJ inhibition. Here, we show that the Uls1 protein is required for the maintenance of NHEJ inhibition at telomeres. Uls1 protein is a non-essential Swi2/Snf2-related translocase and a Small Ubiquitin-related Modifier (SUMO)-Targeted Ubiquitin Ligase (STUbL) with unknown targets. Loss of Uls1 results in telomere-telomere fusions. Uls1 requirement is alleviated by the absence of poly-SUMO chains and by rap1 alleles lacking SUMOylation sites. Furthermore, Uls1 limits the accumulation of Rap1 poly-SUMO conjugates. We propose that one of Uls1 functions is to clear non-functional poly-SUMOylated Rap1 molecules from telomeres to ensure the continuous efficiency of NHEJ inhibition. Since Uls1 is the only known STUbL with a translocase activity, it can be the general molecular sweeper for the clearance of poly-SUMOylated proteins on DNA in eukaryotes.

  18. DNA breaks and repair in interstitial telomere sequences: Influence of chromatin structure

    International Nuclear Information System (INIS)

    Revaud, D.

    2009-06-01

    Interstitial Telomeric Sequences (ITS) are over-involved in spontaneous and radiationinduced chromosome aberrations in chinese hamster cells. We have performed a study to investigate the origin of their instability, spontaneously or after low doses irradiation. Our results demonstrate that ITS have a particular chromatin structure: short nucleotide repeat length, less compaction of the 30 nm chromatin fiber, presence of G-quadruplex structures. These features would modulate breaks production and would favour the recruitment of alternative DNA repair mechanisms, which are prone to produce chromosome aberrations. These pathways could be at the origin of chromosome aberrations in ITS whereas NHEJ and HR Double Strand Break repair pathways are rather required for a correct repair in these regions. (author)

  19. Hypomethylating drugs efficiently decrease cytosine methylation in telomeric DNA and activate telomerase without affecting telomere lengths in tobacco cells

    Czech Academy of Sciences Publication Activity Database

    Majerová, E.; Fojtová, M.; Mozgová, I.; Bittová, M.; Fajkus, Jiří

    2011-01-01

    Roč. 77, 4-5 (2011), s. 371-380 ISSN 0167-4412 Institutional support: RVO:68081707 Keywords : Nicotiana tabacum * Cell culture * Telomere Subject RIV: BO - Biophysics Impact factor: 4.150, year: 2011

  20. Detection of circular telomeric DNA without 2D gel electrophoresis.

    Science.gov (United States)

    Dlaska, Margit; Anderl, Conrad; Eisterer, Wolfgang; Bechter, Oliver E

    2008-09-01

    The end of linear chromosomes forms a lasso-like structure called the t-loop. Such t-loops resemble a DNA recombination intermediate, where the single-stranded 3' overhang is arrested in a stretch of duplex DNA. Presumably, such a t-loop can also be deleted via a recombination process. This would result in the occurrence of circular extrachromosomal telomeric DNA (t-circles), which are known to be abundantly present in immortal cells engaging the recombination-based alternative lengthening of telomeres pathway (ALT pathway). Little is known about the basic mechanism of telomeric recombination in these cells and what ultimately causes the generation of such t-circles. Current standard procedures for detecting these molecules involve 2D gel electrophoresis or electron microscopy. However, both methods are labor intense and sophisticated to perform. Here, we present a simpler, faster, and equally sensitive method for detecting t-circles. Our approach is a telomere restriction fragment assay that involves the enzymatic preservation of circular DNA with Klenow enzyme followed by Bal31 degradation of the remaining linear DNA molecules. We show that with this approach t-circles can be detected in ALT cell lines, whereas no t-circles are present in telomerase-positive cell lines. We consider our approach a valid method in which t-circle generation is the experimental readout.

  1. Conformation and stability of intramolecular telomeric G-quadruplexes: sequence effects in the loops.

    Directory of Open Access Journals (Sweden)

    Giovanna Sattin

    Full Text Available Telomeres are guanine-rich sequences that protect the ends of chromosomes. These regions can fold into G-quadruplex structures and their stabilization by G-quadruplex ligands has been employed as an anticancer strategy. Genetic analysis in human telomeres revealed extensive allelic variation restricted to loop bases, indicating that the variant telomeric sequences maintain the ability to fold into G-quadruplex. To assess the effect of mutations in loop bases on G-quadruplex folding and stability, we performed a comprehensive analysis of mutant telomeric sequences by spectroscopic techniques, molecular dynamics simulations and gel electrophoresis. We found that when the first position in the loop was mutated from T to C or A the resulting structure adopted a less stable antiparallel topology; when the second position was mutated to C or A, lower thermal stability and no evident conformational change were observed; in contrast, substitution of the third position from A to C induced a more stable and original hybrid conformation, while mutation to T did not significantly affect G-quadruplex topology and stability. Our results indicate that allelic variations generate G-quadruplex telomeric structures with variable conformation and stability. This aspect needs to be taken into account when designing new potential anticancer molecules.

  2. Human regulator of telomere elongation helicase 1 (RTEL1) is required for the nuclear and cytoplasmic trafficking of pre-U2 RNA.

    Science.gov (United States)

    Schertzer, Michael; Jouravleva, Karina; Perderiset, Mylene; Dingli, Florent; Loew, Damarys; Le Guen, Tangui; Bardoni, Barbara; de Villartay, Jean-Pierre; Revy, Patrick; Londoño-Vallejo, Arturo

    2015-02-18

    Hoyeraal-Hreidarsson syndrome (HHS) is a severe form of Dyskeratosis congenita characterized by developmental defects, bone marrow failure and immunodeficiency and has been associated with telomere dysfunction. Recently, mutations in Regulator of Telomere ELongation helicase 1 (RTEL1), a helicase first identified in Mus musculus as being responsible for the maintenance of long telomeres, have been identified in several HHS patients. Here we show that RTEL1 is required for the export and the correct cytoplasmic trafficking of the small nuclear (sn) RNA pre-U2, a component of the major spliceosome complex. RTEL1-HHS cells show abnormal subcellular partitioning of pre-U2, defects in the recycling of ribonucleotide proteins (RNP) in the cytoplasm and splicing defects. While most of these phenotypes can be suppressed by re-expressing the wild-type protein in RTEL1-HHS cells, expression of RTEL1 mutated variants in immortalized cells provokes cytoplasmic mislocalizations of pre-U2 and other RNP components, as well as splicing defects, thus phenocopying RTEL1-HHS cellular defects. Strikingly, expression of a cytoplasmic form of RTEL1 is sufficient to correct RNP mislocalizations both in RTEL1-HHS cells and in cells expressing nuclear mutated forms of RTEL1. This work unravels completely unanticipated roles for RTEL1 in RNP trafficking and strongly suggests that defects in RNP biogenesis pathways contribute to the pathology of HHS. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  3. Association Between Leukocyte Telomere Length and the Risk of Incident Atrial Fibrillation

    DEFF Research Database (Denmark)

    Staerk, Laila; Wang, Biqi; Lunetta, Kathryn L

    2017-01-01

    BACKGROUND: Advancing age is a prominent risk factor for atrial fibrillation (AF). Shorter telomere length is a biomarker of biological aging, but the link between shorter telomere length and increased risk of AF remains unclear. We examined the association between shorter leukocyte telomere length...... at baseline was 6.95±0.57 kb. During 15.1±4.2 years mean follow-up, 184 participants (64 women) developed AF. Chronological age was associated with increased risk of AF (hazard ratio per 10-year increase, 2.16; 95% confidence interval, 1.71-2.72). There was no significant association between LTL and incident...... evidence for a significant association between LTL and risk of incident AF....

  4. Shorter preschool, leukocyte telomere length is associated with obesity at age 9 in Latino children.

    Science.gov (United States)

    Kjaer, T W; Faurholt-Jepsen, D; Mehta, K M; Christensen, V B; Epel, E; Lin, J; Blackburn, E; Wojcicki, J M

    2018-04-01

    The aim of this study was to determine the potential role of leukocyte telomere length as a biomarker for development of childhood obesity in a low-income Latino population. A birth cohort of Latino children (N = 201) in San Francisco (recruited May 2006-May 2007) was followed until age 9 and assessed annually for obesity and dietary intake. Leukocyte telomere length was measured at 4 and 5 years (n = 102) and assessed as a predictor for obesity at age 9, adjusting for known risk factors. Furthermore, leukocyte telomere length at age 4 and 5 was evaluated as a possible mediator of the relationship between excessive sugar-sweetened beverage consumption and obesity at age 9. Shorter leukocyte telomere length in preschoolers was associated with obesity at age 9 (adjusted odds ratio 0.35, 95% confidence interval 0.13-0.94) after adjustment for known risk factors. Telomere length mediated 11% of the relationship between excessive sugar-sweetened beverage consumption and obesity. Shorter leukocyte telomere length may be an indicator of future obesity risk in high-risk populations as it is particularly sensitive to damage from oxidative stress exposure, including those from sugar-sweetened beverages. © 2017 World Obesity Federation.

  5. Accelerated telomere shortening: Tracking the lasting impact of early institutional care at the cellular level.

    Science.gov (United States)

    Humphreys, Kathryn L; Esteves, Kyle; Zeanah, Charles H; Fox, Nathan A; Nelson, Charles A; Drury, Stacy S

    2016-12-30

    Studies examining the association between early adversity and longitudinal changes in telomere length within the same individual are rare, yet are likely to provide novel insight into the subsequent lasting effects of negative early experiences. We sought to examine the association between institutional care history and telomere shortening longitudinally across middle childhood and into adolescence. Buccal DNA was collected 2-4 times, between the ages of 6 and 15 years, in 79 children enrolled in the Bucharest Early Intervention Project (BEIP), a longitudinal study exploring the impact of early institutional rearing on child health and development. Children with a history of early institutional care (n=50) demonstrated significantly greater telomere shortening across middle childhood and adolescence compared to never institutionalized children (n=29). Among children with a history of institutional care, randomization to high quality foster care was not associated with differential telomere attrition across development. Cross-sectional analysis of children randomized to the care as usual group indicated shorter telomere length was associated with greater percent of the child's life spent in institutional care up to age 8. These results suggest that early adverse care from severe psychosocial deprivation may be embedded at the molecular genetic level through accelerated telomere shortening. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Telomere length is highly inherited and associated with hyperactivity-impulsivity in children with attention deficit/hyperactivity disorder

    Directory of Open Access Journals (Sweden)

    Danielle Souza Costa

    2015-07-01

    Full Text Available Telomere length (TL is highly heritable, and a shorter telomere at birth may increase the risk of age-related problems. Telomere length (TL is highly heritable, and a shorter telomere at birth may increase the risk of age-related problems. Additionally, a shorter TL may represent a biomarker of chronic stress and has been associated with psychiatric disorders. However, no study has explored whether there is an association between TL and the symptoms of one of the most common neurodevelopmental disorders in childhood: Attention Deficit/Hyperactive Disorder (ADHD. We evaluated 61 (range, 6-16 years ADHD children and their parents between 2012 and 2014. Telomere length was measured with a quantitative polymerase chain reaction method with telomere signal normalized to the signal from a single copy gene (36B4 to generate a T/S ratio. Family data was processed through a GEE model to determine the effect of parental TL on children TL. Inattentive and hyperactive-impulsive symptoms were also evaluated in relation to TL. For the first time, we found general heritability to be the major mechanism explaining interindividual telomere length variation in ADHD (father-child: 95%CI=0.35/0.91, p0.05. The ADHD inattentive dimension was not significant associated with TL in this study (p>0.05. TL was shown to be a potential biomarker of the ADHD symptoms burden in families affected by this neurodevelopmental disorder. However, it is crucial that future studies investigating the rate of telomere attrition in relation to psychiatric problems to consider the strong determination of telomere length at birth by inheritance.

  7. Telomere-mediated chromosomal instability triggers TLR4 induced inflammation and death in mice.

    Directory of Open Access Journals (Sweden)

    Rabindra N Bhattacharjee

    Full Text Available BACKGROUND: Telomeres are essential to maintain chromosomal stability. Cells derived from mice lacking telomerase RNA component (mTERC-/- mice display elevated telomere-mediated chromosome instability. Age-dependent telomere shortening and associated chromosome instability reduce the capacity to respond to cellular stress occurring during inflammation and cancer. Inflammation is one of the important risk factors in cancer progression. Controlled innate immune responses mediated by Toll-like receptors (TLR are required for host defense against infection. Our aim was to understand the role of chromosome/genome instability in the initiation and maintenance of inflammation. METHODOLOGY/PRINCIPAL FINDINGS: We examined the function of TLR4 in telomerase deficient mTERC-/- mice harbouring chromosome instability which did not develop any overt immunological disorder in pathogen-free condition or any form of cancers at this stage. Chromosome instability was measured in metaphase spreads prepared from wildtype (mTERC+/+, mTERC+/- and mTERC-/- mouse splenocytes. Peritoneal and/or bone marrow-derived macrophages were used to examine the responses of TLR4 by their ability to produce inflammatory mediators TNFalpha and IL6. Our results demonstrate that TLR4 is highly up-regulated in the immune cells derived from telomerase-null (mTERC-/- mice and lipopolysaccharide, a natural ligand for TLR4 stabilises NF-kappaB binding to its promoter by down-regulating ATF-3 in mTERC-/- macrophages. CONCLUSIONS/SIGNIFICANCE: Our findings implied that background chromosome instability in the cellular level stabilises the action of TLR4-induced NF-kappaB action and sensitises cells to produce excess pro-inflammatory mediators. Chromosome/genomic instability data raises optimism for controlling inflammation by non-toxic TLR antagonists among high-risk groups.

  8. Suppression of the initial transient in Monte Carlo criticality simulations

    International Nuclear Information System (INIS)

    Richet, Y.

    2006-12-01

    Criticality Monte Carlo calculations aim at estimating the effective multiplication factor (k-effective) for a fissile system through iterations simulating neutrons propagation (making a Markov chain). Arbitrary initialization of the neutron population can deeply bias the k-effective estimation, defined as the mean of the k-effective computed at each iteration. A simplified model of this cycle k-effective sequence is built, based on characteristics of industrial criticality Monte Carlo calculations. Statistical tests, inspired by Brownian bridge properties, are designed to discriminate stationarity of the cycle k-effective sequence. The initial detected transient is, then, suppressed in order to improve the estimation of the system k-effective. The different versions of this methodology are detailed and compared, firstly on a plan of numerical tests fitted on criticality Monte Carlo calculations, and, secondly on real criticality calculations. Eventually, the best methodologies observed in these tests are selected and allow to improve industrial Monte Carlo criticality calculations. (author)

  9. Telomere Dynamics in Immune Senescence and Exhaustion Triggered by Chronic Viral Infection

    Directory of Open Access Journals (Sweden)

    Marcia Bellon

    2017-10-01

    Full Text Available The progressive loss of immunological memory during aging correlates with a reduced proliferative capacity and shortened telomeres of T cells. Growing evidence suggests that this phenotype is recapitulated during chronic viral infection. The antigenic volume imposed by persistent and latent viruses exposes the immune system to unique challenges that lead to host T-cell exhaustion, characterized by impaired T-cell functions. These dysfunctional memory T cells lack telomerase, the protein capable of extending and stabilizing chromosome ends, imposing constraints on telomere dynamics. A deleterious consequence of this excessive telomere shortening is the premature induction of replicative senescence of viral-specific CD8+ memory T cells. While senescent cells are unable to expand, they can survive for extended periods of time and are more resistant to apoptotic signals. This review takes a closer look at T-cell exhaustion in chronic viruses known to cause human disease: Epstein–Barr virus (EBV, Hepatitis B/C/D virus (HBV/HCV/HDV, human herpesvirus 8 (HHV-8, human immunodeficiency virus (HIV, human T-cell leukemia virus type I (HTLV-I, human papillomavirus (HPV, herpes simplex virus-1/2(HSV-1/2, and Varicella–Zoster virus (VZV. Current literature linking T-cell exhaustion with critical telomere lengths and immune senescence are discussed. The concept that enduring antigen stimulation leads to T-cell exhaustion that favors telomere attrition and a cell fate marked by enhanced T-cell senescence appears to be a common endpoint to chronic viral infections.

  10. Evidence for alternative lengthening of telomeres in liposarcomas in the absence of ALT-associated PML bodies.

    Science.gov (United States)

    Jeyapalan, Jennie N; Mendez-Bermudez, Aaron; Zaffaroni, Nadia; Dubrova, Yuri E; Royle, Nicola J

    2008-06-01

    Immortalized and cancer cells maintain their telomeres by activation of a telomere maintenance mechanism (TMM). In approximately 85% of cancers telomerase is activated (TA) but in some tumours, in particular sarcomas, an alternative lengthening of telomeres (ALT) pathway is used. Liposarcomas are the most common soft-tissue sarcoma in adults and they activate ALT or telomerase with equal frequency, however no TMM has been identified in approximately 50% of liposarcomas. In our study, we have shown that instability at the minisatellite MS32, usually associated with ALT activation, aids the identification of liposarcomas that have recombination-like activity at telomeres in absence of ALT associated PML-bodies (APBs). Furthermore, using single molecule telomere analysis, we have detected complex telomere mutations directly in ALT positive liposarcomas and interestingly in some liposarcomas with an unknown TMM but high MS32 instability. We have shown by sequence analysis that some of these complex telomere mutations must arise by an inter-molecular recombination-like process rather than by deletion caused by t-loop excision or by unequal telomere-sister-chromatid-exchange (T-SCE), which is known to be elevated in ALT cell lines. Preliminary evidence also suggests that inter-molecular recombination events may be processed differently in liposarcomas with APBs compared to those without. In conclusion, we have shown for the first time, that some telomerase negative liposarcomas without APBs have other features associated with ALT, indicating that the incidence of ALT in these tumours has previously been under-estimated. This has major implications for the use of cancer treatments targeted at TMMs. (c) 2008 Wiley-Liss, Inc.

  11. Marital disruption is associated with shorter salivary telomere length in a probability sample of older adults.

    Science.gov (United States)

    Whisman, Mark A; Robustelli, Briana L; Sbarra, David A

    2016-05-01

    Marital disruption (i.e., marital separation, divorce) is associated with a wide range of poor mental and physical health outcomes, including increased risk for all-cause mortality. One biological intermediary that may help explain the association between marital disruption and poor health is accelerated cellular aging. This study examines the association between marital disruption and salivary telomere length in a United States probability sample of adults ≥50 years of age. Participants were 3526 individuals who participated in the 2008 wave of the Health and Retirement Study. Telomere length assays were performed using quantitative real-time polymerase chain reaction (qPCR) on DNA extracted from saliva samples. Health and lifestyle factors, traumatic and stressful life events, and neuroticism were assessed via self-report. Linear regression analyses were conducted to examine the associations between predictor variables and salivary telomere length. Based on their marital status data in the 2006 wave, people who were separated or divorced had shorter salivary telomeres than people who were continuously married or had never been married, and the association between marital disruption and salivary telomere length was not moderated by gender or neuroticism. Furthermore, the association between marital disruption and salivary telomere length remained statistically significant after adjusting for demographic and socioeconomic variables, neuroticism, cigarette use, body mass, traumatic life events, and other stressful life events. Additionally, results revealed that currently married adults with a history of divorce evidenced shorter salivary telomeres than people who were continuously married or never married. Accelerated cellular aging, as indexed by telomere shortening, may be one pathway through which marital disruption is associated with morbidity and mortality. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. TERRA Expression Levels Do Not Correlate With Telomere Length and Radiation Sensitivity in Human Cancer Cell Lines

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    Alexandra eSmirnova

    2013-05-01

    Full Text Available Mammalian telomeres are transcribed into long non-coding telomeric RNA molecules (TERRA that seem to play a role in the maintenance of telomere stability. In human cells, CpG island promoters drive TERRA transcription and are regulated by methylation. It was suggested that the amount of TERRA may be related to telomere length. To test this hypothesis we measured telomere length and TERRA levels in single clones isolated from five human cell lines: HeLa (cervical carcinoma, BRC-230 (breast cancer, AKG and GK2 (gastric cancers and GM847 (SV40 immortalized skin fibroblasts. We observed great clonal heterogeneity both in TRF (Terminal Restriction Fragment length and in TERRA levels. However, these two parameters did not correlate with each other. Moreover, cell survival to γ-rays did not show a significant variation among the clones, suggesting that, in this cellular system, the intra-population variability in telomere length and TERRA levels does not influence sensitivity to ionizing radiation. This conclusion was supported by the observation that in a cell line in which telomeres were greatly elongated by the ectopic expression of telomerase, TERRA expression levels and radiation sensitivity were similar to the parental HeLa cell line.

  13. Childhood socioeconomic status, telomere length, and susceptibility to upper respiratory infection.

    Science.gov (United States)

    Cohen, Sheldon; Janicki-Deverts, Denise; Turner, Ronald B; Marsland, Anna L; Casselbrant, Margaretha L; Li-Korotky, Ha-Sheng; Epel, Elissa S; Doyle, William J

    2013-11-01

    Low socioeconomic status (SES) during childhood and adolescence has been found to predict greater susceptibility to common cold viruses in adults. Here, we test whether low childhood SES is associated with shorter leukocyte telomere length in adulthood, and whether telomere length mediates the association between childhood SES and susceptibility to acute upper respiratory disease in adulthood. At baseline, 196 healthy volunteers reported whether they currently owned their home and, for each year of their childhood, whether their parents owned the family home. Volunteers also had blood drawn for assessment of specific antibody to the challenge virus, and for CD8+ CD28- T-lymphocyte telomere length (in a subset, n=135). They were subsequently quarantined in a hotel, exposed to a virus (rhinovirus [RV] 39) that causes a common cold and followed for infection and illness (clinical cold) over five post-exposure days. Lower childhood SES as measured by fewer years of parental home ownership was associated with shorter adult CD8+ CD28- telomere length and with an increased probability of developing infection and clinical illness when exposed to a common cold virus in adulthood. These associations were independent of adult SES, age, sex, race, body mass, neuroticism, and childhood family characteristics. Associations with infections and colds were also independent of pre-challenge viral-specific antibody and season. Further analyses do not support mediating roles for smoking, alcohol consumption or physical activity but suggest that CD8+ CD28- cell telomere length may act as a partial mediator of the associations between childhood SES and infection and childhood SES and colds. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Systemic lupus erythematosus and vitamin D deficiency are associated with shorter telomere length among African Americans: a case-control study.

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    Brett M Hoffecker

    Full Text Available Systemic lupus erythematosus (SLE is a chronic systemic autoimmune disease that disproportionately affects African American females. The causes of SLE are unknown but postulated to be a combination of genetic predisposition and environmental triggers. Vitamin D deficiency is one of the possible environmental triggers. In this study we evaluated relationships between vitamin D status, cellular aging (telomere length and anti-telomere antibodies among African American Gullah women with SLE. The study population included African American female SLE patients and unaffected controls from the Sea Island region of South Carolina. Serum 25-hydroxyvitamin D levels were measured using a nonchromatographic radioimmunoassay. Telomere length was measured in genomic DNA of peripheral blood mononuclear cells (PBMCs by monochrome multiplex quantitative PCR. Anti-telomere antibody levels were measured by enzyme-linked immunosorbent assay (ELISA. Patients with SLE had significantly shorter telomeres and higher anti-telomere antibody titers compared to age- and gender-matched unaffected controls. There was a positive correlation between anti-telomere antibody levels and disease activity among patients and a significant correlation of shorter telomeres with lower 25-hydroxyvitamin D levels in both patients and controls. In follow-up examination of a subset of the patients, the patients who remained vitamin D deficient tended to have shorter telomeres than those patients whose 25-hydroxyvitamin D levels were repleted. Increasing 25-hydroxyvitamin D levels in African American patients with SLE may be beneficial in maintaining telomere length and preventing cellular aging. Moreover, anti-telomere antibody levels may be a promising biomarker of SLE status and disease activity.

  15. Long telomeres and cancer risk among 95 568 individuals from the general population

    DEFF Research Database (Denmark)

    Rode, Line; Nordestgaard, Børge G; Bojesen, Stig E

    2016-01-01

    BACKGROUND: Results regarding telomere length and cancer risk are conflicting. We tested the hypothesis that long telomeres are associated with increased risk of any cancer and specific cancer types in genetic and observational analyses. METHODS: Individuals (N = 95 568) from the Copenhagen City...... specific cancer types. We conducted Cox regression analyses and logistic regression analyses. The three genotypes were combined as an allele sum. RESULTS: Telomere length increased 67 base-pairs [95% confidence interval (CI) 61-74] per allele. In logistic regression models, the per-allele odds ratio (OR...

  16. Telomere length and long-term endurance exercise: does exercise training affect biological age? A pilot study.

    Directory of Open Access Journals (Sweden)

    Ida Beate Ø Østhus

    Full Text Available BACKGROUND: Telomeres are potential markers of mitotic cellular age and are associated with physical ageing process. Long-term endurance training and higher aerobic exercise capacity (VO(2max are associated with improved survival, and dynamic effects of exercise are evident with ageing. However, the association of telomere length with exercise training and VO(2max has so far been inconsistent. Our aim was to assess whether muscle telomere length is associated with endurance exercise training and VO(2max in younger and older people. METHODS: Twenty men; 10 young (22-27 years and 10 old (66-77 years, were studied in this cross-sectional study. Five out of 10 young adults and 5 out of 10 older were endurance athletes, while other halves were exercising at a medium level of activity. Mean telomere length was measured as telomere/single copy gene-ratio (T/S-ratio using quantitative real time polymerase chain reaction. VO(2max was measured directly running on a treadmill. RESULTS: Older endurance trained athletes had longer telomere length compared with older people with medium activity levels (T/S ratio 1.12±0.1 vs. 0.92±0.2, p = 0.04. Telomere length of young endurance trained athletes was not different than young non-athletes (1.47±0.2 vs. 1.33±0.1, p = 0.12. Overall, there was a positive association between T/S ratio and VO(2max (r = 0.70, p = 0.001. Among endurance trained athletes, we found a strong correlation between VO(2max and T/S ratio (r = 0.78, p = 0.02. However, corresponding association among non-athlete participants was relatively weak (r = 0.58, p = 0.09. CONCLUSION: Our data suggest that VO(2max is positively associated with telomere length, and we found that long-term endurance exercise training may provide a protective effect on muscle telomere length in older people.

  17. Father Loss and Child Telomere Length.

    Science.gov (United States)

    Mitchell, Colter; McLanahan, Sara; Schneper, Lisa; Garfinkel, Irv; Brooks-Gunn, Jeanne; Notterman, Daniel

    2017-08-01

    Father loss during childhood has negative health and behavioral consequences, but the biological consequences are unknown. Our goal was to examine how father loss (because of separation and/or divorce, death, or incarceration) is associated with cellular function as estimated by telomere length. Data come from the 9-year follow-up of the Fragile Families and Child Wellbeing Study, a birth cohort study of children in 20 large American cities ( N = 2420). Principal measures are as follows: salivary telomere length (sTL), mother reports of father loss, and polymorphisms in genes related to serotonergic and dopaminergic signaling. At 9 years of age, children with father loss have significantly shorter telomeres (14% reduction). Paternal death has the largest association (16%), followed by incarceration (10%), and separation and/or divorce (6%). Changes in income partially mediate these associations (95% mediation for separation and/or divorce, 30% for incarceration, and 25% for death). Effects are 40% greater for boys and 90% greater for children with the most reactive alleles of the serotonin transporter genes when compared with those with the least reactive alleles. No differences were found by age at father loss or a child's race/ethnicity. Father loss has a significant association with children's sTL, with the death of a father showing the largest effect. Income loss explains most of the association between child sTL and separation and/or divorce but much less of the association with incarceration or death. This underscores the important role of fathers in the care and development of children and supplements evidence of the strong negative effects of parental incarceration. Copyright © 2017 by the American Academy of Pediatrics.

  18. Telomere length in children environmentally exposed to low-to-moderate levels of lead

    International Nuclear Information System (INIS)

    Pawlas, Natalia; Płachetka, Anna; Kozłowska, Agnieszka; Broberg, Karin; Kasperczyk, Sławomir

    2015-01-01

    Shorter relative telomere length in peripheral blood is a risk marker for some types of cancers and cardiovascular diseases. Several environmental hazards appear to shorten telomeres, and this shortening may predispose individuals to disease. The aim of the present cross-sectional study was to assess the effect of environmental exposure to lead on relative telomere length (rTL) in children. A cohort of 99 8-year-old children was enrolled from 2007–2010. Blood lead concentrations (B-Pb) were measured by graphite furnace atomic absorption spectrometry, and blood rTL was measured by quantitative PCR. The geometric mean of B-Pb was 3.28 μg/dl (range: 0.90–14.2), and the geometric mean of rTL was 1.08 (range: 0.49–2.09). B-Pb was significantly inversely associated with rTL in the children (r S = − 0.25, p = 0.013; in further analyses both log-transformed-univariate regression analysis β = − 0.13, p = 0.026, and R 2 adj 4%; and β = − 0.12, p = 0.056 when adjusting for mothers' smoking during pregnancy, Apgar score, mother's and father's ages at delivery, sex and mother's education, R 2 adj 12%, p = 0.011). The effect of lead remained significant in children without prenatal tobacco exposure (N = 87, r S = − 0.24, p = 0.024; in further analyses, β = − 0.13, p = 0.029, and R 2 adj 4%). rTL was not affected by sex, the concentrations of other elements in the blood (i.e., cadmium and selenium concentrations), or oxidative injury parameters (total antioxidant status, 8-hydroxydeoxyguanosine and thiobarbituric acid-reactive substances). Lead exposure in childhood appears to be associated with shorter telomeres, which might contribute to diseases, such as cardiovascular disease. The inverse association between blood lead level and the telomeres in children emphasizes the importance of further reducing lead levels in the environment. - Highlights: • This cross-sectional study analyzes the association between environmental lead exposure

  19. Telomere length in children environmentally exposed to low-to-moderate levels of lead

    Energy Technology Data Exchange (ETDEWEB)

    Pawlas, Natalia, E-mail: n-pawlas@wp.pl [Institute of Occupational Medicine and Environmental Health, PL 41-200 Sosnowiec (Poland); Płachetka, Anna [Department of Animal Physiology and Ecotoxicology, University of Silesia, Bankowa str. 9, 40-007 Katowice (Poland); Kozłowska, Agnieszka [Institute of Occupational Medicine and Environmental Health, PL 41-200 Sosnowiec (Poland); Broberg, Karin [Institute of Environmental Medicine, Unit of Metals & Health, Box 210, SE-171 77 Stockholm (Sweden); Kasperczyk, Sławomir [Department of Biochemistry, Medical University of Silesia, Katowice, SMDZ in Zabrze, 41-808 Zabrze (Poland)

    2015-09-01

    Shorter relative telomere length in peripheral blood is a risk marker for some types of cancers and cardiovascular diseases. Several environmental hazards appear to shorten telomeres, and this shortening may predispose individuals to disease. The aim of the present cross-sectional study was to assess the effect of environmental exposure to lead on relative telomere length (rTL) in children. A cohort of 99 8-year-old children was enrolled from 2007–2010. Blood lead concentrations (B-Pb) were measured by graphite furnace atomic absorption spectrometry, and blood rTL was measured by quantitative PCR. The geometric mean of B-Pb was 3.28 μg/dl (range: 0.90–14.2), and the geometric mean of rTL was 1.08 (range: 0.49–2.09). B-Pb was significantly inversely associated with rTL in the children (r{sub S} = − 0.25, p = 0.013; in further analyses both log-transformed-univariate regression analysis β = − 0.13, p = 0.026, and R{sup 2}adj 4%; and β = − 0.12, p = 0.056 when adjusting for mothers' smoking during pregnancy, Apgar score, mother's and father's ages at delivery, sex and mother's education, R{sup 2}adj 12%, p = 0.011). The effect of lead remained significant in children without prenatal tobacco exposure (N = 87, r{sub S} = − 0.24, p = 0.024; in further analyses, β = − 0.13, p = 0.029, and R{sup 2}adj 4%). rTL was not affected by sex, the concentrations of other elements in the blood (i.e., cadmium and selenium concentrations), or oxidative injury parameters (total antioxidant status, 8-hydroxydeoxyguanosine and thiobarbituric acid-reactive substances). Lead exposure in childhood appears to be associated with shorter telomeres, which might contribute to diseases, such as cardiovascular disease. The inverse association between blood lead level and the telomeres in children emphasizes the importance of further reducing lead levels in the environment. - Highlights: • This cross-sectional study analyzes the association between

  20. An in silico investigation into the causes of telomere length heterogeneity and its implications for the Hayflick limit.

    Science.gov (United States)

    Golubev, A; Khrustalev, S; Butov, A

    2003-11-21

    In telomerase-negative cell populations the mean telomere length (TL) decreases with increasing population doubling number (PD). A critically small TL is believed to stop cell proliferation at a cell-, age- and species-specific PD thus defining the Hayflick limit. However, positively skewed TL distributions are broad compared to differences between initial and final mean TL and strongly overlap at middle and late PD, which is inconsistent with a limiting role of TL. We used computer-assisted modelling to define what set of premises may account for the above. Our model incorporates the following concepts. DNA end replication problem: telomeres loose 1 shortening unit (SU) upon each cell division. Free radical-caused TL decrease: telomeres experience random events resulting in the loss of a random SU number within a remaining TL. Stochasticity of gene expression and cell differentiation: cells experience random events inducing mitoses or committing cells to proliferation arrest, the latter option requiring a specified number of mitoses to be passed. Cells whose TL reaches 1SU cannot divide. The proliferation kinetics of such virtual cells conforms to the transition probability model of cell cycle. When no committing events occur and at realistic SU estimates of the initial TL, maximal PD values far exceed the Hayflick limit observed in normal cells and are consistent with the crisis stage entered by transformed cells that have surpassed the Hayflick limit. At intermediate PD, symmetrical TL distributions are yielded. Upon introduction of committing events making the ratio of the rates of proliferating and committing events (P/C) range from 1.10 to 1.25, TL distributions at intermediate PD become positively skewed, and virtual cell clones show bimodal size distributions. At P/C as high as 1.25 the majority of virtual cells at maximal PD contain telomeres with TL>1SU. A 10% increase in P/C within the 1.10-1.25 range produces a two-fold increase in the maximal PD, which

  1. Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture.

    Science.gov (United States)

    Shimamoto, Akira; Kagawa, Harunobu; Zensho, Kazumasa; Sera, Yukihiro; Kazuki, Yasuhiro; Osaki, Mitsuhiko; Oshimura, Mitsuo; Ishigaki, Yasuhito; Hamasaki, Kanya; Kodama, Yoshiaki; Yuasa, Shinsuke; Fukuda, Keiichi; Hirashima, Kyotaro; Seimiya, Hiroyuki; Koyama, Hirofumi; Shimizu, Takahiko; Takemoto, Minoru; Yokote, Koutaro; Goto, Makoto; Tahara, Hidetoshi

    2014-01-01

    Werner syndrome (WS) is a premature aging disorder characterized by chromosomal instability and cancer predisposition. Mutations in WRN are responsible for the disease and cause telomere dysfunction, resulting in accelerated aging. Recent studies have revealed that cells from WS patients can be successfully reprogrammed into induced pluripotent stem cells (iPSCs). In the present study, we describe the effects of long-term culture on WS iPSCs, which acquired and maintained infinite proliferative potential for self-renewal over 2 years. After long-term cultures, WS iPSCs exhibited stable undifferentiated states and differentiation capacity, and premature upregulation of senescence-associated genes in WS cells was completely suppressed in WS iPSCs despite WRN deficiency. WS iPSCs also showed recapitulation of the phenotypes during differentiation. Furthermore, karyotype analysis indicated that WS iPSCs were stable, and half of the descendant clones had chromosomal profiles that were similar to those of parental cells. These unexpected properties might be achieved by induced expression of endogenous telomerase gene during reprogramming, which trigger telomerase reactivation leading to suppression of both replicative senescence and telomere dysfunction in WS cells. These findings demonstrated that reprogramming suppressed premature senescence phenotypes in WS cells and WS iPSCs could lead to chromosomal stability over the long term. WS iPSCs will provide opportunities to identify affected lineages in WS and to develop a new strategy for the treatment of WS.

  2. Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture.

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    Akira Shimamoto

    Full Text Available Werner syndrome (WS is a premature aging disorder characterized by chromosomal instability and cancer predisposition. Mutations in WRN are responsible for the disease and cause telomere dysfunction, resulting in accelerated aging. Recent studies have revealed that cells from WS patients can be successfully reprogrammed into induced pluripotent stem cells (iPSCs. In the present study, we describe the effects of long-term culture on WS iPSCs, which acquired and maintained infinite proliferative potential for self-renewal over 2 years. After long-term cultures, WS iPSCs exhibited stable undifferentiated states and differentiation capacity, and premature upregulation of senescence-associated genes in WS cells was completely suppressed in WS iPSCs despite WRN deficiency. WS iPSCs also showed recapitulation of the phenotypes during differentiation. Furthermore, karyotype analysis indicated that WS iPSCs were stable, and half of the descendant clones had chromosomal profiles that were similar to those of parental cells. These unexpected properties might be achieved by induced expression of endogenous telomerase gene during reprogramming, which trigger telomerase reactivation leading to suppression of both replicative senescence and telomere dysfunction in WS cells. These findings demonstrated that reprogramming suppressed premature senescence phenotypes in WS cells and WS iPSCs could lead to chromosomal stability over the long term. WS iPSCs will provide opportunities to identify affected lineages in WS and to develop a new strategy for the treatment of WS.

  3. DNA-PKcs phosphorylates hnRNP-A1 to facilitate the RPA-to-POT1 switch and telomere capping after replication.

    Science.gov (United States)

    Sui, Jiangdong; Lin, Yu-Fen; Xu, Kangling; Lee, Kyung-Jong; Wang, Dong; Chen, Benjamin P C

    2015-07-13

    The heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) has been implicated in telomere protection and telomerase activation. Recent evidence has further demonstrated that hnRNP-A1 plays a crucial role in maintaining newly replicated telomeric 3' overhangs and facilitating the switch from replication protein A (RPA) to protection of telomeres 1 (POT1). The role of hnRNP-A1 in telomere protection also involves DNA-dependent protein kinase catalytic subunit (DNA-PKcs), although the detailed regulation mechanism has not been clear. Here we report that hnRNP-A1 is phosphorylated by DNA-PKcs during the G2 and M phases and that DNA-PK-dependent hnRNP-A1 phosphorylation promotes the RPA-to-POT1 switch on telomeric single-stranded 3' overhangs. Consequently, in cells lacking hnRNP-A1 or DNA-PKcs-dependent hnRNP-A1 phosphorylation, impairment of the RPA-to-POT1 switch results in DNA damage response at telomeres during mitosis as well as induction of fragile telomeres. Taken together, our results indicate that DNA-PKcs-dependent hnRNP-A1 phosphorylation is critical for capping of the newly replicated telomeres and prevention of telomeric aberrations. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  4. Telomere 1 (POT1) gene expression and its association with telomerase activity in colorectal tumor samples with different pathological features.

    Science.gov (United States)

    Izgi, Ahu; Gunal, Armagan; Yalcin, Serap; Gunduz, Ufuk

    2014-09-01

    The ends of chromosoms, telomeres are bound with a number of proteins which protect and stabilize telomeres against degredation, end to end fusion and aberrant recombinations. Telomeric DNA is bound of two groups of proteins, which are double-stranded telomeric DNA bindings proteins, and single stranded telomeric binding proteins. Among telomere binding proteins, protections of telomere 1 protein is a single stranded telomere binding proteins and suggested to be a significant player for telomere elongation and has an association with an enzyme called as telomerase which is an intrinsic reverse transcriptase. Telomerase synthesizes hexameric telomeric repeats onto the chromosomes thereby compansating telomere loss in immortal cells, such as tumor cells, whereas telomeres are shorthened with each division in normal cells. PCR-based TRAP (telomeric repeat amplification protocol) assay is a very sensitive assay for the detection of enzymatic activity of telomerase even if a few numbers of cancerous cells are available. The association between telomerase activity and hPOT1 expression in colorectal cancer is still unclear. Protein extraction was performed from specimens of matched normal and colorectal cancer specimens. Protein concentrations were determined by Bradford assay. Optimized protein concentrations were used for TRAP Assay. TRAP products were seperated by vertical gel electrophoresis on 12.5% polyacrylamide gels and visualized by silver staining. Gene expression of hPOT1 was determined by qPCR analysis. The results demonstrated that all tumor tissues were telomerase positive whereas all corresponding normal tissue was telomerase negative. Among clinicopathological findings, telomerase activity was found to be associated with stage, histology, localization, distant metastasis and lymph node metastasis of tumor in the current study. Although all of the clinicopathological findings differed in the expression of hPOT1 compared to normal tissues, they did not

  5. The Association of Telomere Length With Family Violence and Disruption

    Science.gov (United States)

    Mabile, Emily; Brett, Zoë H.; Esteves, Kyle; Jones, Edward; Shirtcliff, Elizabeth A.; Theall, Katherine P.

    2014-01-01

    BACKGROUND: To enhance the understanding of biological mechanisms connecting early adversity and negative health, we examine the association between family interpersonal violence and disruption and telomere length in youth. These specific exposures were selected because of their established links with negative health consequences across the life-course. METHODS: Children, age 5 to 15, were recruited from the greater New Orleans area, and exposure to family disruption and violence was assessed through caregiver report. Telomere length, from buccal cell DNA (buccal telomere length [bTL]), was determined by using monochrome multiplex quantitative real-time polymerase chain reaction. The association between bTL and adversity exposure was tested (n = 80). RESULTS: Cumulative exposure to interpersonal violence and family disruption was correlated with bTL. Controlling for other sociodemographic factors, bTL was significantly shorter in children with higher exposure to family violence and disruption. Witnessing family violence exerted a particularly potent impact. A significant gender interaction was found (β = −0.0086, SE = 0.0031, z test= −2.79, P = .0053) and analysis revealed the effect only in girls. CONCLUSIONS: bTL is a molecular biomarker of adversity and allostatic load that is detectable in childhood. The present results extend previous studies by demonstrating that telomeres are sensitive to adversity within the overarching family domain. These findings suggest that the family ecology may be an important target for interventions to reduce the biological impact of adversity in the lives of children. PMID:24936002

  6. The association of telomere length with family violence and disruption.

    Science.gov (United States)

    Drury, Stacy S; Mabile, Emily; Brett, Zoë H; Esteves, Kyle; Jones, Edward; Shirtcliff, Elizabeth A; Theall, Katherine P

    2014-07-01

    To enhance the understanding of biological mechanisms connecting early adversity and negative health, we examine the association between family interpersonal violence and disruption and telomere length in youth. These specific exposures were selected because of their established links with negative health consequences across the life-course. Children, age 5 to 15, were recruited from the greater New Orleans area, and exposure to family disruption and violence was assessed through caregiver report. Telomere length, from buccal cell DNA (buccal telomere length [bTL]), was determined by using monochrome multiplex quantitative real-time polymerase chain reaction. The association between bTL and adversity exposure was tested (n = 80). Cumulative exposure to interpersonal violence and family disruption was correlated with bTL. Controlling for other sociodemographic factors, bTL was significantly shorter in children with higher exposure to family violence and disruption. Witnessing family violence exerted a particularly potent impact. A significant gender interaction was found (β = -0.0086, SE = 0.0031, z test= -2.79, P = .0053) and analysis revealed the effect only in girls. bTL is a molecular biomarker of adversity and allostatic load that is detectable in childhood. The present results extend previous studies by demonstrating that telomeres are sensitive to adversity within the overarching family domain. These findings suggest that the family ecology may be an important target for interventions to reduce the biological impact of adversity in the lives of children. Copyright © 2014 by the American Academy of Pediatrics.

  7. Single Stem Cell Imaging and Analysis Reveals Telomere Length Differences in Diseased Human and Mouse Skeletal Muscles

    Directory of Open Access Journals (Sweden)

    Elisia D. Tichy

    2017-10-01

    Full Text Available Muscle stem cells (MuSCs contribute to muscle regeneration following injury. In many muscle disorders, the repeated cycles of damage and repair lead to stem cell dysfunction. While telomere attrition may contribute to aberrant stem cell functions, methods to accurately measure telomere length in stem cells from skeletal muscles have not been demonstrated. Here, we have optimized and validated such a method, named MuQ-FISH, for analyzing telomere length in MuSCs from either mice or humans. Our analysis showed no differences in telomere length between young and aged MuSCs from uninjured wild-type mice, but MuSCs isolated from young dystrophic mice exhibited significantly shortened telomeres. In corroboration, we demonstrated that telomere attrition is present in human dystrophic MuSCs, which underscores its importance in diseased regenerative failure. The robust technique described herein provides analysis at a single-cell resolution and may be utilized for other cell types, especially rare populations of cells.

  8. The association between intelligence and telomere length: a longitudinal population based study.

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    Eva M Kingma

    Full Text Available Low intelligence has been associated with poor health and mortality, but underlying mechanisms remain obscure. We hypothesized that low intelligence is associated with accelerated biological ageing as reflected by telomere length; we suggested potential mediation of this association by unhealthy behaviors and low socioeconomic position. The study was performed in a longitudinal population-based cohort study of 895 participants (46.8% males. Intelligence was measured with the Generalized Aptitude-Test Battery at mean age 52.8 years (33-79 years, SD=11.3. Leukocyte telomere length was measured by PCR. Lifestyle and socioeconomic factors were assessed using written self-report measures. Linear regression analyses, adjusted for age, sex, and telomere length measured at the first assessment wave (T1, showed that low intelligence was associated with shorter leukocyte telomere length at approximately 2 years follow-up (beta= .081, t=2.160, p= .031. Nearly 40% of this association was explained by an unhealthy lifestyle, while low socioeconomic position did not add any significant mediation. Low intelligence may be a risk factor for accelerated biological ageing, thereby providing an explanation for its association with poor health and mortality.

  9. Long telomeres produced by telomerase-resistant recombination are established from a single source and are subject to extreme sequence scrambling.

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    Jianing Xu

    Full Text Available Considerable evidence now supports the idea that the moderate telomere lengthening produced by recombinational telomere elongation (RTE in a Kluyveromyces lactis telomerase deletion mutant occurs through a roll-and-spread mechanism. However, it is unclear whether this mechanism can account for other forms of RTE that produce much longer telomeres such as are seen in human alternative lengthening of telomere (ALT cells or in the telomerase-resistant type IIR "runaway" RTE such as occurs in the K. lactis stn1-M1 mutant. In this study we have used mutationally tagged telomeres to examine the mechanism of RTE in an stn1-M1 mutant both with and without telomerase. Our results suggest that the establishment stage of the mutant state in newly generated stn1-M1 ter1-Δ mutants surprisingly involves a first stage of sudden telomere shortening. Our data also show that, as predicted by the roll-and-spread mechanism, all lengthened telomeres in a newly established mutant cell commonly emerge from a single telomere source. However, in sharp contrast to the RTE of telomerase deletion survivors, we show that the RTE of stn1-M1 ter1-Δ cells produces telomeres whose sequences undergo continuous intense scrambling via recombination. While telomerase was not necessary for the long telomeres in stn1-M1 cells, its presence during their establishment was seen to interfere with the amplification of repeats via recombination, a result consistent with telomerase retaining its ability to add repeats during active RTE. Finally, we observed that the presence of active mismatch repair or telomerase had important influences on telomeric amplification and/or instability.

  10. Telomere length shortening is associated with treatment-free remission in chronic myeloid leukemia patients

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    Giovanni Caocci

    2016-07-01

    Full Text Available Abstract We studied telomere length in 32 CML patients who discontinued imatinib after achieving complete molecular remission and 32 age-sex-matched controls. The relative telomere length (RTL was determined by q-PCR as the telomere to single copy gene (36B4 ratio normalized to a reference sample (K-562 DNA. Age-corrected RTL (acRTL was also obtained. The 36-month probability of treatment-free remission (TFR was 59.4 %. TFR patients showed shorter acRTL compared to relapsed (mean ± SD = 0.01 ± 0.14 vs 0.20 ± 0.21; p = 0.01. TFR was significantly higher in CML patients with acRTL ≤0.09 (78.9 vs 30.8 %, p = 0.002. CML stem cells harboring longer telomeres possibly maintain a proliferative potential after treatment discontinuation.

  11. Early Extinction after Fear Conditioning Yields a Context-Independent and Short-Term Suppression of Conditional Freezing in Rats

    Science.gov (United States)

    Chang, Chun-hui; Maren, Stephen

    2009-01-01

    Extinction of Pavlovian fear conditioning in rats is a useful model for therapeutic interventions in humans with anxiety disorders. Recently, we found that delivering extinction trials soon (15 min) after fear conditioning yields a short-term suppression of fear, but little long-term extinction. Here, we explored the possible mechanisms underlying…

  12. Dual roles of TRF1 in tethering telomeres to the nuclear envelope and protecting them from fusion during meiosis.

    Science.gov (United States)

    Wang, Lina; Tu, Zhaowei; Liu, Chao; Liu, Hongbin; Kaldis, Philipp; Chen, Zijiang; Li, Wei

    2018-01-08

    Telomeres integrity is indispensable for chromosomal stability by preventing chromosome erosion and end-to-end fusions. During meiosis, telomeres attach to the inner nuclear envelope and cluster into a highly crowded microenvironment at the bouquet stage, which requires specific mechanisms to protect the telomeres from fusion. Here, we demonstrate that germ cell-specific knockout of a shelterin complex subunit, Trf1, results in arrest of spermatocytes at two different stages. The obliterated telomere-nuclear envelope attachment in Trf1-deficient spermatocytes impairs homologue synapsis and recombination, resulting in a pachytene-like arrest, while the meiotic division arrest might stem from chromosome end-to-end fusion due to the failure of recruiting meiosis specific telomere associated proteins. Further investigations uncovered that TRF1 could directly interact with Speedy A, and Speedy A might work as a scaffold protein to further recruit Cdk2, thus protecting telomeres from fusion at this stage. Together, our results reveal a novel mechanism of TRF1, Speedy A, and Cdk2 in protecting telomere from fusion in a highly crowded microenvironment during meiosis.

  13. Quadruplexes of human telomere DNA

    Czech Academy of Sciences Publication Activity Database

    Vorlíčková, Michaela; Chládková, Jana; Kejnovská, Iva; Kypr, Jaroslav

    2007-01-01

    Roč. 24, č. 6 (2007), s. 710 ISSN 0739-1102. [The 15th Conversation . 19.06.2007-23.06.2007, Albany] R&D Projects: GA ČR(CZ) GA204/07/0057; GA AV ČR(CZ) IAA100040701 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : DNA tetraplex * human telomere * CD spectroscopy Subject RIV: BO - Biophysics

  14. Variants in TERT influencing telomere length are associated with paranoid schizophrenia risk.

    Science.gov (United States)

    Rao, Shuquan; Ye, Ning; Hu, Huiling; Shen, Yan; Xu, Qi

    2016-04-01

    Schizophrenia is one of the most severe psychiatric disorders, with a high heritability of up to 80%. Several studies have reported telomere dysfunction in schizophrenia, and common variants in the telomerase reverse transcriptase (TERT) gene. TERT is a key component of the telomerase complex that maintains telomere length by addition of telomere repeats to telomere ends, and has repeatedly shown association with mean lymphocyte telomere length (LTL). Thus, we hypothesized that TERT may be a novel susceptibility gene for schizophrenia. Using a Taqman protocol, we genotyped eight tag SNPs from the TERT locus in 1,072 patients with paranoid schizophrenia and 1,284 control subjects from a Chinese Han population. We also measured mean LTL in 98 cases and 109 controls using a quantitative PCR-based technique. Chi-square tests showed that two SNPs, rs2075786 (P = 0.0009, OR = 0.76, 95%CI = 0.65-0.90) and rs4975605 (P = 0.0026, OR = 0.73, 95%CI = 0.60-0.90), were associated with a protective effect, while rs10069690 was associated with risk of paranoid schizophrenia (P = 0.0044, OR = 1.23, 95%CI = 1.07-1.42). Additionally, the rs2736118-rs2075786 haplotype showed significant association with paranoid schizophrenia (P = 0.0013). Moreover, mean LTL correlated with rs2075786 genotypes was significantly shorter in the patient group than the control group. The present results suggest that the TERT gene may be a novel candidate involved in the development of paranoid schizophrenia. © 2016 Wiley Periodicals, Inc.

  15. Dual Recognition of Human Telomeric G-quadruplex by Neomycin-anthraquinone Conjugate

    Science.gov (United States)

    Ranjan, Nihar; Davis, Erik; Xue, Liang

    2013-01-01

    The authors report the recognition of a G-quadruplex formed by four repeat human telomeric DNA with aminosugar intercalator conjugates. The recognition of G-quadruplex through dual binding mode ligands significantly increased the affinity of ligands for G-quadruplex. One such example is a neomycin-anthraquinone 2 which exhibited nanomolar affinity for the quadruplex, and the affinity of 2 is nearly 1000 fold higher for human telomeric G-quadruplex DNA than its constituent units, neomycin and anthraquinone. PMID:23698792

  16. Karyotype rearrangements and telomere analysis in Myzus persicae (Hemiptera, Aphididae) strains collected on Lavandula sp. plants

    Science.gov (United States)

    Mandrioli, Mauro; Zanasi, Federica; Manicardi, Gian Carlo

    2014-01-01

    Abstract Karyotype analysis of nine strains of the peach-potato aphid Myzus persicae (Sulzer, 1776), collected on Lavandula sp. plants, evidenced showed that five of them had a standard 2n = 12 karyotype, one possessed a fragmentation of the X chromosome occurring at the telomere opposite to the NOR-bearing one and three strains had a chromosome number 2n = 11 due to a non-reciprocal translocation of an autosome A3 onto an A1 chromosome. Interestingly, the terminal portion of the autosome A1 involved in the translocation was the same in all the three strains, as evidenced by FISH with the histone cluster as a probe. The study of telomeres in the Myzus persicae strain with the X fission evidenced that telomerase synthesised de novo telomeres at the breakpoints resulting in the stabilization of the chromosomal fragments. Lastly, despite the presence of a conserved telomerase, aphid genome is devoid of genes coding for shelterin, a complex of proteins involved in telomere functioning frequently reported as conserved in eukaryotes. The absence of this complex, also confirmed in the genome of other arthropods, suggests that the shift in the sequence of the telomeric repeats has been accompanied by other changes in the telomere components in arthropods in respect to other metazoans. PMID:25610541

  17. cDNA Library Screening Identifies Protein Interactors Potentially Involved in Non-telomeric Roles of Arabidopsis Telomerase

    Directory of Open Access Journals (Sweden)

    Ladislav eDokládal

    2015-11-01

    Full Text Available Telomerase-reverse transcriptase (TERT plays an essential catalytic role in maintaining telomeres. However, in animal systems telomerase plays additional non-telomeric functional roles. We previously screened an Arabidopsis cDNA library for proteins that interact with the C-terminal extension (CTE TERT domain and identified a nuclear-localized protein that contains a RNA recognition motif (RRM. This RRM-protein forms homodimers in both plants and yeast. Mutation of the gene encoding the RRM-protein had no detectable effect on plant growth and development, nor did it affect telomerase activity or telomere length in vivo, suggesting a non-telomeric role for TERT/RRM-protein complexes. The gene encoding the RRM-protein is highly expressed in leaf and reproductive tissues. We further screened an Arabidopsis cDNA library for proteins that interact with the RRM-protein and identified five interactors. These proteins are involved in numerous non-telomere-associated cellular activities. In plants, the RRM-protein, both alone and in a complex with its interactors, localizes to nuclear speckles. Transcriptional analyses in wild-type and rrm mutant plants, as well as transcriptional co-analyses, suggest that TERT, the RRM-protein, and the RRM-protein interactors may play important roles in non-telomeric cellular functions.

  18. Leukocyte telomere length and hippocampus volume: a meta-analysis [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Gustav Nilsonne

    2015-10-01

    Full Text Available Leukocyte telomere length has been shown to correlate to hippocampus volume, but effect estimates differ in magnitude and are not uniformly positive. This study aimed primarily to investigate the relationship between leukocyte telomere length and hippocampus gray matter volume by meta-analysis and secondarily to investigate possible effect moderators. Five studies were included with a total of 2107 participants, of which 1960 were contributed by one single influential study. A random-effects meta-analysis estimated the effect to r = 0.12 [95% CI -0.13, 0.37] in the presence of heterogeneity and a subjectively estimated moderate to high risk of bias. There was no evidence that apolipoprotein E (APOE genotype was an effect moderator, nor that the ratio of leukocyte telomerase activity to telomere length was a better predictor than leukocyte telomere length for hippocampus volume. This meta-analysis, while not proving a positive relationship, also is not able to disprove the earlier finding of a positive correlation in the one large study included in analyses. We propose that a relationship between leukocyte telomere length and hippocamus volume may be mediated by transmigrating monocytes which differentiate into microglia in the brain parenchyma.

  19. Theory of suppressing avalanche process of carrier in short pulse laser irradiated dielectrics

    Energy Technology Data Exchange (ETDEWEB)

    Deng, H. X., E-mail: hxdeng@uestc.edu.cn, E-mail: xtzu@uestc.edu.cn, E-mail: kaisun@umich.edu; Zu, X. T., E-mail: hxdeng@uestc.edu.cn, E-mail: xtzu@uestc.edu.cn, E-mail: kaisun@umich.edu; Xiang, X. [School of Physical Electronics, University of Electronic Science and Technology of China, Chengdu 610054 (China); Zheng, W. G.; Yuan, X. D. [Research Center of Laser Fusion, China Academy of Engineering Physics, Mianyang 621900 (China); Sun, K., E-mail: hxdeng@uestc.edu.cn, E-mail: xtzu@uestc.edu.cn, E-mail: kaisun@umich.edu [Department of Materials Engineering and Sciences, University of Michigan, 413B Space Research Building, Ann Arbor, Michigan 48109-2143 (United States); Gao, F. [Pacific Northwest National Laboratory, P. O. Box 999, Richland, Washington 99352 (United States)

    2014-05-28

    A theory for controlling avalanche process of carrier during short pulse laser irradiation is proposed. We show that avalanche process of conduction band electrons (CBEs) is determined by the occupation number of phonons in dielectrics. The theory provides a way to suppress avalanche process and a direct judgment for the contribution of avalanche process and photon ionization process to the generation of CBEs. The obtained temperature dependent rate equation shows that the laser induced damage threshold of dielectrics, e.g., fused silica, increase nonlinearly with the decreases of temperature. Present theory predicts a new approach to improve the laser induced damage threshold of dielectrics.

  20. Development and characterization of polyclonal antibodies against the linker region of the telomere-binding protein TRF2

    Directory of Open Access Journals (Sweden)

    Nadya V. Ilicheva

    2018-03-01

    Full Text Available Background: TRF2 (telomeric repeat binding factor 2 is an essential component of the telomere-binding protein complex shelterin. TRF2 induces the formation of a special structure of telomeric DNA and counteracts activation of DNA damage-response pathways telomeres. TRF2 has a poorly characterized linker region (udTRF2 between its homodimerization and DNA-binding domains. Some lines of evidence have shown that this region could be involved in TRF2 interaction with nuclear lamina. Results: In this study, the fragment of the TERF2 gene encoding udTRF2 domain of telomere-binding protein TRF2 was produced by PCR and cloned into the pET32a vector. The resulting plasmid pET32a-udTRF2 was used for the expression of the recombinant udTRF2 in E. coli RosettaBlue (DE3. The protein was isolated and purified using ammonium sulfate precipitation followed by ion-exchange chromatography. The purified recombinant protein udTRF2 was injected into guinea pigs to generate polyclonal antibodies. The ability of anti-udTRF2 antibodies to bind endogenous TRF2 in human skin fibroblasts was tested by western blotting and immunofluorescent staining. Conclusions: In this study, the recombinant protein udTRF2 and antibodies to it were generated. Both protein and antibodies will provide a useful tool for investigation of the functions of the udTRF2 domain and its role in the interaction between TRF2 and nuclear lamina. Keywords: Chromosomes, Molecular cloning, Nuclear lamina, Nucleoprotein complexes, Polyclonal antibodies, Recombinant polypeptide, Shelterin, Telomere-binding protein TRF2, Telomeres, Telomeric DNA, TTAGGG repeats

  1. Leukocyte telomere length and late-life depression

    NARCIS (Netherlands)

    Schaakxs, R.; Verhoeven, J.E.; Oude Voshaar, R.C.; Comijs, H.C.; Penninx, B.W.

    2015-01-01

    Objective Depressive disorders have been associated with increased risk for aging-related diseases, possibly as a consequence of accelerated cellular aging. Cellular aging, indexed by telomere length (TL) shortening, has been linked to depression in adults younger than 60 years; however, it remains

  2. Super DNAging-New insights into DNA integrity, genome stability and telomeres in the oldest old.

    Science.gov (United States)

    Franzke, Bernhard; Neubauer, Oliver; Wagner, Karl-Heinz

    2015-01-01

    Reductions in DNA integrity, genome stability, and telomere length are strongly associated with the aging process, age-related diseases as well as the age-related loss of muscle mass. However, in people reaching an age far beyond their statistical life expectancy the prevalence of diseases, such as cancer, cardiovascular disease, diabetes or dementia, is much lower compared to "averagely" aged humans. These inverse observations in nonagenarians (90-99 years), centenarians (100-109 years) and super-centenarians (110 years and older) require a closer look into dynamics underlying DNA damage within the oldest old of our society. Available data indicate improved DNA repair and antioxidant defense mechanisms in "super old" humans, which are comparable with much younger cohorts. Partly as a result of these enhanced endogenous repair and protective mechanisms, the oldest old humans appear to cope better with risk factors for DNA damage over their lifetime compared to subjects whose lifespan coincides with the statistical life expectancy. This model is supported by study results demonstrating superior chromosomal stability, telomere dynamics and DNA integrity in "successful agers". There is also compelling evidence suggesting that life-style related factors including regular physical activity, a well-balanced diet and minimized psycho-social stress can reduce DNA damage and improve chromosomal stability. The most conclusive picture that emerges from reviewing the literature is that reaching "super old" age appears to be primarily determined by hereditary/genetic factors, while a healthy lifestyle additionally contributes to achieving the individual maximum lifespan in humans. More research is required in this rapidly growing population of super old people. In particular, there is need for more comprehensive investigations including short- and long-term lifestyle interventions as well as investigations focusing on the mechanisms causing DNA damage, mutations, and telomere

  3. Renaturation of telomere-binding proteins after the fractionation by SDS-polyacrylamide gel electrophoresis

    Czech Academy of Sciences Publication Activity Database

    Rotková, Gabriela

    2007-01-01

    Roč. 53, č. 7 (2007), s. 317-320 ISSN 1214-1178 R&D Projects: GA ČR(CZ) GA521/05/0055; GA AV ČR(CZ) IAA600040505; GA MŠk(CZ) LC06004 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : renaturation * telomere-binding proteins * telomeres Subject RIV: BO - Biophysics

  4. Aberrant leukocyte telomere length in Birdshot Uveitis.

    Science.gov (United States)

    Vazirpanah, Nadia; Verhagen, Fleurieke H; Rothova, Anna; Missotten, Tom O A R; van Velthoven, Mirjam; Den Hollander, Anneke I; Hoyng, Carel B; Radstake, Timothy R D J; Broen, Jasper C A; Kuiper, Jonas J W

    2017-01-01

    Birdshot Uveitis (BU) is an archetypical chronic inflammatory eye disease, with poor visual prognosis, that provides an excellent model for studying chronic inflammation. BU typically affects patients in the fifth decade of life. This suggests that it may represent an age-related chronic inflammatory disease, which has been linked to increased erosion of telomere length of leukocytes. To study this in detail, we exploited a sensitive standardized quantitative real-time polymerase chain reaction to determine the peripheral blood leukocyte telomere length (LTL) in 91 genotyped Dutch BU patients and 150 unaffected Dutch controls. Although LTL erosion rates were very similar between BU patients and healthy controls, we observed that BU patients displayed longer LTL, with a median of log (LTL) = 4.87 (= 74131 base pair) compared to 4.31 (= 20417 base pair) in unaffected controls (PRTEL1. These findings suggest that BU is accompanied by significantly longer LTL.

  5. Non-classical polycrystalline silicon thin-film transistor with embedded block-oxide for suppressing the short channel effect

    International Nuclear Information System (INIS)

    Lin, Jyi-Tsong; Huang, Kuo-Dong; Hu, Shu-Fen

    2008-01-01

    In this paper, a polycrystalline silicon (polysilicon) thin-film transistor with a block oxide enclosing body, BTFT, is fabricated and investigated. By utilizing the block-oxide structure of thin-film transistors, the BTFT is shown to suppress the short channel effect. This proposed structure is formed by burying self-aligned oxide spacers along the sidewalls of the source and drain junctions, which reduces the P–N junction area, thereby reducing the junction capacitance and leakage current. Measurements demonstrate that the BTFT eliminates the punch-through effect even down to gate lengths of 1.5 µm, whereas the conventional TFT suffers serious short channel effects at this gate length

  6. A rare variant P507L in TPP1 interrupts TPP1-TIN2 interaction, influences telomere length, and confers colorectal cancer risk in Chinese population.

    Science.gov (United States)

    Li, Jiaoyuan; Chang, Jiang; Tian, Jianbo; Ke, Juntao; Zhu, Ying; Yang, Yang; Gong, Yajie; Zou, Danyi; Peng, Xiating; Yang, Nan; Mei, Shufang; Wang, Xiaoyang; Cheng, Liming; Hu, Weiguo; Gong, Jing; Zhong, Rong; Miao, Xiaoping

    2018-06-11

    Telomere dysfunction triggers cellular senescence and constitutes a driving force for cancer initiation. Genetic variants in genes involved in telomere maintenance may contribute to colorectal cancer (CRC) susceptibility. In this study, we firstly captured germline mutations in 192 CRC patients by sequencing the coding regions of 13 core components implicated in telomere biology. Five potential functional variants were then genotyped and assessed in a case-control set with 3,761 CRC cases and 3,839 healthy controls. The promising association was replicated in additional 6,765 cases and 6,906 controls. Functional experiments were used to further clarify the potential function of the significant variant and uncover the underlying mechanism in CRC development. The two-stage association studies showed that a rare missense variant rs149418249 (c.C1520T, p.P507L) in the 11th exon of TPP1 (also known as ACD, gene ID 65057) was significantly associated with CRC risk with the ORs being 2.90 (95% CI:1.04-8.07, P=0.041), 2.50 (95% CI:1.04-6.04, P=0.042), and 2.66 (95%CI:1.36-5.18, P=0.004) in discovery, replication, and the combined samples, respectively. Further functional annotation indicated that the TPP1 P507L substitution interrupted TPP1-TIN2 interaction, impaired telomerase processivity, and shortened telomere length, which subsequently facilitated cell proliferation and promoted CRC development. A rare variant P507L in TPP1 confers increased risk of CRC through interrupting TPP1-TIN2 interaction, impairing telomerase processivity, and shrinking telomere length. These findings emphasize the important role of telomere dysfunction in CRC development, and provide new insights about the prevention of this type of cancer. Copyright ©2018, American Association for Cancer Research.

  7. Leukocyte telomere length and personality : Associations with the big five and type d personality traits

    NARCIS (Netherlands)

    Schoormans, D.; Verhoeven, J.E.; Denollet, J.; van de Poll-Franse, L.V.; Penninx, B.W.J.H.

    2018-01-01

    Accelerated cellular ageing, which can be examined by telomere length (TL), may be an overarching mechanism underlying the association between personality and adverse health outcomes. This 6-year longitudinal study examined the relation between personality and leukocyte telomere length (LTL) across

  8. RECG maintains plastid and mitochondrial genome stability by suppressing extensive recombination between short dispersed repeats.

    Directory of Open Access Journals (Sweden)

    Masaki Odahara

    2015-03-01

    Full Text Available Maintenance of plastid and mitochondrial genome stability is crucial for photosynthesis and respiration, respectively. Recently, we have reported that RECA1 maintains mitochondrial genome stability by suppressing gross rearrangements induced by aberrant recombination between short dispersed repeats in the moss Physcomitrella patens. In this study, we studied a newly identified P. patens homolog of bacterial RecG helicase, RECG, some of which is localized in both plastid and mitochondrial nucleoids. RECG partially complements recG deficiency in Escherichia coli cells. A knockout (KO mutation of RECG caused characteristic phenotypes including growth delay and developmental and mitochondrial defects, which are similar to those of the RECA1 KO mutant. The RECG KO cells showed heterogeneity in these phenotypes. Analyses of RECG KO plants showed that mitochondrial genome was destabilized due to a recombination between 8-79 bp repeats and the pattern of the recombination partly differed from that observed in the RECA1 KO mutants. The mitochondrial DNA (mtDNA instability was greater in severe phenotypic RECG KO cells than that in mild phenotypic ones. This result suggests that mitochondrial genomic instability is responsible for the defective phenotypes of RECG KO plants. Some of the induced recombination caused efficient genomic rearrangements in RECG KO mitochondria. Such loci were sometimes associated with a decrease in the levels of normal mtDNA and significant decrease in the number of transcripts derived from the loci. In addition, the RECG KO mutation caused remarkable plastid abnormalities and induced recombination between short repeats (12-63 bp in the plastid DNA. These results suggest that RECG plays a role in the maintenance of both plastid and mitochondrial genome stability by suppressing aberrant recombination between dispersed short repeats; this role is crucial for plastid and mitochondrial functions.

  9. Telomere structure and maintenance gene variants and risk of five cancer types

    Science.gov (United States)

    Karami, Sara; Han, Younghun; Pande, Mala; Cheng, Iona; Rudd, James; Pierce, Brandon L.; Nutter, Ellen L.; Schumacher, Fredrick R.; Kote-Jarai, Zsofia; Lindstrom, Sara; Witte, John S.; Fang, Shenying; Han, Jiali; Kraft, Peter; Hunter, David; Song, Fengju; Hung, Rayjean J.; McKay, James; Gruber, Stephen B.; Chanock, Stephen J.; Risch, Angela; Shen, Hongbing; Haiman, Christopher A.; Boardman, Lisa; Ulrich, Cornelia M.; Casey, Graham; Peters, Ulrike; Al Olama, Ali Amin; Berchuck, Andrew; Berndt, Sonja I.; Bezieau, Stephane; Brennan, Paul; Brenner, Hermann; Brinton, Louise; Caporaso, Neil; Chan, Andrew T.; Chang-Claude, Jenny; Christiani, David C.; Cunningham, Julie M.; Easton, Douglas; Eeles, Rosalind A.; Eisen, Timothy; Gala, Manish; Gallinger, Steven J.; Gayther, Simon A.; Goode, Ellen L.; Grönberg, Henrik; Henderson, Brian E.; Houlston, Richard; Joshi, Amit D.; Küry, Sébastien; Landi, Mari T.; Le Marchand, Loic; Muir, Kenneth; Newcomb, Polly A.; Permuth-Wey, Jenny; Pharoah, Paul; Phelan, Catherine; Potter, John D.; Ramus, Susan J.; Risch, Harvey; Schildkraut, Joellen; Slattery, Martha L.; Song, Honglin; Wentzensen, Nicolas; White, Emily; Wiklund, Fredrik; Zanke, Brent W.; Sellers, Thomas A.; Zheng, Wei; Chatterjee, Nilanjan; Amos, Christopher I.; Doherty, Jennifer A.

    2016-01-01

    Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level P-value cutoffs ≤3.08×10−5). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the TERT-CLPTML1 region, rs12655062 was associated positively with prostate cancer, and inversely with colorectal and ovarian cancers, and rs115960372 was associated positively with prostate cancer. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and ovarian cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk. PMID:27459707

  10. Telomere structure and maintenance gene variants and risk of five cancer types.

    Science.gov (United States)

    Karami, Sara; Han, Younghun; Pande, Mala; Cheng, Iona; Rudd, James; Pierce, Brandon L; Nutter, Ellen L; Schumacher, Fredrick R; Kote-Jarai, Zsofia; Lindstrom, Sara; Witte, John S; Fang, Shenying; Han, Jiali; Kraft, Peter; Hunter, David J; Song, Fengju; Hung, Rayjean J; McKay, James; Gruber, Stephen B; Chanock, Stephen J; Risch, Angela; Shen, Hongbing; Haiman, Christopher A; Boardman, Lisa; Ulrich, Cornelia M; Casey, Graham; Peters, Ulrike; Amin Al Olama, Ali; Berchuck, Andrew; Berndt, Sonja I; Bezieau, Stephane; Brennan, Paul; Brenner, Hermann; Brinton, Louise; Caporaso, Neil; Chan, Andrew T; Chang-Claude, Jenny; Christiani, David C; Cunningham, Julie M; Easton, Douglas; Eeles, Rosalind A; Eisen, Timothy; Gala, Manish; Gallinger, Steven J; Gayther, Simon A; Goode, Ellen L; Grönberg, Henrik; Henderson, Brian E; Houlston, Richard; Joshi, Amit D; Küry, Sébastien; Landi, Mari T; Le Marchand, Loic; Muir, Kenneth; Newcomb, Polly A; Permuth-Wey, Jenny; Pharoah, Paul; Phelan, Catherine; Potter, John D; Ramus, Susan J; Risch, Harvey; Schildkraut, Joellen; Slattery, Martha L; Song, Honglin; Wentzensen, Nicolas; White, Emily; Wiklund, Fredrik; Zanke, Brent W; Sellers, Thomas A; Zheng, Wei; Chatterjee, Nilanjan; Amos, Christopher I; Doherty, Jennifer A

    2016-12-15

    Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10 -5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk. © 2016 UICC.

  11. Telomere dysfunction and cell survival: Roles for distinct TIN2-containing complexes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sahn-ho; Davalos, Albert R.; Heo, Seok-Jin; Rodier, Francis; Zou, Ying; Beausejour, Christian; Kaminker, Patrick; Yannone, Steven M.; Campisi, Judith

    2007-10-02

    Telomeres are maintained by three DNA binding proteins (TRF1, TRF2 and POT1), and several associated factors. One factor, TIN2, binds TRF1 and TRF2 directly and POT1 indirectly. Along with two other proteins, TPP1 and hRap1, these form a soluble complex that may be the core telomere maintenance complex. It is not clear whether sub-complexes also exist in vivo. We provide evidence for two TIN2 sub-complexes with distinct functions in human cells. We isolated these two TIN2 sub-complexes from nuclear lysates of unperturbed cells and cells expressing TIN2 mutants TIN2-13, TIN2-15C, which cannot bind TRF2 or TRF1, respectively. In cells with wild-type p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere uncapping and eventual growth arrest. In cells lacking p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere dysfunction and cell death. Our findings suggest that distinct TIN2 complexes exist, and that TIN2-15C-sensitive subcomplexes are particularly important for cell survival in the absence of functional p53.

  12. Telomere length is short in PCOS and oral contraceptive does not affect the telomerase activity in granulosa cells of patients with PCOS.

    Science.gov (United States)

    Li, Ying; Deng, Bingbing; Ouyang, Nengyong; Yuan, Ping; Zheng, Lingyan; Wang, Wenjun

    2017-07-01

    Our study aimed to investigate the association of telomerase activity (TA) and telomere length (TL) in granulosa cells (GCs) with IVF outcomes of polycystic ovary syndrome (PCOS) patients, and the effects of oral contraceptive pill (OCP) pretreatment on these two parameters. One hundred sixty-three infertile women were enrolled and divided into a PCOS group (n = 65) and a non-PCOS group (n = 98). The PCOS group was further divided into an OCP pretreatment group (n = 35) and a non-OCP pretreatment group (n = 30), a TA PCOS group and 1.118 in non-PCOS group (P = 0.005). The patients with TL ≥1 accounted for 36.9% in PCOS group and 54.1% in non-PCOS group (P = 0.032). The average duration of infertility for PCOS patients was 5 years in TA PCOS patients. Shorter TL was found in PCOS patients. The TA levels did not change significantly in PCOS patients. PCOS patients with a lower TA level and shorter telomeres had an earlier onset of infertility symptoms. No predictive value was found for TA and TL in terms of embryo quality or IVF outcomes in PCOS patients, and no effect OCP pretreatment was observed on either TA and TL.

  13. Two tandemly repeated telomere-associated sequences in Nicotiana plumbaginifolia.

    Science.gov (United States)

    Chen, C M; Wang, C T; Wang, C J; Ho, C H; Kao, Y Y; Chen, C C

    1997-12-01

    Two tandemly repeated telomere-associated sequences, NP3R and NP4R, have been isolated from Nicotiana plumbaginifolia. The length of a repeating unit for NP3R and NP4R is 165 and 180 nucleotides respectively. The abundance of NP3R, NP4R and telomeric repeats is, respectively, 8.4 x 10(4), 6 x 10(3) and 1.5 x 10(6) copies per haploid genome of N. plumbaginifolia. Fluorescence in situ hybridization revealed that NP3R is located at the ends and/or in interstitial regions of all 10 chromosomes and NP4R on the terminal regions of three chromosomes in the haploid genome of N. plumbaginifolia. Sequence homology search revealed that not only are NP3R and NP4R homologous to HRS60 and GRS, respectively, two tandem repeats isolated from N. tabacum, but that NP3R and NP4R are also related to each other, suggesting that they originated from a common ancestral sequence. The role of these repeated sequences in chromosome healing is discussed based on the observation that two to three copies of a telomere-similar sequence were present in each repeating unit of NP3R and NP4R.

  14. The telomere repeat motif of basal Metazoa

    Czech Academy of Sciences Publication Activity Database

    Traut, W.; Szczepanowski, M.; Vítková, Magda; Opitz, Ch.; Marec, František; Zrzavý, Jan

    2007-01-01

    Roč. 15, č. 3, (2007), s. 371-382 ISSN 0967-3849 R&D Projects: GA ČR GA206/06/1860 Institutional research plan: CEZ:AV0Z50070508 Keywords : ancestral telomere * Choanozoa * Cnidaria Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.469, year: 2007

  15. Fundamental mechanisms of telomerase action in yeasts and mammals: understanding telomeres and telomerase in cancer cells.

    Science.gov (United States)

    Armstrong, Christine A; Tomita, Kazunori

    2017-03-01

    Aberrant activation of telomerase occurs in 85-90% of all cancers and underpins the ability of cancer cells to bypass their proliferative limit, rendering them immortal. The activity of telomerase is tightly controlled at multiple levels, from transcriptional regulation of the telomerase components to holoenzyme biogenesis and recruitment to the telomere, and finally activation and processivity. However, studies using cancer cell lines and other model systems have begun to reveal features of telomeres and telomerase that are unique to cancer. This review summarizes our current knowledge on the mechanisms of telomerase recruitment and activation using insights from studies in mammals and budding and fission yeasts. Finally, we discuss the differences in telomere homeostasis between normal cells and cancer cells, which may provide a foundation for telomere/telomerase targeted cancer treatments. © 2017 The Authors.

  16. Sex-Specific Associations between Telomere Dynamics and Oxidative Status in Adult and Nestling Pied Flycatchers.

    Science.gov (United States)

    López-Arrabé, Jimena; Monaghan, Pat; Cantarero, Alejandro; Boner, Winnie; Pérez-Rodríguez, Lorenzo; Moreno, Juan

    Oxidative stress can contribute to an acceleration of telomere erosion, leading to cellular senescence and aging. Increased investment in reproduction is known to accelerate senescence, generally resulting in reduced future reproductive potential and survival. To better understand the role played by oxidative status and telomere dynamics in the conflict between maintenance and reproduction, it is important to determine how these factors are related in parents and their offspring. We investigated the relationship between oxidative status and telomere measurements in pied flycatchers (Ficedula hypoleuca). Total antioxidant status (TAS) in plasma, total levels of glutathione in red blood cells (RBCs), and oxidative damage in plasma lipids (malondialdehyde [MDA]) were assessed in both parents and nestlings. Telomeres were measured in RBCs in adults. Our results showed sex differences in oxidative variables in adults that are likely to be mediated by sex steroids, with testosterone and estrogens increasing and reducing, respectively, the production of reactive oxygen and nitrogen species. We found a negative association between telomere length (TL) and MDA in adults in the previous season. Moreover, TL was positively associated with TAS in females, while telomere shortening (ΔTL) correlated positively with MDA in males in the current year. These associations could be reflecting differences between sexes in reproductive physiology. We found a positive correlation between parental ΔTL and nestling MDA, an example of how parental physiological aging could affect offspring quality in terms of oxidative stress that highlights the constraints imposed by higher rates of ΔTL during reproduction and rearing.

  17. Identification of TTAGGG-binding proteins in Neurospora crassa, a fungus with vertebrate-like telomere repeats.

    Science.gov (United States)

    Casas-Vila, Núria; Scheibe, Marion; Freiwald, Anja; Kappei, Dennis; Butter, Falk

    2015-11-17

    To date, telomere research in fungi has mainly focused on Saccharomyces cerevisiae and Schizosaccharomyces pombe, despite the fact that both yeasts have degenerated telomeric repeats in contrast to the canonical TTAGGG motif found in vertebrates and also several other fungi. Using label-free quantitative proteomics, we here investigate the telosome of Neurospora crassa, a fungus with canonical telomeric repeats. We show that at least six of the candidates detected in our screen are direct TTAGGG-repeat binding proteins. While three of the direct interactors (NCU03416 [ncTbf1], NCU01991 [ncTbf2] and NCU02182 [ncTay1]) feature the known myb/homeobox DNA interaction domain also found in the vertebrate telomeric factors, we additionally show that a zinc-finger protein (NCU07846) and two proteins without any annotated DNA-binding domain (NCU02644 and NCU05718) are also direct double-strand TTAGGG binders. We further find two single-strand binders (NCU02404 [ncGbp2] and NCU07735 [ncTcg1]). By quantitative label-free interactomics we identify TTAGGG-binding proteins in Neurospora crassa, suggesting candidates for telomeric factors that are supported by phylogenomic comparison with yeast species. Intriguingly, homologs in yeast species with degenerated telomeric repeats are also TTAGGG-binding proteins, e.g. in S. cerevisiae Tbf1 recognizes the TTAGGG motif found in its subtelomeres. However, there is also a subset of proteins that is not conserved. While a rudimentary core TTAGGG-recognition machinery may be conserved across yeast species, our data suggests Neurospora as an emerging model organism with unique features.

  18. Magnetic resonance imaging of lipoma and liposarcoma: potential of short tau inversion recovery as a technique of fat suppression

    International Nuclear Information System (INIS)

    Pang, A.K.K.; Hughes, T.

    2000-01-01

    The present limited retrospective study was performed to assess MR imaging of lipomatous tumours of the musculoskeletal system and to evaluate the potential of the T2 short tau inversion-recovery (STIR) technique for differentiating lipomas from liposarcomas. Magnetic resonance imaging of 12 patients with lipomatous tumours of the musculoskeletal system (eight benign lipomas, three well differentiated liposarcomas and one myxoid liposarcoma) were reviewed. Benign lipomas were usually superficial and showed homogeneity on T1- and T2-weighted spin echo sequences. Full suppression at T2-STIR was readily demonstrated. In contrast the liposarcomas in the present series were all deep-seated. Two well-differentiated liposarcomas showed homogeneity at long and short relaxation time (TR) but failed to show complete suppression at T2-STIR. One case of well-differentiated liposarcoma (dedifferentiated liposarcoma) and one of myxoid liposarcoma showed mild and moderate heterogeneity at T1 and T2, respectively and posed no difficulty in being diagnosed correctly. In conclusion, short and long TR in combination with T2 STIR show promise in differentiating benign from malignant lipomatous tumours of the musculoskeletal system, when taken in combination with the position of the tumour. Copyright (1999) Blackwell Science Pty Ltd

  19. Prenatal undernutrition and leukocyte telomere length in late adulthood: the Dutch famine birth cohort study

    NARCIS (Netherlands)

    de Rooij, Susanne R.; van Pelt, Ans M. M.; Ozanne, Susan E.; Korver, Cindy M.; van Daalen, Saskia K. M.; Painter, Rebecca C.; Schwab, Matthias; Viegas, Marcelo H.; Roseboom, Tessa J.

    2015-01-01

    Energy restriction in prenatal life has detrimental effects on later life health and longevity. Studies in rats have shown that the shortening of telomeres in key tissues plays an important role in this association. The aim of the current study was to investigate leukocyte telomere length in

  20. Telomere shortening is associated to TRF1 and PARP1 overexpression in Duchenne muscular dystrophy.

    Science.gov (United States)

    Aguennouz, M'Hammed; Vita, Gian Luca; Messina, Sonia; Cama, Annamaria; Lanzano, Natalia; Ciranni, Annamaria; Rodolico, Carmelo; Di Giorgio, Rosa Maria; Vita, Giuseppe

    2011-12-01

    Telomere shortening is thought to contribute to premature senescence of satellite cells in Duchenne muscular dystrophy (DMD) muscle. Telomeric repeat binding factor-1 (TRF1) and poly (ADP-ribose) polymerase-1 (PARP1) are proteins known to modulate telomerase reverse transcriptase (TERT) activity, which controls telomere elongation. Here we show that an age-dependent telomere shortening occurs in DMD muscles and is associated to overexpression of mRNA and protein levels of TRF1 and PARP1. TERT expression and activity are detectable in normal control muscles and they slightly increase in DMD. This is the first demonstration of TRF1 and PARP1 overexpression in DMD muscles. They can be directly involved in replicative senescence of satellite cells and/or in the pathogenetic cascade through a cross-talk with oxidative stress and inflammatory response. Modulation of these events by TRF1 or PARP1 inhibition might represent a novel strategy for treatment of DMD and other muscular dystrophies. Copyright © 2010 Elsevier Inc. All rights reserved.

  1. Processing of semen by density gradient centrifugation selects spermatozoa with longer telomeres for assisted reproduction techniques.

    Science.gov (United States)

    Yang, Qingling; Zhang, Nan; Zhao, Feifei; Zhao, Wanli; Dai, Shanjun; Liu, Jinhao; Bukhari, Ihtisham; Xin, Hang; Niu, Wenbing; Sun, Yingpu

    2015-07-01

    The ends of eukaryotic chromosomes contain specialized chromatin structures called telomeres, the length of which plays a key role in early human embryonic development. Although the effect of sperm preparation techniques on major sperm characteristics, such as concentration, motility and morphology have been previously documented, the possible status of telomere length and its relation with sperm preparation techniques is not well-known for humans. The aim of this study was to investigate the role of density gradient centrifugation in the selection of spermatozoa with longer telomeres for use in assisted reproduction techniques in 105 samples before and after sperm processing. After density gradient centrifugation, the average telomere length of the sperm was significantly longer (6.51 ± 2.54 versus 5.16 ± 2.29, P average motile sperm rate was significantly higher (77.9 ± 11.8 versus 44.6 ± 11.2, P average DNA fragmentation rate was significantly lower (11.1 ± 5.9 versus 25.9 ± 12.9, P sperm count (rs = 0.58; P sperm with longer telomeres. Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  2. The Telomere Effect: A Revolutionary Approach to Living Younger, Healthier, Longer Blackburn Elizabeth and Epel Elissa The Telomere Effect: A Revolutionary Approach to Living Younger, Healthier, Longer 417pp £14.99 Orion Books 9780297609230 0297609238 [Formula: see text].

    Science.gov (United States)

    2017-06-28

    Elizabeth Blackburn received a Nobel prize for discovering the molecular nature of telomeres (the ends of our chromosomes that serve as protective caps) and telomerase (the enzyme that maintains telomeres).

  3. Temporal suppression and augmentation of click-evoked otoacoustic emissions

    DEFF Research Database (Denmark)

    Verhulst, Sarah; Harte, James; Dau, Torsten

    2008-01-01

    This study investigates and models temporal suppression of click-evoked otoacoustic emissions (CEOAEs). This suppression-effect is created when a suppressor-click is presented close in time to a test-click. The analysis was carried out for short time-frames of short- and long-latency CEOAEs...... suppression is present in all CEOAEs for inter-click intervals (ICIs) less than 8 ms. The long-latency CEOAEs showed augmentation (i.e., negative suppression) for ICIs of 6-7 ms which was not reported for the short-latency CEOAE at these ICIs. A phenomenological approach is adopted here to explain both...

  4. Lack of association of colonic epithelium telomere length and oxidative DNA damage in Type 2 diabetes under good metabolic control

    Directory of Open Access Journals (Sweden)

    Kennedy Hugh

    2008-10-01

    Full Text Available Abstract Background Telomeres are DNA repeat sequences necessary for DNA replication which shorten at cell division at a rate directly related to levels of oxidative stress. Critical telomere shortening predisposes to cell senescence and to epithelial malignancies. Type 2 diabetes is characterised by increased oxidative DNA damage, telomere attrition, and an increased risk of colonic malignancy. We hypothesised that the colonic mucosa in Type 2 diabetes would be characterised by increased DNA damage and telomere shortening. Methods We examined telomere length (by flow fluorescent in situ hybridization and oxidative DNA damage (flow cytometry of 8 – oxoguanosine in the colonic mucosal cells of subjects with type 2 diabetes (n = 10; mean age 62.2 years, mean HbA1c 6.9% and 22 matched control subjects. No colonic pathology was apparent in these subjects at routine gastrointestinal investigations. Results Mean colonic epithelial telomere length in the diabetes group was not significantly different from controls (10.6 [3.6] vs. 12.1 [3.4] Molecular Equivalent of Soluble Fluorochrome Units [MESF]; P = 0.5. Levels of oxidative DNA damage were similar in both T2DM and control groups (2.6 [0.6] vs. 2.5 [0.6] Mean Fluorescent Intensity [MFI]; P = 0.7. There was no significant relationship between oxidative DNA damage and telomere length in either group (both p > 0.1. Conclusion Colonic epithelium in Type 2 diabetes does not differ significantly from control colonic epithelium in oxidative DNA damage or telomere length. There is no evidence in this study for increased oxidative DNA damage or significant telomere attrition in colonic mucosa as a carcinogenic mechanism.

  5. Comparison of telomere length in black and white teachers from South Africa: the sympathetic activity and ambulatory blood pressure in Africans study.

    Science.gov (United States)

    von Känel, Roland; Malan, Nico T; Hamer, Mark; Malan, Leoné

    2015-01-01

    Telomere length is a marker of biological aging that has been linked to cardiovascular disease risk. The black South African population is witnessing a tremendous increase in the prevalence of cardiovascular disease, part of which might be explained through urbanization. We compared telomere length between black South Africans and white South Africans and examined which biological and psychosocial variables played a role in ethnic difference in telomere length. We measured leukocyte telomere length in 161 black South African teachers and 180 white South African teachers aged 23 to 66 years without a history of atherothrombotic vascular disease. Age, sex, years having lived in the area, human immunodeficiency virus (HIV) infection, hypertension, body mass index, dyslipidemia, hemoglobin A1c, C-reactive protein, smoking, physical activity, alcohol abuse, depressive symptoms, psychological distress, and work stress were considered as covariates. Black participants had shorter (median, interquartile range) relative telomere length (0.79, 0.70-0.95) than did white participants (1.06, 0.87-1.21; p < .001), and this difference changed very little after adjusting for covariates. In fully adjusted models, age (p < .001), male sex (p = .011), and HIV positive status (p = .023) were associated with shorter telomere length. Ethnicity did not significantly interact with any covariates in determining telomere length, including psychosocial characteristics. Black South Africans showed markedly shorter telomeres than did white South African counterparts. Age, male sex, and HIV status were associated with shorter telomere length. No interactions between ethnicity and biomedical or psychosocial factors were found. Ethnic difference in telomere length might primarily be explained by genetic factors.

  6. The association between post-traumatic stress disorder and shorter telomere length: A systematic review and meta-analysis.

    Science.gov (United States)

    Li, Xuemei; Wang, Jiang; Zhou, Jianghua; Huang, Pan; Li, Jiping

    2017-08-15

    Post-traumatic stress disorder (PTSD) is a common psychiatric disorder, which may accelerate aging. Many study have investigated the association between telomeres length and PTSD, but results from published studies are contradictory. Therefore, Meta-analysis approaches were conducted to give more precise estimate of relationship between telomere length and PTSD. We systematically reviewed the databases of PUBMED, PsycINFO, Medline(Ovid SP) and EMBASE for all articles on the association between telomere length and PTSD. Data were summarized by using random-effects in the meta-analysis. The heterogeneity among studies were examined by using Cochrane's Q statistic and I-squared. Five eligible studies containing 3851 participants were included in our meta-analysis. Shorten telomere length was significantly associated with PTSD with mean difference of -0.19( 95% CI: -0.27, -0.01; P<0.001) with I-square of 96%. The results from subgroup analysis demonstrated that shorter telomere length was significantly associated with PTSD across all gender groups, with mean difference of -0.15( 95% CI: -0.29, -0.01; P=0.04) for female, mean difference of -0.17( 95% CI: -0.19, -0.15; P<0.001) for male. Meanwhile, shorten telomere length was significantly associated with sexual assault(mean difference =-0.15, 95% CI: -0.29, -0.01), childhood trauma (mean difference =-0.08, 95% CI: -0.19, -0.07), but not combat (mean difference =-0.39, 95% CI: -0.83, 0.05). Compared to the individuals without PTSD, individuals with PTSD have shorter telomere length, which has implications for early intervention and timely treatment to prevent future adverse health outcomes. Copyright © 2017. Published by Elsevier B.V.

  7. Human telomeric DNA: G-quadruplex, i-motif and Watson–Crick double helix

    Science.gov (United States)

    Phan, Anh Tuân; Mergny, Jean-Louis

    2002-01-01

    Human telomeric DNA composed of (TTAGGG/CCCTAA)n repeats may form a classical Watson–Crick double helix. Each individual strand is also prone to quadruplex formation: the G-rich strand may adopt a G-quadruplex conformation involving G-quartets whereas the C-rich strand may fold into an i-motif based on intercalated C·C+ base pairs. Using an equimolar mixture of the telomeric oligonucleotides d[AGGG(TTAGGG)3] and d[(CCCTAA)3CCCT], we defined which structures existed and which would be the predominant species under a variety of experimental conditions. Under near-physiological conditions of pH, temperature and salt concentration, telomeric DNA was predominantly in a double-helix form. However, at lower pH values or higher temperatures, the G-quadruplex and/or the i-motif efficiently competed with the duplex. We also present kinetic and thermodynamic data for duplex association and for G-quadruplex/i-motif unfolding. PMID:12409451

  8. Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.

    Science.gov (United States)

    Levy, Daniel; Neuhausen, Susan L; Hunt, Steven C; Kimura, Masayuki; Hwang, Shih-Jen; Chen, Wei; Bis, Joshua C; Fitzpatrick, Annette L; Smith, Erin; Johnson, Andrew D; Gardner, Jeffrey P; Srinivasan, Sathanur R; Schork, Nicholas; Rotter, Jerome I; Herbig, Utz; Psaty, Bruce M; Sastrasinh, Malinee; Murray, Sarah S; Vasan, Ramachandran S; Province, Michael A; Glazer, Nicole L; Lu, Xiaobin; Cao, Xiaojian; Kronmal, Richard; Mangino, Massimo; Soranzo, Nicole; Spector, Tim D; Berenson, Gerald S; Aviv, Abraham

    2010-05-18

    Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

  9. Telomere length of anterior crucial ligament after rupture

    DEFF Research Database (Denmark)

    Ponsot, Elodie; Langberg, Henning; Krogsgaard, Michael R

    2011-01-01

    The regeneration of ligaments following injury is a slow process compared to the healing of many other tissues and the underlying mechanisms remain unknown. The purpose of the study was to evaluate the proliferative potential of ligaments by assessing telomere length within three distinct parts...... of human anterior cruciate ligament (ACL) obtained during ACL reconstruction: the macroscopically injured proximal part and macroscopically noninjured mid- and distal portions in eight subjects (age 28 ± 8 years). The mean telomere length in ACL was within normal range of values usually reported for other...... tissues indicating that the endogenous machinery responsible for the proliferative potential of ligament is not implicated in its poor healing capacity. The three ACL parts showed similar mean TRF lengths (distal part: 11.5 ± 0.8 kbp, mid-portion: 11.8 ± 1.2 kbp, proximal part: 11.9 ± 1.6 kbp...

  10. Stress exposure in early post-natal life reduces telomere length: an experimental demonstration in a long-lived seabird

    OpenAIRE

    Herborn, Katherine A.; Heidinger, Britt J.; Boner, Winnie; Noguera, Jose C.; Adam, Aileen; Daunt, Francis; Monaghan, Pat

    2014-01-01

    Exposure to stressors early in life is associated with faster ageing and reduced longevity. One important mechanism that could underlie these late life effects is increased telomere loss. Telomere length in early post-natal life is an important predictor of subsequent lifespan, but the factors underpinning its variability are poorly understood. Recent human studies have linked stress exposure to increased telomere loss. These studies have of necessity been non-experimental and are consequentl...

  11. A Shld1-controlled POT1a provides support for repression of ATR signaling at telomeres through RPA exclusion.

    Science.gov (United States)

    Gong, Yi; de Lange, Titia

    2010-11-12

    We previously proposed that POT1 prevents ATR signaling at telomeres by excluding RPA from the single-stranded TTAGGG repeats. Here, we use a Shld1-stabilized degron-POT1a fusion (DD-POT1a) to study the telomeric ATR kinase response. In the absence of Shld1, DD-POT1a degradation resulted in rapid and reversible activation of the ATR pathway in G1 and S/G2. ATR signaling was abrogated by shRNAs to ATR and TopBP1, but shRNAs to the ATM kinase or DNA-PKcs did not affect the telomere damage response. Importantly, ATR signaling in G1 and S/G2 was reduced by shRNAs to RPA. In S/G2, RPA was readily detectable at dysfunctional telomeres, and both POT1a and POT1b were required to exclude RPA and prevent ATR activation. In G1, the accumulation of RPA at dysfunctional telomeres was strikingly less, and POT1a was sufficient to repress ATR signaling. These results support an RPA exclusion model for the repression of ATR signaling at telomeres. Copyright © 2010 Elsevier Inc. All rights reserved.

  12. Physical Activity and Telomere Biology: Exploring the Link with Aging-Related Disease Prevention

    OpenAIRE

    Andrew T. Ludlow; Stephen M. Roth

    2011-01-01

    Physical activity is associated with reduced risk of several age-related diseases as well as with increased longevity in both rodents and humans. Though these associations are well established, evidence of the molecular and cellular factors associated with reduced disease risk and increased longevity resulting from physical activity is sparse. A long-standing hypothesis of aging is the telomere hypothesis: as a cell divides, telomeres shorten resulting eventually in replicative senescence and...

  13. Mesenchymal stem cells with high telomerase expression do not actively restore their chromosome arm specific telomere length pattern after exposure to ionizing radiation

    DEFF Research Database (Denmark)

    Graakjaer, Jesper; Christensen, Rikke; Kolvraa, Steen

    2007-01-01

    were measured using Fluorescence In Situ Hybridization (Q-FISH). RESULTS: A telomere length pattern was found to exist in primary hMSC's as well as in hMSC-telo1. This pattern is similar to what was previously found in lymphocytes and fibroblasts. The cells were then exposed to a high dose of ionizing...... radiation. Irradiation caused profound changes in chromosome specific telomere lengths, effectively destroying the telomere length pattern. Following long term culturing after irradiation, a telomere length pattern was found to re-emerge. However, the new telomere length pattern did not resemble...

  14. Accumulative effects of indoor air pollution exposure on leukocyte telomere length among non-smokers.

    Science.gov (United States)

    Lin, Nan; Mu, Xinlin; Wang, Guilian; Ren, Yu'ang; Su, Shu; Li, Zhiwen; Wang, Bin; Tao, Shu

    2017-08-01

    Indoor air pollution is an important environmental factor that contributes to the burden of various diseases. Long-term exposure to ambient air pollution is associated with telomere shortening. However, the association between chronic indoor air pollution from household fuel combustion and leukocyte telomere length has not been studied. In our study, 137 cancer-free non-smokers were recruited. Their exposure levels to indoor air pollution from 1985 to 2014 were assessed using a face-to-face interview questionnaire, and leukocyte telomere length (LTL) was measured using a monochrome multiplex quantitative PCR method. Accumulative exposure to solid fuel usage for cooking was negatively correlated with LTL. The LTL of residents who were exposed to solid fuel combustion for three decades (LTL = 0.70 ± 0.17) was significantly shorter than that of other populations. In addition, education and occupation were related to both exposure to solid fuel and LTL. Sociodemographic factors may play a mediating role in the correlation between leukocyte telomere length and environmental exposure to indoor air pollution. In conclusion, long-term exposure to indoor air pollution may cause LTL dysfunction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Test anxiety and telomere length: Academic stress in adolescents may not cause rapid telomere erosion.

    Science.gov (United States)

    Zou, Yaru; Leong, Waiian; Yao, Mingling; Hu, Xuefei; Lu, Sixiao; Zhu, Xiaowei; Chen, Lianxiang; Tong, Jianjing; Shi, Jingyi; Gilson, Eric; Ye, Jing; Lu, Yiming

    2017-02-14

    Academic stress (AS) is one of the most important health problems experienced by students, but no biomarker of the potential psychological or physical problems associated with AS has yet been identified. As several cross-sectional studies have shown that psychiatric conditions accelerate aging and shorten telomere length (TL), we explored whether AS affected TL.Between June 2014 and July 2014, we recruited 200 junior high school students with imminent final examinations for participation in this study. The students were divided into three subgroups (mild, moderate, and severe anxiety) using the Sarason Test Anxiety Scale (TAS). Saliva samples were collected for TL measurement via quantitative polymerase chain reaction (qPCR).Students from both a specialized and a general school suffered from anxiety (p > 0.05). A total 35% had severe anxiety (score: 26.09±3.87), 33% had moderate anxiety (16.98±2.64), and 32% had mild anxiety (7.89±1.92). The TAS values differed significantly (p 0.05): 1.14±0.46 for those with severe anxiety, 1.02±0.40 for those with moderate anxiety, and 1.12±0.45 for those with mild anxiety.Previous reports have found that AS is very common in Asian adolescents. We found no immediate telomere shortening in adolescents with AS. Longitudinal observations are required to determine if TL is affected by AS.

  16. Empirical evaluation of humpback whale telomere length estimates; quality control and factors causing variability in the singleplex and multiplex qPCR methods

    DEFF Research Database (Denmark)

    Olsen, Morten Tange; Bérubé, Martine; Robbins, Jooke

    2012-01-01

    BACKGROUND:Telomeres, the protective cap of chromosomes, have emerged as powerful markers of biological age and life history in model and non-model species. The qPCR method for telomere length estimation is one of the most common methods for telomere length estimation, but has received recent...... steps of qPCR. In order to evaluate the utility of the qPCR method for telomere length estimation in non-model species, we carried out four different qPCR assays directed at humpback whale telomeres, and subsequently performed a rigorous quality control to evaluate the performance of each assay. RESULTS...... to 40% depending on assay and quantification method, however this variation only affected telomere length estimates in the worst performing assays. CONCLUSION:Our results suggest that seemingly well performing qPCR assays may contain biases that will only be detected by extensive quality control...

  17. Oxidative stress-induced telomeric erosion as a mechanism underlying airborne particulate matter-related cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Grahame Thomas J

    2012-06-01

    Full Text Available Abstract Particulate matter (PM pollution is responsible for hundreds of thousands of deaths worldwide, the majority due to cardiovascular disease (CVD. While many potential pathophysiological mechanisms have been proposed, there is not yet a consensus as to which are most important in causing pollution-related morbidity/mortality. Nor is there consensus regarding which specific types of PM are most likely to affect public health in this regard. One toxicological mechanism linking exposure to airborne PM with CVD outcomes is oxidative stress, a contributor to the development of CVD risk factors including atherosclerosis. Recent work suggests that accelerated shortening of telomeres and, thus, early senescence of cells may be an important pathway by which oxidative stress may accelerate biological aging and the resultant development of age-related morbidity. This pathway may explain a significant proportion of PM-related adverse health outcomes, since shortened telomeres accelerate the progression of many diseases. There is limited but consistent evidence that vehicular emissions produce oxidative stress in humans. Given that oxidative stress is associated with accelerated erosion of telomeres, and that shortened telomeres are linked with acceleration of biological ageing and greater incidence of various age-related pathology, including CVD, it is hypothesized that associations noted between certain pollution types and sources and oxidative stress may reflect a mechanism by which these pollutants result in CVD-related morbidity and mortality, namely accelerated aging via enhanced erosion of telomeres. This paper reviews the literature providing links among oxidative stress, accelerated erosion of telomeres, CVD, and specific sources and types of air pollutants. If certain PM species/sources might be responsible for adverse health outcomes via the proposed mechanism, perhaps the pathway to reducing mortality/morbidity from PM would become clearer

  18. Detecting telomere elongation in longitudinal datasets: analysis of a proposal by Simons, Stulp and Nakagawa

    Directory of Open Access Journals (Sweden)

    Daniel Nettle

    2017-04-01

    Full Text Available Telomere shortening has emerged as an important biomarker of aging. Longitudinal studies consistently find that, although telomere length shortens over time on average, there is a subset of individuals for whom telomere length is observed to increase. This apparent lengthening could either be a genuine biological phenomenon, or simply due to measurement and sampling error. Simons, Stulp & Nakagawa (2014 recently proposed a statistical test for detecting when the amount of apparent lengthening in a dataset exceeds that which should be expected due to error, and thus indicating that genuine elongation may be operative in some individuals. However, the test is based on a restrictive assumption, namely that each individual’s true rate of telomere change is constant over time. It is not currently known whether this assumption is true. Here we show, using simulated datasets, that with perfect measurement and large sample size, the test has high power to detect true lengthening as long as the true rate of change is either constant, or moderately stable, over time. If the true rate of change varies randomly from year to year, the test systematically returns type-II errors (false negatives; that is, failures to detect lengthening even when a substantial fraction of the population truly lengthens each year. We also consider the impact of measurement error. Using estimates of the magnitude of annual attrition and of measurement error derived from the human telomere literature, we show that power of the test is likely to be low in several empirically-realistic scenarios, even in large samples. Thus, whilst a significant result of the proposed test is likely to indicate that true lengthening is present in a data set, type-II errors are a likely outcome, either if measurement error is substantial, and/or the true rate of telomere change varies substantially over time within individuals.

  19. Single molecule localization imaging of telomeres and centromeres using fluorescence in situ hybridization and semiconductor quantum dots.

    Science.gov (United States)

    Wang, Le; Zong, Shenfei; Wang, Zhuyuan; Lu, Ju; Chen, Chen; Zhang, Ruohu; Cui, Yiping

    2018-07-13

    Single molecule localization microscopy (SMLM) is a powerful tool for imaging biological targets at the nanoscale. In this report, we present SMLM imaging of telomeres and centromeres using fluorescence in situ hybridization (FISH). The FISH probes were fabricated by decorating CdSSe/ZnS quantum dots (QDs) with telomere or centromere complementary DNA strands. SMLM imaging experiments using commercially available peptide nucleic acid (PNA) probes labeled with organic fluorophores were also conducted to demonstrate the advantages of using QDs FISH probes. Compared with the PNA probes, the QDs probes have the following merits. First, the fluorescence blinking of QDs can be realized in aqueous solution or PBS buffer without thiol, which is a key buffer component for organic fluorophores' blinking. Second, fluorescence blinking of the QDs probe needs only one excitation light (i.e. 405 nm). While fluorescence blinking of the organic fluorophores usually requires two illumination lights, that is, the activation light (i.e. 405 nm) and the imaging light. Third, the high quantum yield, multiple switching times and a good optical stability make the QDs more suitable for long-term imaging. The localization precision achieved in telomeres and centromeres imaging experiments is about 30 nm, which is far beyond the diffraction limit. SMLM has enabled new insights into telomeres or centromeres on the molecular level, and it is even possible to determine the length of telomere and become a potential technique for telomere-related investigation.

  20. Live cell CRISPR-imaging in plants reveals dynamic telomere movements

    KAUST Repository

    Dreissig, Steven

    2017-05-16

    Elucidating the spatio-temporal organization of the genome inside the nucleus is imperative to understand the regulation of genes and non-coding sequences during development and environmental changes. Emerging techniques of chromatin imaging promise to bridge the long-standing gap between sequencing studies which reveal genomic information and imaging studies that provide spatial and temporal information of defined genomic regions. Here, we demonstrate such an imaging technique based on two orthologues of the bacterial CRISPR-Cas9 system. By fusing eGFP/mRuby2 to the catalytically inactive version of Streptococcus pyogenes and Staphylococcus aureus Cas9, we show robust visualization of telomere repeats in live leaf cells of Nicotiana benthamiana. By tracking the dynamics of telomeres visualized by CRISPR-dCas9, we reveal dynamic telomere movements of up to 2 μm within 30 minutes during interphase. Furthermore, we show that CRISPR-dCas9 can be combined with fluorescence-labelled proteins to visualize DNA-protein interactions in vivo. By simultaneously using two dCas9 orthologues, we pave the way for imaging of multiple genomic loci in live plants cells. CRISPR-imaging bears the potential to significantly improve our understanding of the dynamics of chromosomes in live plant cells.