WorldWideScience

Sample records for arm specific telomere

  1. Chromosome arm-specific long telomeres: a new clonal event in primary chronic myelogenous leukemia cells.

    Science.gov (United States)

    Samassekou, Oumar; Li, Huiyu; Hébert, Josée; Ntwari, Aimé; Wang, Haixia; Cliché, Catherine Grenier; Bouchard, Eric; Huang, Shiang; Yan, Ju

    2011-06-01

    Previous studies demonstrated that critically shortened telomere lengths correlate with the chromosome instability in carcinogenesis. However, little has been noticed regarding the correlation of long telomeres at specific chromosomes with malignant disorders. We studied relative telomere lengths (RTLs) for individual chromosomes using the quantitative fluorescence in situ hybridization technique in a cohort of 32 patients with chronic myeloid leukemia (CML) and 32 normal samples. We found that telomeres at some specific chromosome arms remain well maintained or even lengthened in a high frequency (27/32) of leukemia cases. In particular, 10 chromosome arms, 4q, 5p, 7q, 11p, 13p, 13q, 14p, 15p, 18p, and Xp, with long telomeres were consistently identified in different samples, and six of them (4q, 5p, 13p, 13q, 14p, and Xp) with relatively long telomeres were also observed in normal samples, but they appeared in lower occurrence rate and shorter RTL than in CML samples. Our results strongly indicate the presence of a special leukemia cell population, or a clone, originated from a common progenitor that is characterized with chromosome arm-specific long telomeres. We suggest that relatively long telomeres located at key chromosomes could be preferentially maintained or further elongated during the early stage of malignant transformation. PMID:21677878

  2. Chromosome Arm-Specific Long Telomeres: A New Clonal Event in Primary Chronic Myelogenous Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Oumar Samassekou

    2011-06-01

    Full Text Available Previous studies demonstrated that critically shortened telomere lengths correlate with the chromosome instability in carcinogenesis. However, little has been noticed regarding the correlation of long telomeres at specific chromosomes with malignant disorders. We studied relative telomere lengths (RTLs for individual chromosomes using the quantitative fluorescence in situ hybridization technique in a cohort of 32 patients with chronic myeloid leukemia (CML and 32 normal samples. We found that telomeres at some specific chromosome arms remain well maintained or even lengthened in a high frequency (27/32 of leukemia cases. In particular, 10 chromosome arms, 4q, 5p, 7q, 11p, 13p, 13q, 14p, 15p, 18p, and Xp, with long telomeres were consistently identified in different samples, and six of them (4q, 5p, 13p, 13q, 14p, and Xp with relatively long telomeres were also observed in normal samples, but they appeared in lower occurrence rate and shorter RTL than in CML samples. Our results strongly indicate the presence of a special leukemia cell population, or a clone, originated from a common progenitor that is characterized with chromosome arm-specific long telomeres. We suggest that relatively long telomeres located at key chromosomes could be preferentially maintained or further elongated during the early stage of malignant transformation.

  3. Chromosome Arm-Specific Long Telomeres: A New Clonal Event in Primary Chronic Myelogenous Leukemia Cells12

    Science.gov (United States)

    Samassekou, Oumar; Li, Huiyu; Hébert, Josée; Ntwari, Aimé; Wang, Haixia; Cliché, Catherine Grenier; Bouchard, Eric; Huang, Shiang; Yan, Ju

    2011-01-01

    Previous studies demonstrated that critically shortened telomere lengths correlate with the chromosome instability in carcinogenesis. However, little has been noticed regarding the correlation of long telomeres at specific chromosomes with malignant disorders. We studied relative telomere lengths (RTLs) for individual chromosomes using the quantitative fluorescence in situ hybridization technique in a cohort of 32 patients with chronic myeloid leukemia (CML) and 32 normal samples. We found that telomeres at some specific chromosome arms remain well maintained or even lengthened in a high frequency (27/32) of leukemia cases. In particular, 10 chromosome arms, 4q, 5p, 7q, 11p, 13p, 13q, 14p, 15p, 18p, and Xp, with long telomeres were consistently identified in different samples, and six of them (4q, 5p, 13p, 13q, 14p, and Xp) with relatively long telomeres were also observed in normal samples, but they appeared in lower occurrence rate and shorter RTL than in CML samples. Our results strongly indicate the presence of a special leukemia cell population, or a clone, originated from a common progenitor that is characterized with chromosome arm-specific long telomeres. We suggest that relatively long telomeres located at key chromosomes could be preferentially maintained or further elongated during the early stage of malignant transformation. PMID:21677878

  4. Chromosome Arm-Specific Long Telomeres: A New Clonal Event in Primary Chronic Myelogenous Leukemia Cells

    OpenAIRE

    Oumar Samassekou; Huiyu Li; Josée Hébert; Aimé Ntwari; Haixia Wang; Catherine Grenier Cliché; Eric Bouchard; Shiang Huang; Ju Yan

    2011-01-01

    Previous studies demonstrated that critically shortened telomere lengths correlate with the chromosome instability in carcinogenesis. However, little has been noticed regarding the correlation of long telomeres at specific chromosomes with malignant disorders. We studied relative telomere lengths (RTLs) for individual chromosomes using the quantitative fluorescence in situ hybridization technique in a cohort of 32 patients with chronic myeloid leukemia (CML) and 32 normal samples. We found th...

  5. Chromosome Arm-Specific Long Telomeres: A New Clonal Event in Primary Chronic Myelogenous Leukemia Cells12

    OpenAIRE

    Samassekou, Oumar; Li, Huiyu; Hébert, Josée; Ntwari, Aimé; Wang, Haixia; Cliché, Catherine Grenier; Bouchard, Eric; Huang, Shiang; Yan, Ju

    2011-01-01

    Previous studies demonstrated that critically shortened telomere lengths correlate with the chromosome instability in carcinogenesis. However, little has been noticed regarding the correlation of long telomeres at specific chromosomes with malignant disorders. We studied relative telomere lengths (RTLs) for individual chromosomes using the quantitative fluorescence in situ hybridization technique in a cohort of 32 patients with chronic myeloid leukemia (CML) and 32 normal samples. We found th...

  6. 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; Kølvrå, Steen;

    2007-01-01

    investigate the existence and maintenance of the telomere length pattern in stem cells. For this aim we studied telomere length in primary human mesenchymal stem cells (hMSC) and their telomerase-immortalised counterpart (hMSC-telo1) during extended proliferation as well as after irradiation. Telomere lengths...

  7. Cause-specific telomere factors deregulation in hepatocellular carcinoma.

    OpenAIRE

    El Idrissi, Manale; Hervieu, Valérie; Merle, Philippe; Mortreux, Franck; Wattel, Eric

    2013-01-01

    International audience BACKGROUND: Among the numerous genetic defects associated with hepatocarcinogenesis, telomere abnormalities appear to play a role both in tumor promotion and maintenance. Telomeres, the chromosome extremities, are protected by specific proteins, the shelterin complex and by additional factors. Besides telomerase dysregulation, expression changes of these telomere factors have been observed in cancers. METHODS: Here, we tested the hypothesis that such dysregulation mi...

  8. Telomerase RNA Template Mutations Reveal Sequence-Specific Requirements for the Activation and Repression of Telomerase Action at Telomeres

    OpenAIRE

    Prescott, John C.; Blackburn, Elizabeth H.

    2000-01-01

    Telomeric DNA is maintained within a length range characteristic of an organism or cell type. Significant deviations outside this range are associated with altered telomere function. The yeast telomere-binding protein Rap1p negatively regulates telomere length. Telomere elongation is responsive to both the number of Rap1p molecules bound to a telomere and the Rap1p-centered DNA-protein complex at the extreme telomeric end. Previously, we showed that a specific trinucleotide substitution in th...

  9. Individual Telomere Lengths in Chronic Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Oumar Samassekou

    2009-11-01

    Full Text Available Chronic myeloid leukemia (CML is a neoplasia characterized by proliferation of a myeloid cell lineage and chromosome translocation t(9;22 (q34;q11.2. As in the case of most cancers, the average telomere length in CML cells is shorter than that in normal blood cells. However, there are currently no data available concerning specific individual telomere length in CML. Here, we studied telomere length on each chromosome arm of CML cells. In situ hybridization with peptide nucleic acid probes was performed on CML cells in metaphase. The fluorescence intensity of each specific telomere was converted into kilobases according to the telomere restriction fragment results for each sample. We found differences in telomere length between short arm ends and long arm ends. We observed recurrent telomere length changes as well as telomere length maintenance and elongation in some individual telomeres. We propose a possible involvement of individual telomere length changes to some chromosomal abnormalities in CML. We suggest that individual telomere length maintenance is chromosome arm-specific associated with leukemia cells.

  10. Base J glucosyltransferase does not regulate the sequence specificity of J synthesis in trypanosomatid telomeric DNA.

    Science.gov (United States)

    Bullard, Whitney; Cliffe, Laura; Wang, Pengcheng; Wang, Yinsheng; Sabatini, Robert

    2015-12-01

    Telomeric DNA of trypanosomatids possesses a modified thymine base, called base J, that is synthesized in a two-step process; the base is hydroxylated by a thymidine hydroxylase forming hydroxymethyluracil (hmU) and a glucose moiety is then attached by the J-associated glucosyltransferase (JGT). To examine the importance of JGT in modifiying specific thymine in DNA, we used a Leishmania episome system to demonstrate that the telomeric repeat (GGGTTA) stimulates J synthesis in vivo while mutant telomeric sequences (GGGTTT, GGGATT, and GGGAAA) do not. Utilizing an in vitro GT assay we find that JGT can glycosylate hmU within any sequence with no significant change in Km or kcat, even mutant telomeric sequences that are unable to be J-modified in vivo. The data suggests that JGT possesses no DNA sequence specificity in vitro, lending support to the hypothesis that the specificity of base J synthesis is not at the level of the JGT reaction. PMID:26815240

  11. hnRNP A2/B1 binds specifically to single stranded vertebrate telomeric repeat TTAGGGn.

    OpenAIRE

    McKay, S.J.; Cooke, H

    1992-01-01

    We have previously isolated a protein from mouse liver nuclei that specifically binds to single stranded (TTAGGG)n repeats. TTAGGG is the telomeric repeats of mammals and we therefore named the new protein single stranded telomere binding protein (sTBP). Further studies now identify sTBP as heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 on the basis of amino acid sequence determination and antibody reactivity. A2 and B1 form a major part of the protein component of hnRNP particles and ...

  12. Telomeric Trans-Silencing in Drosophila melanogaster: Tissue Specificity, Development and Functional Interactions between Non-Homologous Telomeres

    OpenAIRE

    Josse, Thibaut; Maurel-Zaffran, Corinne; de Vanssay, Augustin; Teysset, Laure; Todeschini, Anne-Laure; Delmarre, Valerie; Chaminade, Nicole; Anxolabéhère, Dominique; Ronsseray, Stéphane

    2008-01-01

    Background The study of P element repression in Drosophila melanogaster led to the discovery of the telomeric Trans-Silencing Effect (TSE), a homology-dependent repression mechanism by which a P-transgene inserted in subtelomeric heterochromatin (Telomeric Associated Sequences, “TAS”) has the capacity to repress in trans, in the female germline, a homologous P-lacZ transgene located in euchromatin. TSE can show variegation in ovaries, displays a maternal effect as well as an epigenetic transm...

  13. Evolution of species-specific promoter-associated mechanisms for protecting chromosome ends by Drosophila Het-A telomeric transposons

    Science.gov (United States)

    Traverse, Karen L.; George, Janet A.; DeBaryshe, P. G.; Pardue, Mary-Lou

    2010-01-01

    The non-LTR retrotransposons forming Drosophila telomeres constitute a robust mechanism for telomere maintenance, one which has persisted since before separation of the extant Drosophila species. These elements in D. melanogaster differ from nontelomeric retrotransposons in ways that give insight into general telomere biology. Here, we analyze telomere-specific retrotransposons from D. virilis, separated from D. melanogaster by 40 to 60 million years, to evaluate the evolutionary divergence of their telomeric traits. The telomeric retrotransposon HeT-A from D. melanogaster has an unusual promoter near its 3′ terminus that drives not the element in which it resides, but the adjacent downstream element in a head-to-tail array. An obvious benefit of this promoter is that it adds nonessential sequence to the 5′ end of each transcript, which is reverse transcribed and added to the chromosome. Because the 5′ end of each newly transposed element forms the end of the chromosome until another element transposes onto it, this nonessential sequence can buffer erosion of sequence essential for HeT-A. Surprisingly, we have now found that HeT-A in D. virilis has a promoter typical of non-LTR retrotransposons. This promoter adds no buffering sequence; nevertheless, the complete 5′ end of the element persists in telomere arrays, necessitating a more precise processing of the extreme end of the telomere in D. virilis. PMID:20194755

  14. In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychia lemnae macronuclei

    OpenAIRE

    Schaffitzel, Christiane; Berger, Imre; Postberg, Jan; Hanes, Jozef; Lipps, Hans J; Plückthun, Andreas

    2001-01-01

    Most eukaryotic telomeres contain a repeating motif with stretches of guanine residues that form a 3′-terminal overhang extending beyond the telomeric duplex region. The telomeric repeat of hypotrichous ciliates, d(T4G4), forms a 16-nucleotide 3′-overhang. Such sequences can adopt parallel-stranded as well as antiparallel-stranded quadruplex conformations in vitro. Although it has been proposed that guanine-quadruplex conformations may have important cellular roles including telomere function...

  15. Quantum dots thermal stability improves simultaneous phenotype-specific telomere length measurement by FISH-flow cytometry.

    Science.gov (United States)

    Kapoor, Veena; Hakim, Fran T; Rehman, Najibah; Gress, Ronald E; Telford, William G

    2009-05-15

    -associated decline in telomere length in both human monocytes and T cell subsets. With quantum dot immunolabeling, the mean decrease rate in telomere length for CD4+ cells was calculated at 41.8 bp/year, very close to previously reported values using traditional flow-FISH and Southern blotting. This modification to the traditional flow-FISH technique should therefore allow simultaneous fluorescent immunophenotyping and telomere length measurement, permitting complex cell subset-specific analysis in small numbers of cells without the requirement for prior cell sorting. PMID:19268672

  16. Light duty utility arm software requirements specification

    Energy Technology Data Exchange (ETDEWEB)

    Kiebel, G.R.

    1995-12-18

    This document defines the software requirements for the integrated control and data acquisition system of the Light Duty Utility Arm (LDUA) System. It is intended to be used to guide the design of the application software, to be a basis for assessing the application software design, and to establish what is to be tested in the finished application software product.

  17. Light duty utility arm software requirements specification

    International Nuclear Information System (INIS)

    This document defines the software requirements for the integrated control and data acquisition system of the Light Duty Utility Arm (LDUA) System. It is intended to be used to guide the design of the application software, to be a basis for assessing the application software design, and to establish what is to be tested in the finished application software product

  18. Arm-specific dynamics of chromosome evolution in malaria mosquitoes

    Directory of Open Access Journals (Sweden)

    Xia Ai

    2011-04-01

    Full Text Available Abstract Background The malaria mosquito species of subgenus Cellia have rich inversion polymorphisms that correlate with environmental variables. Polymorphic inversions tend to cluster on the chromosomal arms 2R and 2L but not on X, 3R and 3L in Anopheles gambiae and homologous arms in other species. However, it is unknown whether polymorphic inversions on homologous chromosomal arms of distantly related species from subgenus Cellia nonrandomly share similar sets of genes. It is also unclear if the evolutionary breakage of inversion-poor chromosomal arms is under constraints. Results To gain a better understanding of the arm-specific differences in the rates of genome rearrangements, we compared gene orders and established syntenic relationships among Anopheles gambiae, Anopheles funestus, and Anopheles stephensi. We provided evidence that polymorphic inversions on the 2R arms in these three species nonrandomly captured similar sets of genes. This nonrandom distribution of genes was not only a result of preservation of ancestral gene order but also an outcome of extensive reshuffling of gene orders that created new combinations of homologous genes within independently originated polymorphic inversions. The statistical analysis of distribution of conserved gene orders demonstrated that the autosomal arms differ in their tolerance to generating evolutionary breakpoints. The fastest evolving 2R autosomal arm was enriched with gene blocks conserved between only a pair of species. In contrast, all identified syntenic blocks were preserved on the slowly evolving 3R arm of An. gambiae and on the homologous arms of An. funestus and An. stephensi. Conclusions Our results suggest that natural selection favors specific gene combinations within polymorphic inversions when distant species are exposed to similar environmental pressures. This knowledge could be useful for the discovery of genes responsible for an association of inversion polymorphisms with

  19. Arm-specific dynamics of chromosome evolution in malaria mosquitoes

    Science.gov (United States)

    2011-01-01

    Background The malaria mosquito species of subgenus Cellia have rich inversion polymorphisms that correlate with environmental variables. Polymorphic inversions tend to cluster on the chromosomal arms 2R and 2L but not on X, 3R and 3L in Anopheles gambiae and homologous arms in other species. However, it is unknown whether polymorphic inversions on homologous chromosomal arms of distantly related species from subgenus Cellia nonrandomly share similar sets of genes. It is also unclear if the evolutionary breakage of inversion-poor chromosomal arms is under constraints. Results To gain a better understanding of the arm-specific differences in the rates of genome rearrangements, we compared gene orders and established syntenic relationships among Anopheles gambiae, Anopheles funestus, and Anopheles stephensi. We provided evidence that polymorphic inversions on the 2R arms in these three species nonrandomly captured similar sets of genes. This nonrandom distribution of genes was not only a result of preservation of ancestral gene order but also an outcome of extensive reshuffling of gene orders that created new combinations of homologous genes within independently originated polymorphic inversions. The statistical analysis of distribution of conserved gene orders demonstrated that the autosomal arms differ in their tolerance to generating evolutionary breakpoints. The fastest evolving 2R autosomal arm was enriched with gene blocks conserved between only a pair of species. In contrast, all identified syntenic blocks were preserved on the slowly evolving 3R arm of An. gambiae and on the homologous arms of An. funestus and An. stephensi. Conclusions Our results suggest that natural selection favors specific gene combinations within polymorphic inversions when distant species are exposed to similar environmental pressures. This knowledge could be useful for the discovery of genes responsible for an association of inversion polymorphisms with phenotypic variations in

  20. Telomere Rapid Deletion Regulates Telomere Length in Arabidopsis thaliana▿

    OpenAIRE

    Watson, J. Matthew; Dorothy E Shippen

    2006-01-01

    Telomere length is maintained in species-specific equilibrium primarily through a competition between telomerase-mediated elongation and the loss of terminal DNA through the end-replication problem. Recombinational activities are also capable of both lengthening and shortening telomeres. Here we demonstrate that elongated telomeres in Arabidopsis Ku70 mutants reach a new length set point after three generations. Restoration of wild-type Ku70 in these mutants leads to discrete telomere-shorten...

  1. Recombinogenic Telomeres in Diploid Sorex granarius (Soricidae, Eulipotyphla) Fibroblast Cells

    OpenAIRE

    Zhdanova, N. S.; Draskovic, I.; Minina, J. M.; Karamysheva, T. V.; Novo, C. L.; Liu, W.-Y.; Porreca, R. M.; Gibaud, A.; Zvereva, M.E.; Skvortsov, D. A.; Rubtsov, N.B.; Londoño-Vallejo, A

    2014-01-01

    The telomere structure in the Iberian shrew Sorex granarius is characterized by unique, striking features, with short arms of acrocentric chromosomes carrying extremely long telomeres (up to 300 kb) with interspersed ribosomal DNA (rDNA) repeat blocks. In this work, we investigated the telomere physiology of S. granarius fibroblast cells and found that telomere repeats are transcribed on both strands and that there is no telomere-dependent senescence mechanism. Although telomerase activit...

  2. Nature of telomere dimers and chromosome looping in human spermatozoa

    OpenAIRE

    Solov'eva, Lyudmila; Svetlova, Maria; Bodinski, Dawn; Zalensky, Andrei O.

    2004-01-01

    Specific and well-organized chromosome architecture in human sperm cells is supported by the prominent interactions between centromeres and between telomeres. The telomere-telomere interactions result in telomere dimers that are positioned at the nuclear periphery. It is unknown whether composition of sperm telomere dimers is random or specific. We now report that telomere dimers result from specific interactions between the two ends of each chromosome. FISH using pairs of subtelomeric DNA pr...

  3. Replication Timing of Human Telomeres is Conserved during Immortalization and Influenced by Respective Subtelomeres.

    Science.gov (United States)

    Piqueret-Stephan, Laure; Ricoul, Michelle; Hempel, William M; Sabatier, Laure

    2016-01-01

    Telomeres are specific structures that protect chromosome ends and act as a biological clock, preventing normal cells from replicating indefinitely. Mammalian telomeres are replicated throughout S-phase in a predetermined order. However, the mechanism of this regulation is still unknown. We wished to investigate this phenomenon under physiological conditions in a changing environment, such as the immortalization process to better understand the mechanism for its control. We thus examined the timing of human telomere replication in normal and SV40 immortalized cells, which are cytogenetically very similar to cancer cells. We found that the timing of telomere replication was globally conserved under different conditions during the immortalization process. The timing of telomere replication was conserved despite changes in telomere length due to endogenous telomerase reactivation, in duplicated homologous chromosomes, and in rearranged chromosomes. Importantly, translocated telomeres, possessing their initial subtelomere, retained the replication timing of their homolog, independently of the proportion of the translocated arm, even when the remaining flanking DNA is restricted to its subtelomere, the closest chromosome-specific sequences (inferior to 500 kb). Our observations support the notion that subtelomere regions strongly influence the replication timing of the associated telomere. PMID:27587191

  4. Pilocytic Astrocytomas Have Telomere-Associated Promyelocytic Leukemia Bodies without Alternatively Lengthened Telomeres

    OpenAIRE

    Slatter, Tania; Gifford-Garner, Jennifer; Wiles, Anna; Tan, Xin; Chen, Yu-Jen; MacFarlane, Martin; Sullivan, Michael; Royds, Janice; Hung, Noelyn

    2010-01-01

    Telomere maintenance by either telomerase activity or the recombination-mediated alternative lengthening of telomeres (ALT) mechanism is a hallmark of cancer. Tumors that use ALT as their telomere maintenance mechanism are characterized by long telomeres of great heterogeneity in length and by specific nuclear structures of co-localized promyelocytic leukemia protein and telomere DNA, called ALT-associated promyelocytic leukemia bodies (APBs). Recent advances have revealed a direct role for A...

  5. Nucleolar organization, ribosomal DNA array stability, and acrocentric chromosome integrity are linked to telomere function.

    Directory of Open Access Journals (Sweden)

    Kaitlin M Stimpson

    Full Text Available The short arms of the ten acrocentric human chromosomes share several repetitive DNAs, including ribosomal RNA genes (rDNA. The rDNA arrays correspond to nucleolar organizing regions that coalesce each cell cycle to form the nucleolus. Telomere disruption by expressing a mutant version of telomere binding protein TRF2 (dnTRF2 causes non-random acrocentric fusions, as well as large-scale nucleolar defects. The mechanisms responsible for acrocentric chromosome sensitivity to dysfunctional telomeres are unclear. In this study, we show that TRF2 normally associates with the nucleolus and rDNA. However, when telomeres are crippled by dnTRF2 or RNAi knockdown of TRF2, gross nucleolar and chromosomal changes occur. We used the controllable dnTRF2 system to precisely dissect the timing and progression of nucleolar and chromosomal instability induced by telomere dysfunction, demonstrating that nucleolar changes precede the DNA damage and morphological changes that occur at acrocentric short arms. The rDNA repeat arrays on the short arms decondense, and are coated by RNA polymerase I transcription binding factor UBF, physically linking acrocentrics to one another as they become fusogenic. These results highlight the importance of telomere function in nucleolar stability and structural integrity of acrocentric chromosomes, particularly the rDNA arrays. Telomeric stress is widely accepted to cause DNA damage at chromosome ends, but our findings suggest that it also disrupts chromosome structure beyond the telomere region, specifically within the rDNA arrays located on acrocentric chromosomes. These results have relevance for Robertsonian translocation formation in humans and mechanisms by which acrocentric-acrocentric fusions are promoted by DNA damage and repair.

  6. Binding Specificities of the Telomere Phage ϕKO2 Prophage Repressor CB and Lytic Repressor Cro.

    Science.gov (United States)

    Hammerl, Jens Andre; Jäckel, Claudia; Lanka, Erich; Roschanski, Nicole; Hertwig, Stefan

    2016-01-01

    Temperate bacteriophages possess a genetic switch which regulates the lytic and lysogenic cycle. The genomes of the temperate telomere phages N15, PY54, and ϕKO2 harbor a primary immunity region (immB) comprising genes for the prophage repressor (cI or cB), the lytic repressor (cro) and a putative antiterminator (q). The roles of these products are thought to be similar to those of the lambda proteins CI (CI prophage repressor), Cro (Cro repressor), and Q (antiterminator Q), respectively. Moreover, the gene order and the location of several operator sites in the prototype telomere phage N15 and in ϕKO2 are reminiscent of lambda-like phages. We determined binding sites of the ϕKO2 prophage repressor CB and lytic repressor Cro on the ϕKO2 genome in detail by electrophoretic mobility shift assay (EMSA) studies. Unexpectedly, ϕKO2 CB and Cro revealed different binding specificities. CB was bound to three OR operators in the intergenic region between cB and cro, two OL operators between cB and the replication gene repA and even to operators of N15. Cro bound exclusively to the 16 bp operator site OR3 upstream of the ϕKO2 prophage repressor gene. The ϕKO2 genes cB and cro are regulated by several strong promoters overlapping with the OR operators. The data suggest that Cro represses cB transcription but not its own synthesis, as already reported for PY54 Cro. Thus, not only PY54, but also phage ϕKO2 possesses a genetic switch that diverges significantly from the switch of lambda-like phages. PMID:27527206

  7. Are Drosophila telomeres an exception or the rule?

    OpenAIRE

    Louis, Edward J.

    2002-01-01

    At the ends of eukaryotic chromosomes are telomeres, specialized structures with unusual properties. The repetitive structure of telomere regions makes them difficult to deal with in general genome-sequencing projects. Specific efforts to compare sequences and properties of telomeres across species can reveal the generalities of telomere properties.

  8. Functional interplay between SA1 and TRF1 in telomeric DNA binding and DNA-DNA pairing.

    Science.gov (United States)

    Lin, Jiangguo; Countryman, Preston; Chen, Haijiang; Pan, Hai; Fan, Yanlin; Jiang, Yunyun; Kaur, Parminder; Miao, Wang; Gurgel, Gisele; You, Changjiang; Piehler, Jacob; Kad, Neil M; Riehn, Robert; Opresko, Patricia L; Smith, Susan; Tao, Yizhi Jane; Wang, Hong

    2016-07-27

    Proper chromosome alignment and segregation during mitosis depend on cohesion between sister chromatids. Cohesion is thought to occur through the entrapment of DNA within the tripartite ring (Smc1, Smc3 and Rad21) with enforcement from a fourth subunit (SA1/SA2). Surprisingly, cohesin rings do not play a major role in sister telomere cohesion. Instead, this role is replaced by SA1 and telomere binding proteins (TRF1 and TIN2). Neither the DNA binding property of SA1 nor this unique telomere cohesion mechanism is understood. Here, using single-molecule fluorescence imaging, we discover that SA1 displays two-state binding on DNA: searching by one-dimensional (1D) free diffusion versus recognition through subdiffusive sliding at telomeric regions. The AT-hook motif in SA1 plays dual roles in modulating non-specific DNA binding and subdiffusive dynamics over telomeric regions. TRF1 tethers SA1 within telomeric regions that SA1 transiently interacts with. SA1 and TRF1 together form longer DNA-DNA pairing tracts than with TRF1 alone, as revealed by atomic force microscopy imaging. These results suggest that at telomeres cohesion relies on the molecular interplay between TRF1 and SA1 to promote DNA-DNA pairing, while along chromosomal arms the core cohesin assembly might also depend on SA1 1D diffusion on DNA and sequence-specific DNA binding. PMID:27298259

  9. ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells

    Directory of Open Access Journals (Sweden)

    Stella Suyong Lee

    2015-11-01

    Full Text Available Short telomeres induce a DNA damage response, senescence, and apoptosis, thus maintaining telomere length equilibrium is essential for cell viability. Telomerase addition of telomere repeats is tightly regulated in cells. To probe pathways that regulate telomere addition, we developed the ADDIT assay to measure new telomere addition at a single telomere in vivo. Sequence analysis showed telomerase-specific addition of repeats onto a new telomere occurred in just 48 hr. Using the ADDIT assay, we found that ATM is required for addition of new repeats onto telomeres in mouse cells. Evaluation of bulk telomeres, in both human and mouse cells, showed that blocking ATM inhibited telomere elongation. Finally, the activation of ATM through the inhibition of PARP1 resulted in increased telomere elongation, supporting the central role of the ATM pathway in regulating telomere addition. Understanding this role of ATM may yield new areas for possible therapeutic intervention in telomere-mediated disease.

  10. Telomeric circles: universal players in telomere maintenance?

    OpenAIRE

    Tomaska, Lubomir; Nosek, Jozef; Kramara, Juraj; Griffith, Jack D.

    2009-01-01

    To maintain linear DNA genomes, organisms have evolved numerous means of solving problems associated with DNA ends (telomeres), including telomere-associated retrotransposons, palindromes, hairpins, covalently bound proteins and the addition of arrays of simple DNA repeats. Telomeric arrays can be maintained through various mechanisms such as telomerase activity or recombination. The recombination-dependent maintenance pathways may include telomeric loops (t-loops) and telomeric circles (t-ci...

  11. Novel Kidins220/ARMS Splice Isoforms: Potential Specific Regulators of Neuronal and Cardiovascular Development.

    Directory of Open Access Journals (Sweden)

    Nathalie Schmieg

    Full Text Available Kidins220/ARMS is a transmembrane protein playing a crucial role in neuronal and cardiovascular development. Kidins220/ARMS is a downstream target of neurotrophin receptors and interacts with several signalling and trafficking factors. Through computational modelling, we found two potential sites for alternative splicing of Kidins220/ARMS. The first is located between exon 24 and exon 29, while the second site replaces exon 32 by a short alternative terminal exon 33. Here we describe the conserved occurrence of several Kidins220/ARMS splice isoforms at RNA and protein levels. Kidins220/ARMS splice isoforms display spatio-temporal regulation during development with distinct patterns in different neuronal populations. Neurotrophin receptor stimulation in cortical and hippocampal neurons and neuroendocrine cells induces specific Kidins220/ARMS splice isoforms and alters the appearance kinetics of the full-length transcript. Remarkably, alternative terminal exon splicing generates Kidins220/ARMS variants with distinct cellular localisation: Kidins220/ARMS containing exon 32 is targeted to the plasma membrane and neurite tips, whereas Kidins220/ARMS without exon 33 mainly clusters the full-length protein in a perinuclear intracellular compartment in PC12 cells and primary neurons, leading to a change in neurotrophin receptor expression. Overall, this study demonstrates the existence of novel Kidins220/ARMS splice isoforms with unique properties, revealing additional complexity in the functional regulation of neurotrophin receptors, and potentially other signalling pathways involved in neuronal and cardiovascular development.

  12. Telomeric Heterochromatin in Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Rosaura Hernandez-Rivas

    2010-01-01

    Full Text Available Until very recently, little was known about the chromatin structure of the telomeres and subtelomeric regions in Plasmodium falciparum. In yeast and Drosophila melanogaster, chromatin structure has long been known to be an important aspect in the regulation and functioning of these regions. Telomeres and subtelomeric regions are enriched in epigenetic marks that are specific to heterochromatin, such as methylation of lysine 9 of histone H3 and lysine 20 of histone H4. In P. falciparum, histone modifications and the presence of both the heterochromatin “writing” (PfSir2, PKMT and “reading” (PfHP1 machinery at telomeric and subtelomeric regions indicate that these regions are likely to have heterochromatic structure that is epigenetically regulated. This structure may be important for telomere functions such as the silencing of the var gene family implicated in the cytoadherence and antigenic variation of these parasites.

  13. A selfish DNA element engages a meiosis-specific motor and telomeres for germ-line propagation

    OpenAIRE

    Sau, Soumitra; Conrad, Michael N.; Lee, Chih-Ying; Kaback, David B; Dresser, Michael E.; Jayaram, Makkuni

    2014-01-01

    The chromosome-like mitotic stability of the yeast 2 micron plasmid is conferred by the plasmid proteins Rep1-Rep2 and the cis-acting locus STB, likely by promoting plasmid-chromosome association and segregation by hitchhiking. Our analysis reveals that stable plasmid segregation during meiosis requires the bouquet proteins Ndj1 and Csm4. Plasmid relocalization from the nuclear interior in mitotic cells to the periphery at or proximal to telomeres rises from early meiosis to pachytene. Analog...

  14. Telomere recombination and alternative telomere lengthening mechanisms

    NARCIS (Netherlands)

    Draskovic, I.; Londono Vallejo, A.

    2013-01-01

    Telomeres are nucleoprotein structures at the ends of linear chromosomes that protect them from being recognized as DNA double stranded breaks. Telomeres shorten with every cell division and in the absence of the checkpoint mechanisms critical telomere shortening leads to chromosome end fusions and

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

    Directory of Open Access Journals (Sweden)

    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.

  16. A dynamic model for generating actuator specifications for small arms barrel active stabilization

    Science.gov (United States)

    Pathak, Anupam; Brei, Diann; Luntz, Jonathan; Lavigna, Chris

    2006-03-01

    Due to stresses encountered in combat, it is known that soldier marksmanship noticeably decreases regardless of prior training. Active stabilization systems in small arms have potential to address this problem to increase soldier survivability and mission effectiveness. The key to success is proper actuator design, but this is highly dependent on proper specification which is challenging due to the human/weapon interaction. This paper presents a generic analytical dynamic model which is capable of defining the necessary actuation specifications for a wide range of small arms platforms. The model is unique because it captures the human interface--shoulder and arm--that introduces the jitter disturbance in addition to the geometry, inertial properties and active stabilization stiffness of the small arms platform. Because no data to date is available for actual shooter-induced disturbance in field conditions, a method is given using the model to back-solve from measured shooting range variability data the disturbance amplitude information relative to the input source (arm or shoulder). As examples of the applicability of the model to various small arms systems, two different weapon systems were investigated: the M24 sniper weapon and the M16 assault rifle. In both cases, model based simulations provided valuable insight into impact on the actuation specifications (force, displacement, phase, frequency) due to the interplay of the human-weapon-active stabilization interface including the effect of shooter-disturbance frequency, disturbance location (shoulder vs. arm), and system parameters (stiffness, barrel rotation).

  17. Five dysfunctional telomeres predict onset of senescence in human cells

    OpenAIRE

    Kaul, Zeenia; Cesare, Anthony J.; Huschtscha, Lily I.; Neumann, Axel A.; Reddel, Roger R

    2011-01-01

    Replicative senescence is accompanied by a telomere-specific DNA damage response (DDR). We found that DDR+ telomeres occur spontaneously in early-passage normal human cells and increase in number with increasing cumulative cell divisions. DDR+ telomeres at replicative senescence retain TRF2 and RAP1 proteins, are not associated with end-to-end fusions and mostly result from strand-independent, postreplicative dysfunction. On the basis of the calculated number of DDR+ telomeres in G1-phase cel...

  18. p53 Prevents Entry into Mitosis with Uncapped Telomeres

    Science.gov (United States)

    Thanasoula, Maria; Escandell, Jose Miguel; Martinez, Paula; Badie, Sophie; Muñoz, Purificacion; Blasco, María A.; Tarsounas, Madalena

    2016-01-01

    Summary Telomeres are protected by capping structures consisting of core protein complexes that bind with sequence specificity to telomeric DNA (reviewed in [1]). In their absence, telomeres trigger a DNA damage response, materialized in accumulation at the telomere of damage response proteins, e.g., phosphorylated histone H2AX (γH2AX), into telomere-dysfunction-induced foci [2, 3]. Telomere uncapping occurs transiently in every cell cycle in G2 [4], following DNA replication, but little is known about how protective structures are reassembled or whether this process is controlled by the cell-cycle surveillance machinery. Here, we report that telomere capping is monitored at the G2/M transition by the p53/p21 damage response pathway. Unlike their wild-type counterparts, human and mouse cells lacking p53 or p21 progress into mitosis prematurely with persisting uncapped telomeres. Furthermore, artificially uncapped telomeres delay mitotic entry in a p53- and p21-dependent manner. Uncapped telomeres that persist in mitotic p53-deficient cells are shorter than average and religate to generate end-to-end fusions. These results suggest that a p53-dependent pathway monitors telomere capping after DNA replication and delays G2/M progression in the presence of unprotected telomeres. This mechanism maintains a cell-cycle stage conducive for capping reactions and prevents progression into stages during which uncapped telomeres are prone to deleterious end fusions. PMID:20226664

  19. Armes

    OpenAIRE

    Camps, G.; Chenorkian, R.; Lhote, H.

    2013-01-01

    Préhistoire (G. Camps) Les armes des Paléoberbères de la Préhistoire ne présentent guère d’originalité mais à la documentation archéologique provenant de fouilles s’ajoute, en Afrique du Nord et au Sahara, une documentation iconographique d’une grande richesse que ne possèdent pas les autres pays riverains du bassin occidental de la Méditerranée. Durant les temps paléolithiques, les hommes qui occupèrent le Maghreb et le Sahara utilisèrent, en plus des outils et armes connus ailleurs ; biface...

  20. 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...

  1. Telomeres and reproductive aging.

    Science.gov (United States)

    Keefe, David L; Liu, Lin

    2009-01-01

    Infertility, miscarriage and aneuploid offspring increase with age in women, and meiotic dysfunction underlies reproductive aging. How aging disrupts meiotic function in women remains unclear, but as women increasingly delay having children, solving this problem becomes an urgent priority. Telomeres consist of a (TTAGGG)(n) repeated sequence and associated proteins at chromosome ends, mediate aging in mitotic cells and may also mediate aging during meiosis. Telomeres shorten both during DNA replication and from the response to oxidative DNA damage. Oocytes do not divide in adult mammals, but their precursors do replicate during fetal oogenesis; eggs ovulated from older females have traversed more mitotic cell cycles before entering meiosis during fetal oogenesis than eggs ovulated from younger females. Telomeres also would be expected to shorten from inefficient DNA repair of oxidative damage, because the interval between fetal oogenesis and ovulation is exceptionally prolonged in women. We have tested the hypothesis that telomere shortening disrupts meiosis by shortening telomeres experimentally in mice, which normally do not exhibit age-related meiotic dysfunction. Interestingly, mouse telomeres are much longer than human telomeres, but genetic or pharmacological shortening of mouse telomeres recapitulates in mice the human reproductive aging phenotype as the mouse telomeres reach the length of telomeres from older women. These observations led us to propose a telomere theory of reproductive aging. Moreover, chronological oxidative stress increases with reproductive aging, leading to DNA damage preferentially at (TTAGGG)(n) repeats. Finally, if telomeres shorten with aging, how do they reset across generations? Telomerase could not play a significant role in telomere elongation during early development, because this enzyme is not active until the blastocyst stage, well after the stage when telomere elongation takes place. Rather, telomeres lengthen during the

  2. Telomere Length on Chromosome 17q Shortens More than Global Telomere Length in the Development of Breast Cancer

    Directory of Open Access Journals (Sweden)

    Fariborz Rashid-Kolvear

    2007-04-01

    Full Text Available It is known that total telomere length is shorter in invasive breast cancer than in normal breast tissue but the status of individual telomere lengths has not been studied. Part of the difficulty is that usually telomere length in interphase cells is measured on all chromosomes together. In this study we compared normal breast epithelium, duct carcinoma in situ (DCIS, and invasive duct carcinoma (IDC from 18 patients. Telomere length was specifically measured on chromosome 17q and was found to be shorter in DCIS and IDC than in normal breast epithelial cells, with more heterogeneity in telomere length in DCIS associated with IDC than in DCIS alone. More importantly, we found that the shortening of telomere on chromosome 17q is greater than the average shortening of all telomeres. This finding indicates that telomere shortening is not simply the result of the end replication problem; otherwise, all telomeres should be subjected to the same rate of telomere shortening. It seems there are mechanisms that preferentially erode some telomeres more than others or preferentially protect some chromosome ends. Our results suggest that the increased level of telomere shortening on 17q may be involved in chromosome instability and the progression of DCIS.

  3. Taz1, Rap1 and Rif1 act both interdependently and independently to maintain telomeres

    OpenAIRE

    Miller, Kyle M.; Ferreira, Miguel Godinho; Cooper, Julia Promisel

    2005-01-01

    Telomere protection and maintenance are accomplished through the coordinated actions of telomere-specific DNA binding proteins and their interacting partners. The fission yeast ortholog of human TRF1/2, Taz1, binds telomeric DNA and regulates numerous aspects of telomere function. Here, we ask which aspects of Taz1 function are mediated through its interacting proteins, Rap1 and Rif1. We demonstrate that rap1+ deletion phenocopies some, but not all, aspects of taz1Δ telomere dysfunction, whil...

  4. 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...

  5. Spermatozoa telomeres determine telomere length in early embryos and offspring.

    Science.gov (United States)

    de Frutos, C; López-Cardona, A P; Fonseca Balvís, N; Laguna-Barraza, R; Rizos, D; Gutierrez-Adán, A; Bermejo-Álvarez, P

    2016-01-01

    Offspring telomere length (TL) has been correlated with paternal TL, but the mechanism for this parent of origin-specific inheritance remains unclear. The objective of this study has been to determine the role of spermatozoa TL in embryonic telomere lengthening by using two mouse models showing dimorphism in their spermatozoa TL: Mus musculus vs Mus spretus and old vs young Mus musculus. Mus spretus spermatozoa displayed a shorter TL than Mus musculus. Hybrid offspring exhibited lower TL compared with Mus musculus starting at the two-cell stage, before the onset of telomerase expression. To analyze the role of spermatozoa telomeres in early telomere lengthening, we compared the TL in oocytes, zygotes, two-cell embryos and blastocysts produced by parthenogenesis or by fertilization with Mus musculus or Mus spretus spermatozoa. TL was significantly higher in spermatozoa compared with oocytes, and it increased significantly from the oocyte to the zygote stage in those embryos fertilized with Mus musculus spermatozoa, but not in those fertilized with Mus spretus spermatozoa or produced by parthenogenesis. A further increase was noted from the zygote to the two-cell stage in fertilized Mus musculus embryos, whereas hybrid embryos maintained the oocyte TL. Spermatozoa TL shortened with age in Mus musculus and the offspring from young males showed a significantly higher TL compared with that fathered by old males. These significant differences were already noticeable at the two-cell stage. These results suggest that spermatozoa telomeres act as a guide for telomerase-independent telomere lengthening resulting in differences in TL that persist after birth. PMID:26475708

  6. The Molecular Switch of Telomere Phages: High Binding Specificity of the PY54 Cro Lytic Repressor to a Single Operator Site.

    Science.gov (United States)

    Hammerl, Jens Andre; Roschanski, Nicole; Lurz, Rudi; Johne, Reimar; Lanka, Erich; Hertwig, Stefan

    2015-06-01

    Temperate bacteriophages possess a molecular switch, which regulates the lytic and lysogenic growth. The genomes of the temperate telomere phages N15, PY54 and ɸKO2 harbor a primary immunity region (immB) comprising genes for the prophage repressor, the lytic repressor and a putative antiterminator. The roles of these products are thought to be similar to those of the lambda proteins CI, Cro and Q, respectively. Moreover, the gene order and the location of several operator sites in the prototype telomere phage N15 and in ɸKO2 are also reminiscent of lambda-like phages. By contrast, in silico analyses revealed the presence of only one operator (O\\(_{\\rm{R}}\\)3) in PY54. The purified PY54 Cro protein was used for EMSA studies demonstrating that it exclusively binds to a 16-bp palindromic site (O\\(_{\\rm{R}}\\)3) upstream of the prophage repressor gene. The O\\(_{\\rm{R}}\\)3 operator sequences of PY54 and ɸKO2/N15 only differ by their peripheral base pairs, which are responsible for Cro specificity. PY54 cI and cro transcription is regulated by highly active promoters initiating the synthesis of a homogenious species of leaderless mRNA. The location of the PY54 Cro binding site and of the identified promoters suggests that the lytic repressor suppresses cI transcription but not its own synthesis. The results indicate an unexpected diversity of the growth regulation mechanisms in lambda-related phages. PMID:26043380

  7. The Molecular Switch of Telomere Phages: High Binding Specificity of the PY54 Cro Lytic Repressor to a Single Operator Site

    Directory of Open Access Journals (Sweden)

    Jens Andre Hammerl

    2015-06-01

    Full Text Available Temperate bacteriophages possess a molecular switch, which regulates the lytic and lysogenic growth. The genomes of the temperate telomere phages N15, PY54 and ɸKO2 harbor a primary immunity region (immB comprising genes for the prophage repressor, the lytic repressor and a putative antiterminator. The roles of these products are thought to be similar to those of the lambda proteins CI, Cro and Q, respectively. Moreover, the gene order and the location of several operator sites in the prototype telomere phage N15 and in ɸKO2 are also reminiscent of lambda-like phages. By contrast, in silico analyses revealed the presence of only one operator (O\\(_{\\rm{R}}\\3 in PY54. The purified PY54 Cro protein was used for EMSA studies demonstrating that it exclusively binds to a 16-bp palindromic site (O\\(_{\\rm{R}}\\3 upstream of the prophage repressor gene. The O\\(_{\\rm{R}}\\3 operator sequences of PY54 and ɸKO2/N15 only differ by their peripheral base pairs, which are responsible for Cro specificity. PY54 cI and cro transcription is regulated by highly active promoters initiating the synthesis of a homogenious species of leaderless mRNA. The location of the PY54 Cro binding site and of the identified promoters suggests that the lytic repressor suppresses cI transcription but not its own synthesis. The results indicate an unexpected diversity of the growth regulation mechanisms in lambda-related phages.

  8. Development of chromosome-arm-specific microsatellite markers in Triticum aestivum (Poaceae) using NGS technology

    Czech Academy of Sciences Publication Activity Database

    Nie, X.; Li, B.; Wang, L.; Liu, P.; Biradar, S. S.; Li, T.; Doležel, Jaroslav; Edwards, D.; Luo, M.; Weining, S.

    2012-01-01

    Roč. 99, č. 9 (2012), e369-e371. ISSN 0002-9122 Institutional research plan: CEZ:AV0Z50380511 Keywords : chromosome-arm-specific DNA * flow-sorted chromosomes * next-generation sequencing Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.586, year: 2012

  9. Paclitaxel stimulates chromosomal fusion and instability in cells with dysfunctional telomeres: Implication in multinucleation and chemosensitization

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jeong-Eun [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); 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); Kang, Chang-Mo [Laboratory of Cytogenetics and Tissue Regeneration, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Juhn, Kyoung-Mi; Ju, Yeun-Jin; 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); Lee, Jung-Kee [Department of Life Science and Genetic Engineering, Paichai University, Daejeon 302-735 (Korea, Republic of); Kim, Hae Kwon [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 151-74-2 (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)

    2011-01-14

    Research highlights: {yields} Paclitaxel serves as a stimulator of chromosomal fusion in cells in which telomeres are dysfunctional. {yields} Typical fusions involve p-arms, but paclitaxel-induced fusions occur between both q- and p-arms. {yields} Paclitaxel-stimulated fusions in cells in which telomeres are dysfunctional evoke prolonged G2/M cell cycle arrest and delay multinucleation. {yields} Upon telomere erosion, paclitaxel promotes chromosomal instability and subsequent apoptosis. {yields} Chromosomal fusion enhances paclitaxel chemosensitivity under telomere dysfunction. -- Abstract: The anticancer effect of paclitaxel is attributable principally to irreversible promotion of microtubule stabilization and is hampered upon development of chemoresistance by tumor cells. Telomere shortening, and eventual telomere erosion, evoke chromosomal instability, resulting in particular cellular responses. Using telomerase-deficient cells derived from mTREC-/-p53-/- mice, here we show that, upon telomere erosion, paclitaxel propagates chromosomal instability by stimulating chromosomal end-to-end fusions and delaying the development of multinucleation. The end-to-end fusions involve both the p- and q-arms in cells in which telomeres are dysfunctional. Paclitaxel-induced chromosomal fusions were accompanied by prolonged G2/M cell cycle arrest, delayed multinucleation, and apoptosis. Telomere dysfunctional cells with mutlinucleation eventually underwent apoptosis. Thus, as telomere erosion proceeds, paclitaxel stimulates chromosomal fusion and instability, and both apoptosis and chemosensitization eventually develop.

  10. Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in

    Institute of Scientific and Technical Information of China (English)

    Chenhui Huang; Xueyu Dai; Weihang Chai

    2012-01-01

    Telomere maintenance is critical for genome stability.The newly-identified Ctc1/Stn1/Ten1 complex is important for telomere maintenance,though its precise role is unclear.We report here that depletion of hStn1 induces catastrophic telomere shortening,DNA damage response,and early senescence in human somatic cells.These phenotypes are likely due to the essential role of hStn1 in promoting efficient replication of lagging-strand telomeric DNA.Downregulation of hStn1 accumulates single-stranded G-rich DNA specifically at lagging-strand telomeres,increases telomere fragility,hinders telomere DNA synthesis,as well as delays and compromises telomeric C-strand synthesis.We further show that hStn1 deficiency leads to persistent and elevated association of DNA polymerase α(polα)to telomeres,suggesting that hStn1 may modulate the DNA synthesis activity of polα rather than controlling the loading of polα to telomeres.Additionally,our data suggest that hStn1 is unlikely to be part of the telomere capping complex.We propose that the hStn1 assists DNA polymerases to efficiently duplicate lagging-strand telomeres in order to achieve complete synthesis of telomeric DNA,therefore preventing rapid telomere loss.

  11. Telomeres: Hallmarks of radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Ayouaz, A.; Raynaud, C.; Heride, C.; Revaud, D.; Sabatier, L. [CEA, DSV, IRCM/SRO, F-92265 Fontenay Aux Roses (France)

    2008-07-01

    Telomeres are the very ends of the chromosomes. They can be seen as natural double-strand breaks (DSB), specialized structures which prevent DSB repair and activation of DNA damage checkpoints. In somatic cells, attrition of telomeres occurs after each cell division until replicative senescence. In the absence of telomerase, telomeres shorten due to incomplete replication of the lagging strand at the very end of chromosome termini. Moreover, oxidative stress and accumulating reactive oxygen species (ROS) lead to an increased telomere shortening due to a less efficient repair of SSB in telomeres. The specialized structures at telomeres include proteins involved in both telomere maintenance and DNA repair. However when a telomere is damaged and has to be repaired, those proteins might fail to perform an accurate repair of the damage.This is the starting point of this article in which we first summarize the well-established relationships between DNA repair processes and maintenance of functional telomeres. We then examine how damaged telomeres would be processed, and show that irradiation alters telomere maintenance leading to possibly dramatic consequences. Our point is to suggest that those consequences are not restricted to the short term effects such as increased radiation-induced cell death. On the contrary, we postulate that the major impact of the loss of telomere integrity might occur in the long term, during multistep carcinogenesis. Its major role would be to act as an amplifying event unmasking in one single step recessive radiation-induced mutations among thousands of genes and providing cellular proliferative advantage. Moreover, the chromosomal instability generated by damaged telomeres will favour each step of the transformation from normal to fully transformed cells. (authors)

  12. Cohesin SMC1beta protects telomeres in meiocytes.

    Science.gov (United States)

    Adelfalk, Caroline; Janschek, Johannes; Revenkova, Ekaterina; Blei, Cornelia; Liebe, Bodo; Göb, Eva; Alsheimer, Manfred; Benavente, Ricardo; de Boer, Esther; Novak, Ivana; Höög, Christer; Scherthan, Harry; Jessberger, Rolf

    2009-10-19

    Meiosis-specific mammalian cohesin SMC1beta is required for complete sister chromatid cohesion and proper axes/loop structure of axial elements (AEs) and synaptonemal complexes (SCs). During prophase I, telomeres attach to the nuclear envelope (NE), but in Smc1beta(-/-) meiocytes, one fifth of their telomeres fail to attach. This study reveals that SMC1beta serves a specific role at telomeres, which is independent of its role in determining AE/SC length and loop extension. SMC1beta is necessary to prevent telomere shortening, and SMC3, present in all known cohesin complexes, properly localizes to telomeres only if SMC1beta is present. Very prominently, telomeres in Smc1beta(-/-) spermatocytes and oocytes loose their structural integrity and suffer a range of abnormalities. These include disconnection from SCs and formation of large telomeric protein-DNA extensions, extended telomere bridges between SCs, ring-like chromosomes, intrachromosomal telomeric repeats, and a reduction of SUN1 foci in the NE. We suggest that a telomere structure protected from DNA rearrangements depends on SMC1beta. PMID:19841137

  13. The TPR-containing domain within Est1 homologs exhibits species-specific roles in telomerase interaction and telomere length homeostasis

    Directory of Open Access Journals (Sweden)

    LeBel Catherine

    2011-10-01

    Full Text Available Abstract Background The first telomerase-associated protein (Est1 was isolated in yeast due to its essential role in telomere maintenance. The human counterparts EST1A, EST1B, and EST1C perform diverse functions in nonsense-mediated mRNA decay (NMD, telomere length homeostasis, and telomere transcription. Although Est1 and EST1A/B interact with the catalytic subunit of yeast and human telomerase (Est2 and TERT, respectively, the molecular determinants of these interactions have not been elaborated fully. Results To investigate the functional conservation of the EST1 protein family, we performed protein-protein interaction mapping and structure-function analysis. The domain in hEST1A most conserved between species, containing a TPR (tricotetrapeptide repeat, was sufficient for interaction of hEST1A with multiple fragments of hTERT including the N-terminus. Two mutations within the hTERT N-terminus that perturb in vivo function (NAAIRS92, NAAIRS122 did not affect this protein interaction. ScEst1 hybrids containing the TPR of hEST1A, hEST1B, or hEST1C were expressed in yeast strains lacking EST1, yet they failed to complement senescence. Point mutations within and outside the cognate ScEst1 TPR, chosen to disrupt a putative protein interaction surface, resulted in telomere lengthening or shortening without affecting recruitment to telomeres. Conclusions These results identify a domain encompassing the TPR of hEST1A as an hTERT interaction module. The TPR of S. cerevisiae Est1 is required for telomerase-mediated telomere length maintenance in a manner that appears separable from telomere recruitment. Discrete residues in or adjacent to the TPR of Est1 also regulate telomere length homeostasis.

  14. Telomeric RNAs are essential to maintain telomeres.

    Science.gov (United States)

    Montero, Juan José; López de Silanes, Isabel; Graña, Osvaldo; Blasco, Maria A

    2016-01-01

    Telomeres are transcribed generating long non-coding RNAs known as TERRA. Deciphering the role of TERRA has been one of the unsolved issues of telomere biology in the past decade. This has been, in part, due to lack of knowledge on the TERRA loci, thus preventing functional genetic studies. Here, we describe that long non-coding RNAs with TERRA features are transcribed from the human 20q and Xp subtelomeres. Deletion of the 20q locus by using the CRISPR-Cas9 technology causes a dramatic decrease in TERRA levels, while deletion of the Xp locus does not result in decreased TERRA levels. Strikingly, 20q-TERRA ablation leads to dramatic loss of telomere sequences and the induction of a massive DNA damage response. These findings identify chromosome 20q as a main TERRA locus in human cells and represent the first demonstration in any organism of the essential role of TERRA in the maintenance of telomeres. PMID:27531349

  15. Nuclear-receptor-mediated telomere insertion leads to genome instability in ALT cancers.

    Science.gov (United States)

    Marzec, Paulina; Armenise, Claudia; Pérot, Gaëlle; Roumelioti, Fani-Marlen; Basyuk, Eugenia; Gagos, Sarantis; Chibon, Frédéric; Déjardin, Jérôme

    2015-02-26

    The breakage-fusion-bridge cycle is a classical mechanism of telomere-driven genome instability in which dysfunctional telomeres are fused to other chromosomal extremities, creating dicentric chromosomes that eventually break at mitosis. Here, we uncover a distinct pathway of telomere-driven genome instability, specifically occurring in cells that maintain telomeres with the alternative lengthening of telomeres mechanism. We show that, in these cells, telomeric DNA is added to multiple discrete sites throughout the genome, corresponding to regions regulated by NR2C/F transcription factors. These proteins drive local telomere DNA addition by recruiting telomeric chromatin. This mechanism, which we name targeted telomere insertion (TTI), generates potential common fragile sites that destabilize the genome. We propose that TTI driven by NR2C/F proteins contributes to the formation of complex karyotypes in ALT tumors. PMID:25723166

  16. Telomere dysfunction and chromothripsis.

    Science.gov (United States)

    Ernst, Aurélie; Jones, David T W; Maass, Kendra K; Rode, Agata; Deeg, Katharina I; Jebaraj, Billy Michael Chelliah; Korshunov, Andrey; Hovestadt, Volker; Tainsky, Michael A; Pajtler, Kristian W; Bender, Sebastian; Brabetz, Sebastian; Gröbner, Susanne; Kool, Marcel; Devens, Frauke; Edelmann, Jennifer; Zhang, Cindy; Castelo-Branco, Pedro; Tabori, Uri; Malkin, David; Rippe, Karsten; Stilgenbauer, Stephan; Pfister, Stefan M; Zapatka, Marc; Lichter, Peter

    2016-06-15

    Chromothripsis is a recently discovered form of genomic instability, characterized by tens to hundreds of clustered DNA rearrangements resulting from a single dramatic event. Telomere dysfunction has been suggested to play a role in the initiation of this phenomenon, which occurs in a large number of tumor entities. Here, we show that telomere attrition can indeed lead to catastrophic genomic events, and that telomere patterns differ between cells analyzed before and after such genomic catastrophes. Telomere length and telomere stabilization mechanisms diverge between samples with and without chromothripsis in a given tumor subtype. Longitudinal analyses of the evolution of chromothriptic patterns identify either stable patterns between matched primary and relapsed tumors, or loss of the chromothriptic clone in the relapsed specimen. The absence of additional chromothriptic events occurring between the initial tumor and the relapsed tumor sample points to telomere stabilization after the initial chromothriptic event which prevents further shattering of the genome. PMID:26856307

  17. Functional interaction between telomere protein TPP1 and telomerase

    OpenAIRE

    Zaug, Arthur J.; Podell, Elaine R.; Nandakumar, Jayakrishnan; Cech, Thomas R.

    2010-01-01

    Human chromosome end-capping and telomerase regulation require POT1 (Protection of Telomeres 1) and TPP1 proteins, which bind to the 3′ ssDNA extension of human telomeres. POT1–TPP1 binding to telomeric DNA activates telomerase repeat addition processivity. We now provide evidence that this POT1–TPP1 activation requires specific interactions with telomerase, rather than it being a DNA substrate-specific effect. First, telomerase from the fish medaka, which extends the same telomeric DNA prime...

  18. PML body meets telomere

    OpenAIRE

    Chung, Inn; Osterwald, Sarah; Deeg, Katharina I.; Rippe, Karsten

    2012-01-01

    The unlimited proliferation potential of cancer cells requires the maintenance of their telomeres. This is frequently accomplished by reactivation of telomerase. However, in a significant fraction of tumors an alternative lengthening of telomeres (ALT) mechanism is active. The molecular mechanism of the ALT pathway remains elusive. In particular, the role of characteristic complexes of promyelocytic leukemia nuclear bodies (PML-NBs) with telomeres, the ALT-associated PML-NBs (APBs), is curren...

  19. Telomere maintenance and the etiology of adult glioma.

    Science.gov (United States)

    Walsh, Kyle M; Wiencke, John K; Lachance, Daniel H; Wiemels, Joseph L; Molinaro, Annette M; Eckel-Passow, Jeanette E; Jenkins, Robert B; Wrensch, Margaret R

    2015-11-01

    A growing body of epidemiologic and tumor genomic research has identified an important role for telomere maintenance in glioma susceptibility, initiation, and prognosis. Telomere length has long been investigated in relation to cancer, but whether longer or shorter telomere length might be associated with glioma risk has remained elusive. Recent data address this question and are reviewed here. Common inherited variants near the telomerase-component genes TERC and TERT are associated both with longer telomere length and increased risk of glioma. Exome sequencing of glioma patients from families with multiple affected members has identified rare inherited mutations in POT1 (protection of telomeres protein 1) as high-penetrance glioma risk factors. These heritable POT1 mutations are also associated with increased telomere length in leukocytes. Tumor sequencing studies further indicate that acquired somatic mutations of TERT and ATRX are among the most frequent alterations found in adult gliomas. These mutations facilitate telomere lengthening, thus bypassing a critical mechanism of apoptosis. Although future research is needed, mounting evidence suggests that glioma is, at least in part, a disease of telomere dysregulation. Specifically, several inherited and acquired variants underlying gliomagenesis affect telomere pathways and are also associated with increased telomere length. PMID:26014050

  20. Telomere attrition and Chk2 activation in human heart failure

    OpenAIRE

    Oh, Hidemasa; Wang, Sam C.; Prahash, Arun; Sano, Motoaki; Moravec, Christine S.; Taffet, George E.; Michael, Lloyd H.; Youker, Keith A.; Entman, Mark L.; Schneider, Michael D.

    2003-01-01

    The “postmitotic” phenotype in adult cardiac muscle exhibits similarities to replicative senescence more generally and constitutes a barrier to effective restorative growth in heart disease. Telomere dysfunction is implicated in senescence and apoptotic signaling but its potential role in heart disorders is unknown. Here, we report that cardiac apoptosis in human heart failure is associated specifically with defective expression of the telomere repeat- binding factor TRF2, telomere shortening...

  1. Molecular mechanisms of activity and derepression of alternative lengthening of telomeres.

    Science.gov (United States)

    Pickett, Hilda A; Reddel, Roger R

    2015-11-01

    Alternative lengthening of telomeres (ALT) involves homology-directed telomere synthesis. This multistep process is facilitated by loss of the ATRX or DAXX chromatin-remodeling factors and by abnormalities of the telomere nucleoprotein architecture, including altered DNA sequence and decreased TRF2 saturation. Induction of telomere-specific DNA damage triggers homology-directed searches, and NuRD-ZNF827 protein-protein interactions provide a platform for the telomeric recruitment of homologous recombination (HR) proteins. Telomere lengthening proceeds by strand exchange and template-driven DNA synthesis, which culminates in dissolution of HR intermediates. PMID:26581522

  2. 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.

  3. Mammalian 5’ C-rich telomeric overhangs are a mark of recombination-dependent telomere maintenance

    OpenAIRE

    Oganesian, Liana; Karlseder, Jan

    2011-01-01

    Recent evidence for 5’ cytosine (C)-rich overhangs at the telomeres of the nematode C. elegans provided the impetus to re-examine the end structure of mammalian telomeres. Two-dimensional (2D) gel electrophoresis, Single Telomere Length Analysis (STELA) and strand-specific exonuclease assays revealed the presence of a 5’ C-rich overhang at the telomeres of human and mouse chromosomes. C-overhangs were prominent in G1/S arrested as well as terminally differentiated cells, indicating that they ...

  4. Telomere Maintenance through Spatial Control of Telomeric Proteins▿

    OpenAIRE

    Chen, Liuh-Yow; Liu, Dan; Songyang, Zhou

    2007-01-01

    The six human telomeric proteins TRF1, TRF2, RAP1, TIN2, POT1, and TPP1 can form a complex called the telosome/shelterin, which is required for telomere protection and length control. TPP1 has been shown to regulate both POT1 telomere localization and telosome assembly through its binding to TIN2. It remains to be determined where such interactions take place and whether cellular compartmentalization of telomeric proteins is important for telomere maintenance. We systematically investigated h...

  5. Short Telomeres Initiate Telomere Recombination in Primary and Tumor Cells

    OpenAIRE

    Morrish, Tammy A.; Greider, Carol W

    2009-01-01

    Human tumors that lack telomerase maintain telomeres by alternative lengthening mechanisms. Tumors can also form in telomerase-deficient mice; however, the genetic mechanism responsible for tumor growth without telomerase is unknown. In yeast, several different recombination pathways maintain telomeres in the absence of telomerase-some result in telomere maintenance with minimal effects on telomere length. To examine non-telomerase mechanisms for telomere maintenance in mammalian cells, we us...

  6. Modern genome editing meets telomeres: the many functions of TPP1

    OpenAIRE

    Karlseder, Jan

    2014-01-01

    TPP1 is one of the six telomere-specific components of the shelterin complex, which helps to distinguish telomeres from sites of DNA damage and thereby protect chromosome ends. In this perspective, Karlseder discusses Sexton et al.’s use of advanced genome-editing techniques in human embryonic stem cells to investigate novel roles of TPP1 in telomere homeostasis.

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

    Science.gov (United States)

    Cukusic Kalajzic, Andrea; Vidacek, Nikolina Skrobot; Huzak, Miljenko; Ivankovic, Milena; Rubelj, Ivica

    2014-01-01

    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. PMID:24643066

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Short telomeres initiate telomere recombination in primary and tumor cells.

    Directory of Open Access Journals (Sweden)

    Tammy A Morrish

    2009-01-01

    Full Text Available Human tumors that lack telomerase maintain telomeres by alternative lengthening mechanisms. Tumors can also form in telomerase-deficient mice; however, the genetic mechanism responsible for tumor growth without telomerase is unknown. In yeast, several different recombination pathways maintain telomeres in the absence of telomerase-some result in telomere maintenance with minimal effects on telomere length. To examine non-telomerase mechanisms for telomere maintenance in mammalian cells, we used primary cells and lymphomas from telomerase-deficient mice (mTR-/- and Emumyc+mTR-/- and CAST/EiJ mouse embryonic fibroblast cells. These cells were analyzed using pq-ratio analysis, telomere length distribution outliers, CO-FISH, Q-FISH, and multicolor FISH to detect subtelomeric recombination. Telomere length was maintained during long-term growth in vivo and in vitro. Long telomeres, characteristic of human ALT cells, were not observed in either late passage or mTR-/- tumor cells; instead, we observed only minimal changes in telomere length. Telomere length variation and subtelomeric recombination were frequent in cells with short telomeres, indicating that length maintenance is due to telomeric recombination. We also detected telomere length changes in primary mTR-/- cells that had short telomeres. Using mouse mTR+/- and human hTERT+/- primary cells with short telomeres, we found frequent length changes indicative of recombination. We conclude that telomere maintenance by non-telomerase mechanisms, including recombination, occurs in primary cells and is initiated by short telomeres, even in the presence of telomerase. Most intriguing, our data indicate that some non-telomerase telomere maintenance mechanisms occur without a significant increase in telomere length.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Alternative lengthening of telomeres: recurrent cytogenetic aberrations and chromosome stability under extreme telomere dysfunction.

    Science.gov (United States)

    Sakellariou, Despoina; Chiourea, Maria; Raftopoulou, Christina; Gagos, Sarantis

    2013-11-01

    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. PMID:24339742

  12. 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.

  13. Oxidative stress induces persistent telomeric DNA damage responsible for nuclear morphology change in mammalian cells.

    Directory of Open Access Journals (Sweden)

    Elisa Coluzzi

    Full Text Available One main function of telomeres is to maintain chromosome and genome stability. The rate of telomere shortening can be accelerated significantly by chemical and physical environmental agents. Reactive oxygen species are a source of oxidative stress and can produce modified bases (mainly 8-oxoG and single strand breaks anywhere in the genome. The high incidence of guanine residues in telomeric DNA sequences makes the telomere a preferred target for oxidative damage. Our aim in this work is to evaluate whether chromosome instability induced by oxidative stress is related specifically to telomeric damage. We treated human primary fibroblasts (MRC-5 in vitro with hydrogen peroxide (100 and 200 µM for 1 hr and collected data at several time points. To evaluate the persistence of oxidative stress-induced DNA damage up to 24 hrs after treatment, we analysed telomeric and genomic oxidative damage by qPCR and a modified comet assay, respectively. The results demonstrate that the genomic damage is completely repaired, while the telomeric oxidative damage persists. The analysis of telomere length reveals a significant telomere shortening 48 hrs after treatment, leading us to hypothesise that residual telomere damage could be responsible for the telomere shortening observed. Considering the influence of telomere length modulation on genomic stability, we quantified abnormal nuclear morphologies (Nucleoplasmic Bridges, Nuclear Buds and Micronuclei and observed an increase of chromosome instability in the same time frame as telomere shortening. At subsequent times (72 and 96 hrs, we observed a restoration of telomere length and a reduction of chromosome instability, leaving us to conjecture a correlation between telomere shortening/dysfunction and chromosome instability. We can conclude that oxidative base damage leads to abnormal nuclear morphologies and that telomere dysfunction is an important contributor to this effect.

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

    OpenAIRE

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

  15. The G-Quadruplex Ligand Telomestatin Impairs Binding of Topoisomerase IIIα to G-Quadruplex-Forming Oligonucleotides and Uncaps Telomeres in ALT Cells

    OpenAIRE

    Nassima Temime-Smaali; Lionel Guittat; Assitan Sidibe; Kazuo Shin-ya; Chantal Trentesaux; Jean-François Riou

    2009-01-01

    In Alternative Lengthening of Telomeres (ALT) cell lines, specific nuclear bodies called APBs (ALT-associated PML bodies) concentrate telomeric DNA, shelterin components and recombination factors associated with telomere recombination. Topoisomerase IIIalpha (Topo III) is an essential telomeric-associated factor in ALT cells. We show here that the binding of Topo III to telomeric G-overhang is modulated by G-quadruplex formation. Topo III binding to G-quadruplex-forming oligonucleotides was s...

  16. Telomere elongation chooses TERRA ALTernatives

    OpenAIRE

    Arora, Rajika; Azzalin, Claus M.

    2015-01-01

    Alternative Lengthening of Telomeres (ALT) mechanisms allow telomerase-negative immortal cells to buffer replicative telomere shortening. ALT is naturally active in a number of human cancers and might be selected upon telomerase inactivation. ALT is thought to operate through homologous recombination (HR) occurring between telomeric repeats from independent chromosome ends. Indeed, suppression of a number of HR factors impairs ALT cell proliferation. Yet, how HR is initiated at ALT telomeres ...

  17. Telomere Restriction Fragment (TRF) Analysis

    Science.gov (United States)

    Mender, Ilgen; Shay, Jerry W.

    2016-01-01

    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

  18. Primary Studies on Cotton Telomere

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The Arabidopsis-type telomere sequence was amplified and cloned using the primers designed from the fragment which contained the telomere sequence in an Arabidopsis BAC.In situ hybridizations with cotton metaphase chromosomes,using the telomere as probe,it indicated that the signals

  19. Telomerers rolle ved aldersbetingede sygdomme

    DEFF Research Database (Denmark)

    Bendix, Laila; Kølvraa, Steen

    2010-01-01

    Telomeres are specialized DNA structures, protecting the ends of linear chromosomes. The association between telomeres and cellular aging is well-established, and it has been shown that there is a negative correlation between telomere length and chronological age for many types of human tissue. O...

  20. Ticking Telomeres/Telltale Telomerase.

    Science.gov (United States)

    Biermann, Carol A.

    1997-01-01

    Discusses telomeres, complexes of DNA and protein that form the chromatin at the ends of chromosomes. Highlights telomeres as controllers of chromosome integrity, expendable telomeres, DNA replication requirements and their consequences, protection of structural genes, telomerase as indicators of immortality, cancer cells and other immortals, and…

  1. ALT Telomeres borrow from meiosis

    OpenAIRE

    Arnoult, Nausica; Karlseder, Jan

    2014-01-01

    The clustering of telomeres is required for the homologous recombination events that maintain chromosome ends in cells relying on alternative lengthening of telomeres (ALT). New data emerged to demonstrate that damage signaling at telomeres induces directional movement and synapsis, driven by the machinery responsible for recombination in meiosis.

  2. Genetic architecture of natural variation of telomere length in Arabidopsis thaliana.

    Science.gov (United States)

    Fulcher, Nick; Teubenbacher, Astrid; Kerdaffrec, Envel; Farlow, Ashley; Nordborg, Magnus; Riha, Karel

    2015-02-01

    Telomeres represent the repetitive sequences that cap chromosome ends and are essential for their protection. Telomere length is known to be highly heritable and is derived from a homeostatic balance between telomeric lengthening and shortening activities. Specific loci that form the genetic framework underlying telomere length homeostasis, however, are not well understood. To investigate the extent of natural variation of telomere length in Arabidopsis thaliana, we examined 229 worldwide accessions by terminal restriction fragment analysis. The results showed a wide range of telomere lengths that are specific to individual accessions. To identify loci that are responsible for this variation, we adopted a quantitative trait loci (QTL) mapping approach with multiple recombinant inbred line (RIL) populations. A doubled haploid RIL population was first produced using centromere-mediated genome elimination between accessions with long (Pro-0) and intermediate (Col-0) telomere lengths. Composite interval mapping analysis of this population along with two established RIL populations (Ler-2/Cvi-0 and Est-1/Col-0) revealed a number of shared and unique QTL. QTL detected in the Ler-2/Cvi-0 population were examined using near isogenic lines that confirmed causative regions on chromosomes 1 and 2. In conclusion, this work describes the extent of natural variation of telomere length in A. thaliana, identifies a network of QTL that influence telomere length homeostasis, examines telomere length dynamics in plants with hybrid backgrounds, and shows the effects of two identified regions on telomere length regulation. PMID:25488978

  3. Genomic organization and expression of the expanded SCG/L/R gene family of Leishmania major: internal clusters and telomeric localization of SCGs mediating species-specific LPG modifications.

    Science.gov (United States)

    Dobson, Deborah E; Scholtes, Luella D; Myler, Peter J; Turco, Salvatore J; Beverley, Stephen M

    2006-04-01

    Stage-specific modifications to the abundant surface lipophosphoglycan (LPG) adhesin of Leishmania play critical roles in binding and release of the parasite during its infectious cycle in the sand fly, and control the ability of different fly species to transmit different parasite strains and species. In Leishmania major Friedlin V1, binding to a sand fly midgut lectin is mediated by side chain galactosyl (scGal) modifications of the LPG phosphoglycan (PG) repeats, while release occurs following arabinose-capping of scGals. Previously we identified a family of six SCG genes encoding PG scbeta-galactosyltransferases, and here we show that the extended SCG gene family (now termed SCG/L/R) encompasses 14 members in three subfamilies (SCG, SCGL and SCGR). Northern blot and RT-PCR analyses suggest that most of the SCG/L/R genes are expressed, with distinct patterns during the infectious cycle. The six SCGR subfamily genes are clustered and interspersed with the two SCA genes responsible for developmentally regulated arabinosylation of PG scGals; relationships amongst the SCGR revealed clear evidence of extensive gene conversion. In contrast, the seven SCG 'core' family members are localized adjacent to telomeres. These telomeres share varying amounts of sequence upstream and/or downstream of the SCG ORFs, again providing evidence of past gene conversions. Multiple SCG1-7 RNAs were expressed simultaneously within parasite populations. Potentially, telomeric localization of SCG genes may function primarily to facilitate gene conversion and the elaboration of functional evolutionary diversity in the degree of PG sc-galactosylation observed in other strains of L. major. PMID:16464509

  4. Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas.

    Science.gov (United States)

    Liau, Jau-Yu; Lee, Jen-Chieh; Tsai, Jia-Huei; Yang, Ching-Yao; Liu, Tsung-Lin; Ke, Zhi-Long; Hsu, Hung-Han; Jeng, Yung-Ming

    2015-12-01

    According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomeres-positive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (Plengthening of

  5. Hepatocellular telomere shortening correlates with chromosomal instability and the development of human hepatoma.

    Science.gov (United States)

    Plentz, Ruben R; Caselitz, Martin; Bleck, Joerg S; Gebel, Michael; Flemming, Peer; Kubicka, Stefan; Manns, Michael P; Rudolph, K Lenhard

    2004-07-01

    The telomere hypothesis of cancer initiation indicates that telomere shortening initiates cancer by induction of chromosomal instability. To test whether this hypothesis applies to human hepatocellular carcinoma (HCC), we analyzed the telomere length of hepatocytes in cytological smears of fine-needle biopsies of liver tumors from patients with cirrhosis (n = 39). The tumors consisted of 24 HCC and 15 regenerative nodules as diagnosed by combined histological and cytological diagnostics. In addition, we analyzed the telomere length of hepatocytes in HCC and surrounding noncancerous liver tissue within individual patients in another cohort of 10 patients with cirrhosis. Telomere length analysis of hepatocytes was correlated with tumor pathology and ploidy grade of the tumors, which was analyzed by cytophotometry. Telomeres were significantly shortened in hepatocytes of HCC compared to hepatocytes in regenerative nodules or surrounding noncancerous liver tissue. Hepatocyte telomere shortening in HCC was independent of the patient's age. There was no overlap in mean telomere lengths of individual samples when comparing HCC with regenerative nodules or noncancerous surrounding liver. Within the HCC group, telomeres were significantly shorter in hepatocytes of aneuploid tumors compared to diploid tumors. In conclusion, our data suggest that the telomere hypothesis of cancer initiation applies to human HCC and that cell type-specific telomere length analysis might indicate the risk of HCC development. PMID:15239089

  6. The Ku subunit of telomerase binds Sir4 to recruit telomerase to lengthen telomeres in S. cerevisiae.

    Science.gov (United States)

    Hass, Evan P; Zappulla, David C

    2015-01-01

    In Saccharomyces cerevisiae and in humans, the telomerase RNA subunit is bound by Ku, a ring-shaped protein heterodimer best known for its function in DNA repair. Ku binding to yeast telomerase RNA promotes telomere lengthening and telomerase recruitment to telomeres, but how this is achieved remains unknown. Using telomere-length analysis and chromatin immunoprecipitation, we show that Sir4 - a previously identified Ku-binding protein that is a component of telomeric silent chromatin - is required for Ku-mediated telomere lengthening and telomerase recruitment. We also find that specifically tethering Sir4 directly to Ku-binding-defective telomerase RNA restores otherwise-shortened telomeres to wild-type length. These findings suggest that Sir4 is the telomere-bound target of Ku-mediated telomerase recruitment and provide one mechanism for how the Sir4-competing Rif1 and Rif2 proteins negatively regulate telomere length in yeast. PMID:26218225

  7. Dysfunctional mammalian telomeres join to double-strand breaks

    International Nuclear Information System (INIS)

    Telomeres are highly specialized nucleoprotein structures that maintain genomic stability by protecting the ends of linear chromosomes, an essential function inferred cytogenetically from the end-to-end fusions that result when telomeric end-capping fails. In striking contrast to natural chromosomal termini, broken chromosome ends produced by DNA double strand breaks (DSB) are highly recombinogenic, and represent a major threat to the integrity of the cell's genome due to their potential for causing chromosomal rearrangements that contribute to genomic instability and tumorigenesis. Previously, we demonstrated that effective end-capping of mammalian telomeres has a seemingly paradoxical requirement for proteins more commonly associated with DNA DSB repair. Ku70, Ku80, and DNA-PKcs all participate in DSB repair through non-homologous end-joining. Somewhat surprisingly, mutations in any of these genes cause spontaneous chromosomal end-to-end fusions that maintain large blocks of telomeric sequence at the points of fusion and are not a consequence of telomere shortening. We have also shown that nascent telomeres produced via leading-strand DNA synthesis are especially susceptible to these end-to-end fusions. Here we report that impaired end-capping in DNA-PKcs-deficient backgrounds not only allows these dysfunctional telomeres to join to one another, but also to broken chromosome ends created by radiation-induced DSB. Mouse cell lines were exposed to graded doses of gamma-rays and examined utilizing the strand-specific fluorescence in situ hybridization technique of CO-FISH, in order to distinguish true telomere-to-DSB events from telomere-to-telomere fusions. Telomere-to-DSB fusions were observed in a dose-dependent fashion in each mutant cell line analyzed, including BALB/c, which is both radiosensitive and susceptible to radiogenic mammary cancer. Telomere-DSB fusion represents a new and sensitive method of detecting telomere dysfunction as measured by failure of

  8. Telomeres and human health

    DEFF Research Database (Denmark)

    Bojesen, S E

    2013-01-01

    marginally-independently associated with risk of common disorders such as cardiovascular, pulmonary and neoplastic diseases. However, in sufficiently powered studies, short telomeres are repeatedly and independently found to be associated with increased risk of early death in the general population or in...

  9. High-resolution telomere fluorescence in situ hybridization reveals intriguing anomalies in germ cell tumors.

    Science.gov (United States)

    Shekhani, Mohammed Talha; Barber, John R; Bezerra, Stephania M; Heaphy, Christopher M; Gonzalez Roibon, Nilda Diana; Taheri, Diana; Reis, Leonardo O; Guner, Gunes; Joshu, Corinne E; Netto, George J; Meeker, Alan K

    2016-08-01

    Testicular germ cell tumor (TGCT) is the most common malignancy of young men. Most patients are completely cured, which distinguishes these from most other malignancies. Orchiectomy specimens (n=76) were evaluated using high-resolution (single-cell discriminative) telomere-specific fluorescence in situ hybridization (FISH) with simultaneous Oct4 immunofluorescence to describe telomere length phenotype in TGCT neoplastic cells. For the first time, the TGCT precursor lesion, germ cell neoplasia in situ (GCNIS) is also evaluated in depth. The intensity of the signals from cancerous cells was compared to the same patient's reference cells-namely, healthy germ cells (defined as "medium" length) and interstitial/somatic cells (defined as "short" telomere length). We observed short telomeres in most GCNIS and pure seminomas (P=.006 and P=.0005, respectively). In contrast, nonseminomas displayed longer telomeres. Lesion-specific telomere lengths were documented in mixed tumor cases. Embryonal carcinoma (EC) demonstrated the longest telomeres. A fraction of EC displays the telomerase-independent alternative lengthening of telomeres (ALT) phenotype (24% of cases). Loss of ATRX or DAXX nuclear expression was strongly associated with ALT; however, nuclear expression of both proteins was retained in half of ALT-positive ECs. The particular distribution of telomere lengths among TGCT and GCNIS precursors implicate telomeres anomalies in pathogenesis. These results may advise management decisions as well. PMID:27085557

  10. Nucleolar Organization, Ribosomal DNA Array Stability, and Acrocentric Chromosome Integrity Are Linked to Telomere Function

    OpenAIRE

    Stimpson, Kaitlin M.; Sullivan, Lori L; Kuo, Molly E.; Sullivan, Beth A.

    2014-01-01

    The short arms of the ten acrocentric human chromosomes share several repetitive DNAs, including ribosomal RNA genes (rDNA). The rDNA arrays correspond to nucleolar organizing regions that coalesce each cell cycle to form the nucleolus. Telomere disruption by expressing a mutant version of telomere binding protein TRF2 (dnTRF2) causes non-random acrocentric fusions, as well as large-scale nucleolar defects. The mechanisms responsible for acrocentric chromosome sensitivity to dysfunctional tel...

  11. Chromosomal mapping of chicken mega-telomere arrays to GGA9, 16, 28 and W using a cytogenomic approach.

    Science.gov (United States)

    Delany, M E; Gessaro, T M; Rodrigue, K L; Daniels, L M

    2007-01-01

    Four mega-telomere loci were mapped to chicken chromosomes 9, 16, 28, and the W sex chromosome by dual-color fluorescence in situ hybridization using a telomeric sequence probe and BAC clones previously assigned to chicken chromosomes. The in-common features of the mega-telomere chromosomes are that microchromosomes are involved rather than macrochromosomes; in three cases (9, 16, 28) acrocentrics are involved with the mega-telomeres mapping to the p arms. Three of the four chromosomes (9, 16, W) encode tandem repeats which in two cases (9 and 16) involve the ribosomal DNA arrays (the 5S and 18S-5.8S-28S gene repeats, respectively). All involved chromosomes have a typical-sized telomere on the opposite terminus. Intra- and interindividual variation for mega-telomere distribution are discussed in terms of karyotype abnormalities and the potential for mitotic instability of some telomeres. The diversity and distribution of telomere array quantity in the chicken genome should be useful in contributing to research related to telomere length regulation - how and by what mechanism genomes and individual chromosomes establish and maintain distinct sets of telomere array sizes, as well as for future studies related to stability of the chicken genome affecting development, growth, cellular lifespan and disease. An additional impact of this study includes the listing of BAC clones (26 autosomal and six W BACs tested) that were cytogenetically verified; this set of BACs provide a useful tool for future cytogenetic analyses of the microchromosomes. PMID:17675845

  12. Alternative lengthening of telomeres: remodeling the telomere architecture

    OpenAIRE

    Conomos, Dimitri; Hilda A Pickett; Reddel, Roger R

    2013-01-01

    To escape from the normal limits on proliferative potential, cancer cells must employ a means to counteract the gradual telomere attrition that accompanies semi-conservative DNA replication. While the majority of human cancers do this by up-regulating telomerase enzyme activity, most of the remainder use a homologous recombination-mediated mechanism of telomere elongation known as alternative lengthening of telomeres (ALT). Many molecular details of the ALT pathway are unknown, and even less ...

  13. Detection of alternative lengthening of telomeres by telomere quantitative PCR

    OpenAIRE

    Lau, Loretta M. S.; Dagg, Rebecca A.; Henson, Jeremy D.; Au, Amy Y.M.; Royds, Janice A; Reddel, Roger R

    2012-01-01

    Alternative lengthening of telomeres (ALT) is one of the two known telomere length maintenance mechanisms that are essential for the unlimited proliferation potential of cancer cells. Existing methods for detecting ALT in tumors require substantial amounts of tumor material and are labor intensive, making it difficult to study prevalence and prognostic significance of ALT in large tumor cohorts. Here, we present a novel strategy utilizing telomere quantitative PCR to diagnose ALT. The protoco...

  14. 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.

  15. Telomere dysfunction and chromosome instability

    Energy Technology Data Exchange (ETDEWEB)

    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

  16. Telomeres in Alliaceae

    Czech Academy of Sciences Publication Activity Database

    Sýkorová, Eva; Fajkus, Jiří; Skleničková, Marie; Lim, K.Y.; Neplechová, Kamila; Blattner, F.R.; Chase, M.W.; Leitch, Andrew R.

    Venice, 2006. P 3.50-P 3.50. [5th Plant Genomics, European Meetings. 11.10.2006-14.10.2006, Venice] R&D Projects: GA ČR(CZ) GP204/04/P105; GA ČR(CZ) GA521/05/0055; GA AV ČR(CZ) IAA600040505 Institutional research plan: CEZ:AV0Z50040507 Keywords : telomere * evolution * Alliaceae Subject RIV: BO - Biophysics

  17. Alternative lengthening of telomeres: remodeling the telomere architecture

    Directory of Open Access Journals (Sweden)

    Dimitri eConomos

    2013-02-01

    Full Text Available To escape from the normal limits on proliferative potential, cancer cells must employ a means to counteract the gradual telomere attrition that accompanies semi-conservative DNA replication. While the majority of human cancers do this by up-regulating telomerase enzyme activity, most of the remainder use a homologous recombination-mediated mechanism of telomere elongation known as alternative lengthening of telomeres (ALT. Many molecular details of the ALT pathway are unknown, and even less is known regarding the mechanisms by which this pathway is activated. Here, we review current findings about telomere structure in ALT cells, including DNA sequence, shelterin content, and heterochromatic state. We speculate that remodeling of the telomere architecture may contribute to the emergence and maintenance of the ALT phenotype.

  18. A two-step model for senescence triggered by a single critically short telomere

    DEFF Research Database (Denmark)

    Abdallah, Pauline; Luciano, Pierre; Runge, Kurt W;

    2009-01-01

    Telomeres protect chromosome ends from fusion and degradation. In the absence of a specific telomere elongation mechanism, their DNA shortens progressively with every round of replication, leading to replicative senescence. Here, we show that telomerase-deficient cells bearing a single, very short...... for several generations despite complete erosion of their shortened telomeres. This pre-senescence growth requires RAD52 (radiation sensitive) and MMS1 (methyl methane sulfonate sensitive), and there is no evidence for major inter-telomeric recombination. We propose that, in the absence of telomerase...

  19. Human Rif1 protein binds aberrant telomeres and aligns along anaphase midzone microtubules

    OpenAIRE

    Xu, Lifeng; Blackburn, Elizabeth H.

    2004-01-01

    We identified and characterized a human orthologue of Rif1 protein, which in budding yeast interacts in vivo with the major duplex telomeric DNA binding protein Rap1p and negatively regulates telomere length. Depletion of hRif1 by RNA interference in human cancer cells impaired cell growth but had no detectable effect on telomere length, although hRif1 overexpression in S. cerevisiae interfered with telomere length control, in a manner specifically dependent on the presence of yeast Rif1p. No...

  20. Two pathways recruit telomerase to Saccharomyces cerevisiae telomeres.

    Directory of Open Access Journals (Sweden)

    Angela Chan

    2008-10-01

    Full Text Available The catalytic subunit of yeast telomerase, Est2p, is a telomere associated throughout most of the cell cycle, while the Est1p subunit binds only in late S/G2 phase, the time of telomerase action. Est2p binding in G1/early S phase requires a specific interaction between telomerase RNA (TLC1 and Ku80p. Here, we show that in four telomerase-deficient strains (cdc13-2, est1A, tlc1-SD, and tlc1-BD, Est2p telomere binding was normal in G1/early S phase but reduced to about 40-50% of wild type levels in late S/G2 phase. Est1p telomere association was low in all four strains. Wild type levels of Est2p telomere binding in late S/G2 phase was Est1p-dependent and required that Est1p be both telomere-bound and associated with a stem-bulge region in TLC1 RNA. In three telomerase-deficient strains in which Est1p is not Est2p-associated (tlc1-SD, tlc1-BD, and est2A, Est1p was present at normal levels but its telomere binding was very low. When the G1/early S phase and the late S/G2 phase telomerase recruitment pathways were both disrupted, neither Est2p nor Est1p was telomere-associated. We conclude that reduced levels of Est2p and low Est1p telomere binding in late S/G2 phase correlated with an est phenotype, while a WT level of Est2p binding in G1 was not sufficient to maintain telomeres. In addition, even though Cdc13p and Est1p interact by two hybrid, biochemical and genetic criteria, this interaction did not occur unless Est1p was Est2p-associated, suggesting that Est1p comes to the telomere only as part of the holoenzyme. Finally, the G1 and late S/G2 phase pathways for telomerase recruitment are distinct and are likely the only ones that bring telomerase to telomeres in wild-type cells.

  1. ALT telomeres get together with nuclear receptors.

    Science.gov (United States)

    Aeby, Eric; Lingner, Joachim

    2015-02-26

    Nuclear receptors bind chromosome ends in "alternative lengthening of telomeres" (ALT) cancer cells that maintain their ends by homologous recombination instead of telomerase. Marzec et al. now demonstrate that, in ALT cells, nuclear receptors not only trigger distal chromatin associations to mediate telomere-telomere recombination events, but also drive chromosome-internal targeted telomere insertions (TTI). PMID:25723159

  2. Caenorhabditis elegans POT-2 telomere protein represses a mode of alternative lengthening of telomeres with normal telomere lengths

    OpenAIRE

    Cheng, Chen; Shtessel, Ludmila; Brady, Megan M.; Ahmed, Shawn

    2012-01-01

    Canonical telomere repeats at chromosome termini can be maintained by a telomerase-independent pathway termed alternative lengthening of telomeres (ALT). Human cancers that survive via ALT can exhibit long and heterogeneous telomeres, although many telomerase-negative tumors possess telomeres of normal length. Here, we report that Caenorhabditis elegans telomerase mutants that survived via ALT possessed either long or normal telomere lengths. Most ALT strains displayed end-to-end chromosome f...

  3. Suv4-20h abrogation enhances telomere elongation during reprogramming and confers a higher tumorigenic potential to iPS cells

    OpenAIRE

    Rosa M Marión; Gunnar Schotta; Sagrario Ortega; Blasco, Maria A.

    2011-01-01

    Reprogramming of adult differentiated cells to induced pluripotent stem cells (iPS) cells has been achieved by over-expression of specific transcription factors. Nuclear reprogramming induces a series of profound changes at the telomeres of the parental differentiated cells, including a telomerase-dependent telomere elongation and the remodeling of telomeric chromatin. In particular, iPS cells show a decreased density of H4K20me3 heterochromatic mark at telomeres compared to the parental cell...

  4. Endogenous Hot Spots of De Novo Telomere Addition in the Yeast Genome Contain Proximal Enhancers That Bind Cdc13.

    Science.gov (United States)

    Obodo, Udochukwu C; Epum, Esther A; Platts, Margaret H; Seloff, Jacob; Dahlson, Nicole A; Velkovsky, Stoycho M; Paul, Shira R; Friedman, Katherine L

    2016-06-15

    DNA double-strand breaks (DSBs) pose a threat to genome stability and are repaired through multiple mechanisms. Rarely, telomerase, the enzyme that maintains telomeres, acts upon a DSB in a mutagenic process termed telomere healing. The probability of telomere addition is increased at specific genomic sequences termed sites of repair-associated telomere addition (SiRTAs). By monitoring repair of an induced DSB, we show that SiRTAs on chromosomes V and IX share a bipartite structure in which a core sequence (Core) is directly targeted by telomerase, while a proximal sequence (Stim) enhances the probability of de novo telomere formation. The Stim and Core sequences are sufficient to confer a high frequency of telomere addition to an ectopic site. Cdc13, a single-stranded DNA binding protein that recruits telomerase to endogenous telomeres, is known to stimulate de novo telomere addition when artificially recruited to an induced DSB. Here we show that the ability of the Stim sequence to enhance de novo telomere addition correlates with its ability to bind Cdc13, indicating that natural sites at which telomere addition occurs at high frequency require binding by Cdc13 to a sequence 20 to 100 bp internal from the site at which telomerase acts to initiate de novo telomere addition. PMID:27044869

  5. Unwinding Protein Complexes in ALTernative Telomere Maintenance

    OpenAIRE

    Bhattacharyya, Saumitri; Sandy, April; Groden, Joanna

    2010-01-01

    Telomeres are composed of specialized chromatin that includes DNA repair/recombination proteins, telomere DNA-binding proteins and a number of three dimensional nucleic acid structures including G-quartets and D-loops. A number of studies suggest that the BLM and WRN recQ-like helicases play important roles in recombination-mediated mechanisms of telomere elongation or Alternative Lengthening of Telomeres (ALT), processes that maintain/elongate telomeres in the absence of telomerase. BLM and ...

  6. Telomere shortening correlates with increasing aneuploidy of chromosome 8 in human hepatocellular carcinoma.

    Science.gov (United States)

    Plentz, Ruben R; Schlegelberger, Brigitte; Flemming, Peer; Gebel, Michael; Kreipe, Hans; Manns, Michael P; Rudolph, K Lenhard; Wilkens, Ludwig

    2005-09-01

    Chromosomal instability (CIN) leads to an increase in aneuploidy and chromosomal aberrations in human hepatocellular carcinoma (HCC). Telomere shortening appears as one mechanism fostering the development of CIN. Whether telomere shortening correlates to specific genetic changes that characterize a certain type of cancer has yet to be established. In our recent study, we combined on a cellular level the analysis of hepatocellular telomere fluorescent intensity (TFI) and copy number of chromosome 8-one of the hallmark chromosomal alterations in hepatocellular carcinoma (HCC). We investigated 15 cytological fine-needle biopsies of aneuploid HCC and 5 touch prints of cadaver livers without cancer. Hepatocyte-specific TFI and the measurement of centromere-specific probe for chromosome 8 were both performed by quantitative fluorescence in situ hybridization (qFISH) or FISH. Combined analysis of both methods (coFISH) allowed measurement of telomere length and chromosome 8 copy number on a single cell level. We observed that telomere shortening correlates significantly with increasing copy number of chromosome 8 in HCC on the cellular level. Above the level of 5 copies of chromosome 8 per nucleus, no further shortening of telomeres was found, indicating that telomeres had reached a critically short length at this stage of aneuploidy. In conclusion, our study gives direct evidence that telomere shortening is linked to a specific genetic alteration characteristic for human HCC. PMID:16116624

  7. Long Telomeres Bypass the Requirement for Telomere Maintenance in Human Tumorigenesis

    OpenAIRE

    Taboski, Michael A. S.; Sealey, David C.F.; Dorrens, Jennifer; Tayade, Chandrakant; Dean H Betts; Harrington, Lea

    2012-01-01

    Despite the importance of telomere maintenance in cancer cell survival via the elongation of telomeres by telomerase reverse transcriptase (TERT) or alternativelengthening of telomeres (ALT), it had not been tested directly whether telomere maintenance is dispensable for human tumorigenesis. We engineered human tumor cells containing loxP-flanked hTERT to enable extensive telomere elongation prior to complete hTERT excision. Despite unabated telomere erosion, hTERT-excised cells formed tumors...

  8. Telomere elongation involves intra-molecular DNA replication in cells utilizing alternative lengthening of telomeres

    OpenAIRE

    Muntoni, Alessandra; Neumann, Axel A.; Hills, Mark; Reddel, Roger R

    2008-01-01

    Alternative lengthening of telomeres (ALT) is a telomere length maintenance mechanism based on recombination, where telomeres use other telomeric DNA as a template for DNA synthesis. About 10% of all human tumors depend on ALT for their continued growth, and understanding its molecular details is critically important for the development of cancer treatments that target this mechanism. We have previously shown that telomeres of ALT-positive human cells can become lengthened via inter-telomeric...

  9. An increase in telomere sister chromatid exchange in murine embryonic stem cells possessing critically shortened telomeres

    OpenAIRE

    Wang, Yisong; Erdmann, Natalie; Giannone, Richard J.; Wu, Jun; Gomez, Marla; Liu, Yie

    2005-01-01

    Telomerase deficiency leads to a progressive loss of telomeric DNA that eventually triggers cell apoptosis in human primary cells during prolonged growth in culture. Rare survivors can maintain telomere length through either activation of telomerase or recombination-based telomere lengthening, and thus proliferate indefinitely. We have explored the possibility that telomeres may be maintained through telomere sister chromatid exchange (T-SCE) in murine telomere reverse transcriptase-deficient...

  10. Suppression of telomere-binding protein TPP1 resulted in telomere dysfunction and enhanced radiation sensitivity in telomerase-negative osteosarcoma cell line

    Energy Technology Data Exchange (ETDEWEB)

    Qiang, Weiguang [Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan (China); Department of Oncology, The Third Affiliated Hospital, Soochow University, Changzhou (China); Wu, Qinqin [Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan (China); Department of Radiation Oncology, Changzhou Tumor Hospital, Soochow University, Changzhou (China); Zhou, Fuxiang; Xie, Conghua [Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan (China); Wu, Changping, E-mail: wcpzlk@163.com [Department of Oncology, The Third Affiliated Hospital, Soochow University, Changzhou (China); Zhou, Yunfeng, E-mail: yfzhouwhu@163.com [Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan (China)

    2014-03-07

    Highlights: • Down-regulation of TPP1 shortened telomere length in telomerase-negative cells. • Down-regulation of TPP1 induced cell apoptosis in telomerase-negative cells. • Down-regulation of TPP1 increased radiosensitivity in telomerase-negative cells. - Abstract: Mammalian telomeres are protected by the shelterin complex that contains the six core proteins POT1, TPP1, TIN2, TRF1, TRF2 and RAP1. TPP1, formerly known as TINT1, PTOP, and PIP1, is a key factor that regulates telomerase recruitment and activity. In addition to this, TPP1 is required to mediate the shelterin assembly and stabilize telomere. Previous work has found that TPP1 expression was elevated in radioresistant cells and that overexpression of TPP1 led to radioresistance and telomere lengthening in telomerase-positive cells. However, the exact effects and mechanism of TPP1 on radiosensitivity are yet to be precisely defined in the ALT cells. Here we report on the phenotypes of the conditional deletion of TPP1 from the human osteosarcoma U2OS cells using ALT pathway to extend the telomeres.TPP1 deletion resulted in telomere shortening, increased apoptosis and radiation sensitivity enhancement. Together, our findings show that TPP1 plays a vital role in telomere maintenance and protection and establish an intimate relationship between TPP1, telomere and cellular response to ionizing radiation, but likely has the specific mechanism yet to be defined.

  11. The human telomere

    Energy Technology Data Exchange (ETDEWEB)

    Moyzis, R.K.

    1989-01-01

    An ultimate goal of human genetics is the generation of a complete physical and ''functional'' map of the human genome. Twenty-five percent of human DNA, however, consists of repetitive DNA sequences. These repetitive DNA sequences are thought to arise by many mechanisms, from direct sequence amplification by the unequal recombination of homologous DNA regions to the reverse flow of genetic information. A general outline of the chromosomal organization of these repetitive sequences will be discussed. Our working hypothesis is that certain classes of human repetitive DNA sequences ''encode'' the information necessary for defining long-range genomic structure. Evidence will be presented that the first goal of this research, the identification and cloning of the human telomere, has been achieved. A human repetitive DNA library was constructed from randomly sheared, reassociated, and oligo(G/center dot/C)-tailed DNA, a method that minimizes the potential loss of sequences devoid of a given restriction enzyme site. Sequences too large to clone efficiently in cosmid or /lambda/ vectors, such as centromeric repeats, or telomeric sequences with an end incompatible for cloning, should be present in this library. In order to isolate highly conserved repetitive DNA sequences, this library was screened with radiolabeled hamster Cot50 repetitive DNA. Two clones, containing tandem arrays of the sequence (TTAGGG), were isolated by this method. 30 refs., 1 fig., 2 tabs.

  12. Primary Studies on Cotton Telomere

    Institute of Scientific and Technical Information of China (English)

    LING Jian; PENG Ren-hai; WANG Kun-bo; WANG Chun-ying; SONG Guo-li; LIU Fang; LI Shao-hui; ZHANG Xiang-di; WANG Yu-hong

    2008-01-01

    @@ The Arabidopsis -type telomere sequence was amplified and cloned using the primers designed from the fragment which contained the telomere sequence in an Arabidopsis BAC.In situ hybridizations with cotton metaphase chromosomes,using the telomere as probe,it indicated that the signals were located at all chromosome ends of 7 diploid and 2 tetraploid cotton species.To identify the signals of FISH,the genome DNA of Xinhai 7,digested by Bal31 kinetics,was used in this study.

  13. Study of specificities of arm wrestlers’ psychological status in competition period

    Directory of Open Access Journals (Sweden)

    Podrigalo L. V.

    2015-06-01

    Full Text Available Purpose: researching and analysis of psychological status dynamic of different qualification arm-wrestlers in competitions’ condition. Material: in the research 21 students-sportsmen of 17-24 years’ age participated. Results: before the beginning of competition experienced sportsmen are characterized by higher workability in comparison with beginners - (56.61±8.31 % against (23.23±11.93 %. After competitions among experienced sportsmen 57.14% had reduced anxiety; 71.43% - reduced activity and self-feeling; 50% - had worse mood. After competitions among sportsmen-beginners 73.73% demonstrated reduction of workability; 54.54% had weakened activity, mood and self-feeling. We established significant prevalence of statistically confident correlations among experienced sportsmen: 65.15% against 46.97%. Contribution of psychological components in system of sportsmen-beginners is significantly lower than of experienced sportsmen. Conclusions: we determined certain changes of psychological status of arm-wrestlers of different qualification under influence of competitions. For experienced sportsmen we confirmed more optimal status and favorable dynamic, illustrating high reliability of functioning.

  14. Long Telomeres Bypass the Requirement for Telomere Maintenance in Human Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Michael A.S. Taboski

    2012-02-01

    Full Text Available Despite the importance of telomere maintenance in cancer cell survival via the elongation of telomeres by telomerase reverse transcriptase (TERT or alternative lengthening of telomeres (ALT, it had not been tested directly whether telomere maintenance is dispensable for human tumorigenesis. We engineered human tumor cells containing loxP-flanked hTERT to enable extensive telomere elongation prior to complete hTERT excision. Despite unabated telomere erosion, hTERT-excised cells formed tumors in mice and proliferated in vitro for up to 1 year. Telomerase reactivation or ALT was not observed, and the eventual loss of telomeric signal coincided with loss of tumorigenic potential and cell viability. Crisis was averted via the reintroduction of active but not inactive hTERT. Thus, telomere maintenance is dispensable for human tumorigenesis when telomere reserves are long. Yet, despite telomere instability and the presence of oncogenic RAS, human tumors remain susceptible to crisis induced by critically short telomeres.

  15. Interactions of TRF2 with model telomeric ends

    International Nuclear Information System (INIS)

    Telomeres are DNA-protein complexes at the ends of eukaryotic chromosomes, the integrity of which is essential for chromosome stability. An important telomere binding protein, TTAGGG repeat factor 2 (TRF2), is thought to protect telomere ends by remodeling them into T-loops. We show that TRF2 specifically interacts with telomeric ss/ds DNA junctions and binding is sensitive to the sequence of the 3', guanine-strand (G-strand) overhang and double-stranded DNA sequence at the junction. Association of TRF2 with DNA junctions hinders cleavage by exonuclease T. TRF2 interactions with the G-strand overhang do not involve the TRF2 DNA binding domain or the linker region. However, mobility shifts and atomic force microscopy show that the previously uncharacterized linker region is involved in DNA-specific, TRF2 oligomerization. We suggest that T-loop formation at telomere ends involves TRF2 binding to the G-strand overhang and oligomerization through both the known TRFH domain and the linker region

  16. Internal genomic regions mobilized for telomere maintenance in C. elegans.

    Science.gov (United States)

    Kim, Chuna; Sung, Sanghyun; Lee, Junho

    2016-01-01

    Because DNA polymerase cannot replicate telomeric DNA at linear chromosomal ends, eukaryotes have developed specific telomere maintenance mechanisms (TMMs). A major TMM involves specialized reverse transcriptase, telomerase. However, there also exist various telomerase-independent TMMs (TI-TMMs), which can arise both in pathological conditions (such as cancers) and during evolution. The TI-TMM in cancer cells is called alternative lengthening of telomeres (ALT), whose mechanism is not fully understood. We generated stably maintained telomerase-independent survivors from C. elegans telomerase mutants and found that, unlike previously described survivors in worms, these survivors "mobilize" specific internal sequence blocks for telomere lengthening, which we named TALTs (templates for ALT). The cis-duplication of internal genomic TALTs produces "reservoirs" of TALTs, whose trans-duplication occurs at all chromosome ends in the ALT survivors. Our discovery that different TALTs are utilized in different wild isolates provides insight into the molecular events leading to telomere evolution. PMID:27073737

  17. Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes.

    Science.gov (United States)

    Cestari, Igor; Stuart, Ken

    2015-05-26

    African trypanosomes evade clearance by host antibodies by periodically changing their variant surface glycoprotein (VSG) coat. They transcribe only one VSG gene at a time from 1 of about 20 telomeric expression sites (ESs). They undergo antigenic variation by switching transcription between telomeric ESs or by recombination of the VSG gene expressed. We show that the inositol phosphate (IP) pathway controls transcription of telomeric ESs and VSG antigenic switching in Trypanosoma brucei. Conditional knockdown of phosphatidylinositol 5-kinase (TbPIP5K) or phosphatidylinositol 5-phosphatase (TbPIP5Pase) or overexpression of phospholipase C (TbPLC) derepresses numerous silent ESs in T. brucei bloodstream forms. The derepression is specific to telomeric ESs, and it coincides with an increase in the number of colocalizing telomeric and RNA polymerase I foci in the nucleus. Monoallelic VSG transcription resumes after reexpression of TbPIP5K; however, most of the resultant cells switched the VSG gene expressed. TbPIP5K, TbPLC, their substrates, and products localize to the plasma membrane, whereas TbPIP5Pase localizes to the nucleus proximal to telomeres. TbPIP5Pase associates with repressor/activator protein 1 (TbRAP1), and their telomeric silencing function is altered by TbPIP5K knockdown. These results show that specific steps in the IP pathway control ES transcription and antigenic switching in T. brucei by epigenetic regulation of telomere silencing. PMID:25964327

  18. Mutant Telomeric Repeats in Yeast Can Disrupt the Negative Regulation of Recombination-Mediated Telomere Maintenance and Create an Alternative Lengthening of Telomeres-Like Phenotype▿

    OpenAIRE

    Bechard, Laura H.; Butuner, Bilge D.; Peterson, George J.; McRae, Will; Topcu, Zeki; McEachern, Michael J.

    2008-01-01

    Some human cancers maintain telomeres using alternative lengthening of telomeres (ALT), a process thought to be due to recombination. In Kluyveromyces lactis mutants lacking telomerase, recombinational telomere elongation (RTE) is induced at short telomeres but is suppressed once telomeres are moderately elongated by RTE. Recent work has shown that certain telomere capping defects can trigger a different type of RTE that results in much more extensive telomere elongation that is reminiscent o...

  19. Chromosome arm-specific BAC end sequences permit comparative analysis of homoeologous chromosomes and genomes of polyploid wheat

    Directory of Open Access Journals (Sweden)

    Sehgal Sunish K

    2012-05-01

    Full Text Available Abstract Background Bread wheat, one of the world’s staple food crops, has the largest, highly repetitive and polyploid genome among the cereal crops. The wheat genome holds the key to crop genetic improvement against challenges such as climate change, environmental degradation, and water scarcity. To unravel the complex wheat genome, the International Wheat Genome Sequencing Consortium (IWGSC is pursuing a chromosome- and chromosome arm-based approach to physical mapping and sequencing. Here we report on the use of a BAC library made from flow-sorted telosomic chromosome 3A short arm (t3AS for marker development and analysis of sequence composition and comparative evolution of homoeologous genomes of hexaploid wheat. Results The end-sequencing of 9,984 random BACs from a chromosome arm 3AS-specific library (TaaCsp3AShA generated 11,014,359 bp of high quality sequence from 17,591 BAC-ends with an average length of 626 bp. The sequence represents 3.2% of t3AS with an average DNA sequence read every 19 kb. Overall, 79% of the sequence consisted of repetitive elements, 1.38% as coding regions (estimated 2,850 genes and another 19% of unknown origin. Comparative sequence analysis suggested that 70-77% of the genes present in both 3A and 3B were syntenic with model species. Among the transposable elements, gypsy/sabrina (12.4% was the most abundant repeat and was significantly more frequent in 3A compared to homoeologous chromosome 3B. Twenty novel repetitive sequences were also identified using de novo repeat identification. BESs were screened to identify simple sequence repeats (SSR and transposable element junctions. A total of 1,057 SSRs were identified with a density of one per 10.4 kb, and 7,928 junctions between transposable elements (TE and other sequences were identified with a density of one per 1.39 kb. With the objective of enhancing the marker density of chromosome 3AS, oligonucleotide primers were successfully designed from

  20. 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. PMID:27118469

  1. Diminished telomeric 3' overhangs are associated with telomere dysfunction in Hoyeraal-Hreidarsson syndrome.

    Directory of Open Access Journals (Sweden)

    Noa Lamm

    Full Text Available BACKGROUND: Eukaryotic chromosomes end with telomeres, which in most organisms are composed of tandem DNA repeats associated with telomeric proteins. These DNA repeats are synthesized by the enzyme telomerase, whose activity in most human tissues is tightly regulated, leading to gradual telomere shortening with cell divisions. Shortening beyond a critical length causes telomere uncapping, manifested by the activation of a DNA damage response (DDR and consequently cell cycle arrest. Thus, telomere length limits the number of cell divisions and provides a tumor-suppressing mechanism. However, not only telomere shortening, but also damaged telomere structure, can cause telomere uncapping. Dyskeratosis Congenita (DC and its severe form Hoyeraal-Hreidarsson Syndrome (HHS are genetic disorders mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency. METHODOLOGY/PRINCIPAL FINDINGS: We studied the telomere phenotypes in a family affected with HHS, in which the genes implicated in other cases of DC and HHS have been excluded, and telomerase expression and activity appears to be normal. Telomeres in blood leukocytes derived from the patients were severely short, but in primary fibroblasts they were normal in length. Nevertheless, a significant fraction of telomeres in these fibroblasts activated DDR, an indication of their uncapped state. In addition, the telomeric 3' overhangs are diminished in blood cells and fibroblasts derived from the patients, consistent with a defect in telomere structure common to both cell types. CONCLUSIONS/SIGNIFICANCE: Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres

  2. Genetic Dissection of the Kluyveromyces lactis Telomere and Evidence for Telomere Capping Defects in TER1 Mutants with Long Telomeres

    OpenAIRE

    Underwood, Dana H.; Carroll, Coleen; McEachern, Michael J.

    2004-01-01

    In the yeast Kluyveromyces lactis, the telomeres are composed of perfect 25-bp repeats copied from a 30-nucleotide RNA template defined by 5-nucleotide terminal repeats. A genetic dissection of the K. lactis telomere was performed by using mutant telomerase RNA (TER1) alleles to incorporate mutated telomeric repeats. This analysis has shown that each telomeric repeat contains several functional regions, some of which may physically overlap. Mutations in the terminal repeats of the template RN...

  3. Platinum(II) phenanthroimidazole G-quadruplex ligand induces selective telomere shortening in A549 cancer cells.

    Science.gov (United States)

    Mancini, Johanna; Rousseau, Philippe; Castor, Katherine J; Sleiman, Hanadi F; Autexier, Chantal

    2016-02-01

    Telomere maintenance, achieved by the binding of protective shelterin capping proteins to telomeres and by either telomerase or a recombination-based alternative lengthening of telomere (ALT) mechanism, is critical for cell proliferation and survival. Extensive telomere shortening or loss of telomere integrity activates DNA damage checkpoints, leading to cell senescence or death. Although telomerase upregulation is an attractive target for anti-cancer therapy, the lag associated with telomere shortening and the potential activation of ALT pose a challenge. An alternative approach is to modify telomere interactions with binding proteins (telomere uncapping). G-quadruplex ligands stabilize structures generated from single-stranded G-rich 3'-telomere end (G-quadruplex) folding, which in principle, cannot be elongated by telomerase, thus leading to telomere shortening. Ligands can also mediate rapid anti-proliferative effects by telomere uncapping. We previously reported that the G-quadruplex ligand, phenylphenanthroimidazole ethylenediamine platinum(II) (PIP), inhibits telomerase activity in vitro[47]. In the current study, a long-term seeding assay showed that PIP significantly inhibited the seeding capacity of A549 lung cancer cells and to a lesser extent primary MRC5 fibroblast cells. Importantly, treatment with PIP caused a significant dose- and time-dependent decrease in average telomere length of A549 but not MRC5 cells. Moreover, cell cycle analysis revealed a significant increase in G1 arrest upon treatment of A549 cells, but not MRC5 cells. Both apoptosis and cellular senescence may contribute to the anti-proliferative effects of PIP. Our studies validate the development of novel and specific therapeutic ligands targeting telomeric G-quadruplex structures in cancer cells. PMID:26724375

  4. 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; Rubelj, Ivica; Kolvraa, Steen

    2010-01-01

    find a strong correlation between the load of short telomeres and cellular senescence. Further we show that the load of short telomeres is higher in senescent cells compared to proliferating cells at the same passage, offering an explanation of premature cell senescence. This new method, Universal...... 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......, Universal STELA, we have a tool that can directly investigate the relationship between senescence and the load of short telomeres. The method is a variant of the chromosome-specific STELA method but has the advantage that it can demonstrate short telomeres regardless of chromosome. With Universal STELA, we...

  5. Maintenance of Very Long Telomeres by Recombination in the Kluyveromyces lactis stn1-M1 Mutant Involves Extreme Telomeric Turnover, Telomeric Circles, and Concerted Telomeric Amplification

    OpenAIRE

    Xu, Jianing; McEachern, Michael J.

    2012-01-01

    Some cancers utilize the recombination-dependent process of alternative lengthening of telomeres (ALT) to maintain long heterogeneous telomeres. Here, we studied the recombinational telomere elongation (RTE) of the Kluyveromyces lactis stn1-M1 mutant. We found that the total amount of the abundant telomeric DNA in stn1-M1 cells is subject to rapid variation and that it is likely to be primarily extrachromosomal. Rad50 and Rad51, known to be required for different RTE pathways in Saccharomyces...

  6. SUMO-Dependent Relocalization of Eroded Telomeres to Nuclear Pore Complexes Controls Telomere Recombination

    OpenAIRE

    Dmitri Churikov; Ferose Charifi; Nadine Eckert-Boulet; Sonia Silva; Marie-Noelle Simon; Michael Lisby; Vincent Géli

    2016-01-01

    In budding yeast, inactivation of telomerase and ensuing telomere erosion cause relocalization of telomeres to nuclear pore complexes (NPCs). However, neither the mechanism of such relocalization nor its significance are understood. We report that proteins bound to eroded telomeres are recognized by the SUMO (small ubiquitin-like modifier)-targeted ubiquitin ligase (STUbL) Slx5-Slx8 and become increasingly SUMOylated. Recruitment of Slx5-Slx8 to eroded telomeres facilitates telomere relocaliz...

  7. Recombination at Long Mutant Telomeres Produces Tiny Single- and Double-Stranded Telomeric Circles

    OpenAIRE

    Groff-Vindman, Cindy; Cesare, Anthony J.; Natarajan, Shobhana; Griffith, Jack D.; McEachern, Michael J.

    2005-01-01

    Recombinational telomere elongation (RTE) known as alternate lengthening of telomeres is the mechanism of telomere maintenance in up to 5 to 10% of human cancers. The telomeres of yeast mutants lacking telomerase can also be maintained by recombination. Previously, we proposed the roll-and-spread model to explain this elongation in the yeast Kluveromyces lactis. This model suggests that a very small (∼100-bp) circular molecule of telomeric DNA is copied by a rolling circle event to generate a...

  8. Alternative Lengthening of Telomeres is characterized by reduced compaction of telomeric chromatin.

    OpenAIRE

    Episkopou, Charikleia; Draskovic, Irena; Van Beneden, Amandine; Tilman, Gaëlle; Mattiussi, Marina; Gobin, Matthieu; Arnoult, Nausica; Londoño-Vallejo, Arturo; Decottignies, Anabelle

    2014-01-01

    International audience Proper telomeric chromatin configuration is thought to be essential for telomere homeostasis and stability. Previous studies in mouse suggested that loss of heterochromatin marks at telomeres might favor onset of Alternative Lengthening of Telomeres (ALT) pathway, by promoting homologous recombination. However, analysis of chromatin status at human ALT telomeres has never been reported. Here, using isogenic human cell lines and cellular hybrids, which rely either on ...

  9. Topoisomerase IIIα is required for normal proliferation and telomere stability in alternative lengthening of telomeres

    OpenAIRE

    Temime-Smaali, Nassima; Guittat, Lionel; Wenner, Thomas; Bayart, Emilie; Douarre, Céline; Gomez, Dennis; Giraud-Panis, Marie-Josèphe; Londono-Vallejo, Arturo; Gilson, Eric; Amor-Guéret, Mounira; Riou, Jean-François

    2008-01-01

    Topoisomerase (Topo) IIIα associates with BLM helicase, which is proposed to be important in the alternative lengthening of telomeres (ALT) pathway that allows telomere recombination in the absence of telomerase. Here, we show that human Topo IIIα colocalizes with telomeric proteins at ALT-associated promyelocytic bodies from ALT cells. In these cells, Topo IIIα immunoprecipitated with telomere binding protein (TRF) 2 and BLM and was shown to be associated with telomeric DNA by chromatin immu...

  10. Novel telomere-anchored PCR approach for studying sexual stage telomeres in Aspergillus nidulans.

    Science.gov (United States)

    Wang, Nengding; Rizvydeen, Saajidha; Vahedi, Mithaq; Vargas Gonzalez, Daysi M; Allred, Amanda L; Perry, Dustin W; Mirabito, Peter M; Kirk, Karen E

    2014-01-01

    Telomere length varies between germline and somatic cells of the same organism, leading to the hypothesis that telomeres are lengthened during meiosis. However, little is known about the meiotic telomere length in many organisms. In the filamentous fungus Aspergillus nidulans, the telomere lengths in hyphae and asexual spores are invariant. No study using existing techniques has determined the telomere length of the sexual ascospores due to the relatively low abundance of pure meiotic cells in A. nidulans and the small quantity of DNA present. To address this, we developed a simple and sensitive PCR strategy to measure the telomere length of A. nidulans meiotic cells. This novel technique, termed "telomere-anchored PCR," measures the length of the telomere on chromosome II-L using a small fraction of the DNA required for the traditional terminal restriction fragment (TRF) Southern analysis. Using this approach, we determined that the A. nidulans ascospore telomere length is virtually identical to telomeres of other cell types from this organism, approximately 110 bp, indicating that a surprisingly strict telomere length regulation exists in the major cell types of A. nidulans. When the hyphal telomeres were measured in a telomerase reverse transcriptase (TERT) knockout strain, small decreases in length were readily detected. Thus, this technique can detect telomeres in relatively rare cell types and is particularly sensitive in measuring exceptionally short telomeres. This rapid and inexpensive telomere-anchored PCR method potentially can be utilized in other filamentous fungi and types of organisms. PMID:24927411

  11. Telomere length in human adults and high level natural background radiation.

    Directory of Open Access Journals (Sweden)

    Birajalaxmi Das

    Full Text Available BACKGROUND: Telomere length is considered as a biomarker of aging, stress, cancer. It has been associated with many chronic diseases such as hypertension and diabetes. Although, telomere shortening due to ionizing radiation has been reported in vitro, no in vivo data is available on natural background radiation and its effect on telomere length. METHODOLOGY/PRINCIPAL FINDINGS: The present investigation is an attempt to determine the telomere length among human adults residing in high level natural radiation areas (HLNRA and the adjacent normal level radiation areas (NLNRA of Kerala coast in Southwest India. Genomic DNA was isolated from the peripheral blood mononuclear cells of 310 individuals (HLNRA: N = 233 and NLNRA: N = 77. Telomere length was determined using real time q-PCR. Both telomere (T and single copy gene (S specific primers were used to calculate the relative T/S and expressed as the relative telomere length. The telomere length was determined to be 1.22+/-0.15, 1.12+/-0.15, 1.08+/-0.08, 1.12+/-0.11, respectively, among the four dose groups (5.00 mGy per year, which did not show any dose response. The results suggested that the high level natural chronic radiation did not have significant effect on telomere length among young adult population living in HLNRA, which is indicative of better repair of telomeric ends. No significant difference in telomere length was observed between male and female individuals. In the present investigation, although the determination of telomere length was studied among the adults with an age group between 18 to 40 years (mean maternal age: 26.10+/-4.49, a negative correlation was observed with respect to age. However, inter-individual variation was (0.81-1.68 was clearly observed. CONCLUSIONS/SIGNIFICANCE: In this preliminary investigation, we conclude that elevated level of natural background radiation has no significant effect on telomere length among the adult population residing in HLNRAs of

  12. Telomere-associated proteins of typical and alternative telomeres

    Czech Academy of Sciences Publication Activity Database

    Sýkorová, Eva; Rotková, Gabriela; Fajkus, Jiří

    Villars-sur-Ollon, 2006. s. 19-19. [Telomeres and Genome Stability 2006. 30.08.2006-03.09.2006, Villars-sur-Ollon] R&D Projects: GA ČR(CZ) GP204/04/P105; GA ČR(CZ) GA521/05/0055; GA AV ČR(CZ) IAA600040505; GA MŠk(CZ) LC06004 Institutional research plan: CEZ:AV0Z50040507 Keywords : alternative telomeres * DNA-protein interaction Subject RIV: BO - Biophysics

  13. Telomere loss, not average telomere length, confers radiosensitivity to TK6-irradiated cells

    Energy Technology Data Exchange (ETDEWEB)

    Berardinelli, F.; Nieri, D.; Sgura, A.; Tanzarella, C. [Dip. Di Biologia, Università “Roma Tre”, Rome (Italy); INFN – “Roma Tre”, Rome (Italy); Antoccia, A., E-mail: antoccia@uniroma3.it [Dip. Di Biologia, Università “Roma Tre”, Rome (Italy); INFN – “Roma Tre”, Rome (Italy)

    2012-12-15

    Highlights: ► Ionizing radiation induced telomere lengthening in TK6 clones from a single cell. ► Telomerase is not involved in the telomere lengthening observed. ► TK6 cells display very heterogeneous values in telomere length and telomere loss. ► A selective process account for telomere lengthening in irradiated cells. ► Telomere loss, not mean telomere length, is predictive of radiosensitivity. - Abstract: Many and varied are the proposed mechanisms that lead to resistance to ionizing radiation treatment. Among them, an inverse relationship between telomere length and radioresistance has been recently advanced. Investigating such a relationship in TK6 lymphoblasts, we found that clones originating from cells survived to 4 Gy of X-rays showed a significantly higher telomere length when compared with clones grown from untreated cells. The lengthening observed was not attributable to a radiation-induced increase in telomerase activity, as demonstrated by TRAP assay performed in the dose range of 1–10 Gy. Given the evidence that TK6 whole population was characterized by heterogeneity in cellular mean telomere length and telomere loss, we tested the hypothesis that a process of selection may favour cells with longer telomeres (more radioresistant cells) following exposure to irradiation. In order to do this 15 independent TK6 clones were selected and characterized for telomere length and loss on the basis of q-FISH and flow-FISH analysis. Among the screened clones four characterized by long telomeres and four characterized by short telomeres were tested for their radiosensitivity by means of clonogenic assay. The results obtained showed that, in our experimental conditions (cellular model, radiation doses) no significant correlation was observed between radiosensitivity and mean telomere lengths, whereas a positive correlation was observed with respect to telomere loss. Overall, these results indicate that telomere loss and not mean telomere length plays

  14. Telomere and telomerase in oncology

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Shortening of the telomeric DNA at the chromosome ends is presumed to limit the lifespan of human cells and elicit a signal for the onset of cellular senescence. To continually proliferate across the senescent checkpoint, cells must restore and preserve telomere length. This can be achieved by telomerase, which has the reverse transcriptase activity. Telomerase activity is negative in human normal somatic cells but can be detected in most tumor cells. The enzyme is proposed to be an essential factor in cell immortalization and cancer progression. In this review we discuss the structure and function of telomere and telomerase and thefr roles in cell immortalization and oncogenesis. Simultaneously the experimental studies of telomerase assays for cancer detection and diagnosis are reviewed. Finally, we discuss the potential use of inhibitors of telomerase in anti-cancer therapy.

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

    International Nuclear Information System (INIS)

    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

  16. Environmental stresses disrupt telomere length homeostasis.

    Directory of Open Access Journals (Sweden)

    Gal Hagit Romano

    Full Text Available Telomeres protect the chromosome ends from degradation and play crucial roles in cellular aging and disease. Recent studies have additionally found a correlation between psychological stress, telomere length, and health outcome in humans. However, studies have not yet explored the causal relationship between stress and telomere length, or the molecular mechanisms underlying that relationship. Using yeast as a model organism, we show that stresses may have very different outcomes: alcohol and acetic acid elongate telomeres, whereas caffeine and high temperatures shorten telomeres. Additional treatments, such as oxidative stress, show no effect. By combining genome-wide expression measurements with a systematic genetic screen, we identify the Rap1/Rif1 pathway as the central mediator of the telomeric response to environmental signals. These results demonstrate that telomere length can be manipulated, and that a carefully regulated homeostasis may become markedly deregulated in opposing directions in response to different environmental cues.

  17. The DNA methylation inhibitor induces telomere dysfunction and apoptosis of leukemia cells that is attenuated by telomerase over-expression.

    Science.gov (United States)

    Zhang, Xiaolu; Li, Bingnan; de Jonge, Nick; Björkholm, Magnus; Xu, Dawei

    2015-03-10

    DNA methyltransferase inhibitors (DNMTIs) such as 5-azacytidine (5-AZA) have been used for treatment of acute myeloid leukemia (AML) and other malignancies. Although inhibiting global/gene-specific DNA methylation is widely accepted as a key mechanism behind DNMTI anti-tumor activity, other mechanisms are likely involved in DNMTI's action. Because telomerase reverse transcriptase (TERT) plays key roles in cancer through telomere elongation and telomere lengthening-independent activities, and TERT has been shown to confer chemo- or radio-resistance to cancer cells, we determine whether DNMTIs affect telomere function and whether TERT/telomerase interferes with their anti-cancer efficacy. We showed that 5-AZA induced DNA damage and telomere dysfunction in AML cell lines by demonstrating the presence of 53-BP1 foci and the co-localization of 53-BP1 foci with telomere signals, respectively. Telomere dysfunction was coupled with diminished TERT expression, shorter telomere and apoptosis in 5-AZA-treated cells. However, 5-AZA treatment did not lead to changes in the methylation status of subtelomere regions. Down-regulation of TERT expression similarly occurred in primary leukemic cells derived from AML patients exposed to 5-AZA. TERT over-expression significantly attenuated 5-AZA-mediated DNA damage, telomere dysfunction and apoptosis of AML cells. Collectively, 5-AZA mediates the down-regulation of TERT expression, and induces telomere dysfunction, which consequently exerts an anti-tumor activity. PMID:25682873

  18. Shelterin Protects Chromosome Ends by Compacting Telomeric Chromatin.

    Science.gov (United States)

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

    2016-02-11

    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, but 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 accumulate DDR signals and become more accessible to telomere-associated proteins. 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

  19. An extremely sensitive species-specific ARMS PCR test for the presence of tiger bone DNA.

    Science.gov (United States)

    Wetton, Jon H; Tsang, Carol S F; Roney, Chris A; Spriggs, Adrian C

    2002-04-18

    The survival of the tiger (Panthera tigris) is seriously threatened by poaching to provide raw materials for traditional Chinese medicines (TCMs). Most highly prized are the tiger's bones, which are used in combination with other animal and plant derivatives in pills and plasters for the treatment of rheumatism and other ailments. Hundreds of patent remedies have been produced which claim to contain tiger bone, but proof of its presence is needed if legislation prohibiting the trade in endangered species is to be enforced.A highly sensitive tiger-specific real-time PCR assay has been developed to address this problem. Using primers specific to the tiger mitochondrial cytochrome b gene, successful amplification has been reliably achieved from blood, hair and bone as well as from a range of TCMs spiked with 0.5% tiger bone. Although capable of detecting fewer than 10 substrate molecules, the seven varieties of TCM pills and plasters tested showed no detectable trace of tiger DNA before spiking. Furthermore, sequencing several "tiger bone" fragments seized from TCM shops has shown that they actually originated from cattle and pigs. The potential effects of traditional bone preparation methods, evidence that much lower concentrations are used than alleged on TCM packaging, and substitution of bones from other species all suggest a low likelihood of detecting tiger DNA in patent medicines. Despite this, the basic methods have been thoroughly proven and can be readily applied to derivatives from other Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) protected species, providing a rapid and highly sensitive forensic test for species of origin. Potential applications to the monitoring of wild populations are demonstrated by the successful identification of shed hairs and faecal samples. PMID:12084490

  20. Counting of Rif1p and Rif2p on Saccharomyces cerevisiae Telomeres Regulates Telomere Length†

    OpenAIRE

    Levy, Daniel L.; Blackburn, Elizabeth H.

    2004-01-01

    Telomere length is negatively regulated by proteins of the telomeric DNA-protein complex. Rap1p in Saccharomyces cerevisiae binds the telomeric TG1-3 repeat DNA, and the Rap1p C terminus interacts with Rif1p and Rif2p. We investigated how these three proteins negatively regulate telomere length. We show that direct tethering of each Rif protein to a telomere shortens that telomere proportionally to the number of tethered molecules, similar to previously reported counting of Rap1p. Surprisingl...

  1. Evolutionary switchpoints in plant telomeres

    Czech Academy of Sciences Publication Activity Database

    Sýkorová, Eva; Lim, K. Y.; Kunická, Zuzana; Chase, M. W.; Bennet, M. D.; Leitch, A. R.; Fajkus, Jiří

    London: Biochemical Society, 2004. s. 28-. [EMBO Workshop / Harden Conference /58./ - Telemeres and Genome Stability . 03.04.2004-07.04.2004, Cambridge] R&D Projects: GA ČR GA204/02/0027; GA ČR GP204/04/P105 Keywords : alternative telomeres in plants * molecular evolution Subject RIV: BO - Biophysics

  2. Telomeres: Their structure and maintenance

    Czech Academy of Sciences Publication Activity Database

    Čapková Frydrychová, Radmila; Mason, J. M.

    Rijeka: InTech, Open Access Publisher, 2013 - (Stuart, D.), s. 423-443 ISBN 978-953-51-0991-4 R&D Projects: GA ČR GAP501/10/1215 Institutional support: RVO:60077344 Keywords : telomeric DNA Subject RIV: EB - Genetics ; Molecular Biology

  3. Switch telomerase to ALT mechanism by inducing telomeric DNA damages and dysfunction of ATRX and DAXX.

    Science.gov (United States)

    Hu, Yang; Shi, Guang; Zhang, Laichen; Li, Feng; Jiang, Yuanling; Jiang, Shuai; Ma, Wenbin; Zhao, Yong; Songyang, Zhou; Huang, Junjiu

    2016-01-01

    Activation of telomerase or alternative lengthening of telomeres (ALT) is necessary for tumours to escape from dysfunctional telomere-mediated senescence. Anti-telomerase drugs might be effective in suppressing tumour growth in approximately 85-90% of telomerase-positive cancer cells. However, there are still chances for these cells to bypass drug treatment after switching to the ALT mechanism to maintain their telomere integrity. But the mechanism underlying this switch is unknown. In this study, we used telomerase-positive cancer cells (HTC75) to discover the mechanism of the telomerase-ALT switch by inducing telomere-specific DNA damage, alpha-thalassemia X-linked syndrome protein (ATRX) knockdown and deletion of death associated protein (DAXX). Surprisingly, two important ALT hallmarks in the ALT-like HTC75 cells were observed after treatments: ALT-associated promyelocytic leukaemia bodies (APBs) and extrachromosomal circular DNA of telomeric repeats. Moreover, knocking out hTERT by utilizing the CRISPR/Cas9 technique led to telomere elongation in a telomerase-independent manner in ALT-like HTC75 cells. In summary, this is the first report to show that inducing telomeric DNA damage, disrupting the ATRX/DAXX complex and inhibiting telomerase activity in telomerase-positive cancer cells lead to the ALT switch. PMID:27578458

  4. Inhibition of telomere recombination by inactivation of KEOPS subunit Cgi121 promotes cell longevity.

    Directory of Open Access Journals (Sweden)

    Jing Peng

    2015-03-01

    Full Text Available DNA double strand break (DSB is one of the major damages that cause genome instability and cellular aging. The homologous recombination (HR-mediated repair of DSBs plays an essential role in assurance of genome stability and cell longevity. Telomeres resemble DSBs and are competent for HR. Here we show that in budding yeast Saccharomyces cerevisiae telomere recombination elicits genome instability and accelerates cellular aging. Inactivation of KEOPS subunit Cgi121 specifically inhibits telomere recombination, and significantly extends cell longevity in both telomerase-positive and pre-senescing telomerase-negative cells. Deletion of CGI121 in the short-lived yku80(tel mutant restores lifespan to cgi121Δ level, supporting the function of Cgi121 in telomeric single-stranded DNA generation and thus in promotion of telomere recombination. Strikingly, inhibition of telomere recombination is able to further slow down the aging process in long-lived fob1Δ cells, in which rDNA recombination is restrained. Our study indicates that HR activity at telomeres interferes with telomerase to pose a negative impact on cellular longevity.

  5. Localization-Dependent and -Independent Roles of SLX4 in Regulating Telomeres

    Directory of Open Access Journals (Sweden)

    Jamie S.J. Wilson

    2013-09-01

    Full Text Available SLX4, a scaffold for structure-specific DNA repair nucleases, is important for several types of DNA repair. Many repair proteins bind to sites of DNA damage, resulting in subnuclear “foci,” but SLX4 forms foci in human cells even without DNA damage. Using several approaches, we show that most, but not all, SLX4 foci localize to telomeres in a range of human cell lines irrespective of the mechanisms used to maintain telomere length. The SLX1 Holliday-junction-processing enzyme is recruited to telomeres by SLX4, and SLX4, in turn, is recruited by a motif that binds to the shelterin subunit TRF2 directly. We also show that TRF2-dependent recruitment of SLX4 prevents telomere damage. Furthermore, SLX4 prevents telomere lengthening and fragility in a manner that appears to be independent of telomere association. These findings reveal that SLX4 plays multiple roles in regulating telomere homeostasis.

  6. Aberrant reduction of telomere repetitive sequences in plasma cell-free DNA for early breast cancer detection

    Science.gov (United States)

    Wu, Xi; Tanaka, Hiromi

    2015-01-01

    Excessive telomere shortening is observed in breast cancer lesions when compared to adjacent non-cancerous tissues, suggesting that telomere length may represent a key biomarker for early cancer detection. Because tumor-derived, cell-free DNA (cfDNA) is often released from cancer cells and circulates in the bloodstream, we hypothesized that breast cancer development is associated with changes in the amount of telomeric cfDNA that can be detected in the plasma. To test this hypothesis, we devised a novel, highly sensitive and specific quantitative PCR (qPCR) assay, termed telomeric cfDNA qPCR, to quantify plasma telomeric cfDNA levels. Indeed, the internal reference primers of our design correctly reflected input cfDNA amount (R2 = 0.910, P = 7.82 × 10−52), implying accuracy of this assay. We found that plasma telomeric cfDNA levels decreased with age in healthy individuals (n = 42, R2 = 0.094, P = 0.048), suggesting that cfDNA is likely derived from somatic cells in which telomere length shortens with increasing age. Our results also showed a significant decrease in telomeric cfDNA level from breast cancer patients with no prior treatment (n = 47), compared to control individuals (n = 42) (P = 4.06 × 10−8). The sensitivity and specificity for the telomeric cfDNA qPCR assay was 91.49% and 76.19%, respectively. Furthermore, the telomeric cfDNA level distinguished even the Ductal Carcinoma In Situ (DCIS) group (n = 7) from the healthy group (n = 42) (P = 1.51 × 10−3). Taken together, decreasing plasma telomeric cfDNA levels could be an informative genetic biomarker for early breast cancer detection. PMID:26356673

  7. Regulation of homologous recombination at telomeres in budding yeast

    DEFF Research Database (Denmark)

    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...

  8. Rad59-facilitated acquisition of Y' elements by short telomeres delays the onset of senescence.

    Directory of Open Access Journals (Sweden)

    Dmitri Churikov

    2014-11-01

    Full Text Available Telomerase-negative yeasts survive via one of the two Rad52-dependent recombination pathways, which have distinct genetic requirements. Although the telomere pattern of type I and type II survivors is well characterized, the mechanistic details of short telomere rearrangement into highly evolved pattern observed in survivors are still missing. Here, we analyze immediate events taking place at the abruptly shortened VII-L and native telomeres. We show that short telomeres engage in pairing with internal Rap1-bound TG1-3-like tracts present between subtelomeric X and Y' elements, which is followed by BIR-mediated non-reciprocal translocation of Y' element and terminal TG1-3 repeats from the donor end onto the shortened telomere. We found that choice of the Y' donor was not random, since both engineered telomere VII-L and native VI-R acquired Y' elements from partially overlapping sets of specific chromosome ends. Although short telomere repair was associated with transient delay in cell divisions, Y' translocation on native telomeres did not require Mec1-dependent checkpoint. Furthermore, the homeologous pairing between the terminal TG1-3 repeats at VII-L and internal repeats on other chromosome ends was largely independent of Rad51, but instead it was facilitated by Rad59 that stimulates Rad52 strand annealing activity. Therefore, Y' translocation events taking place during presenescence are genetically separable from Rad51-dependent Y' amplification process that occurs later during type I survivor formation. We show that Rad59-facilitated Y' translocations on X-only telomeres delay the onset of senescence while preparing ground for type I survivor formation.

  9. The Human Pregnancy-Specific Glycoprotein Genes are Tightly Linked on the Long Arm of Chromosome 19 and are Coordinately Expressed

    OpenAIRE

    Thompson, John A.; Koumari, Rosa; Wagner, Klaus; Barnert, Sabine; Schleussner, Cathrin; Schrewe, Heinrich; Zimmermann, Wolfgang; Müller, Gaby; Schempp, Werner; Zaninetta, Daniela; Ammaturo, Domenico; Hardman, Norman

    1990-01-01

    The pregnancy-specific glycoprotein (PSG) genes encode a group of proteins which are found in large amounts in placenta and maternal serum. In situ hybridization analyses of metaphase chromosomes reveal that all the human pregnancy-specific glycoprotein (PSG) genes are located on the long arm of chromosome 19 (19q13.2–13.3), overlapping the region containing the closely-related carcinoembryonic antigen (CEA) gene subgroup. Higher resolution analyses indicate that the PSG genes are closely lin...

  10. The nature of telomere fusion and a definition of the critical telomere length in human cells

    OpenAIRE

    Capper, Rebecca; Britt-Compton, Bethan; Tankimanova, Maira; Rowson, Jan; Letsolo, Boitelo; Man, Stephen; Haughton, Michele; Baird, Duncan M.

    2007-01-01

    The loss of telomere function can result in telomeric fusion events that lead to the types of genomic rearrangements, such as nonreciprocal translocations, that typify early-stage carcinogenesis. By using single-molecule approaches to characterize fusion events, we provide a functional definition of fusogenic telomeres in human cells. We show that approximately half of the fusion events contained no canonical telomere repeats at the fusion point; of those that did, the longest was 12.8 repeat...

  11. Alternative lengthening of telomeres pathway: recombination-mediated telomere maintenance mechanism in human cells.

    OpenAIRE

    Nabetani, Akira; Ishikawa, Fuyuki

    2011-01-01

    Unlimitedly proliferating cells need to acquire the telomere DNA maintenance mechanism, to counteract possible shortening through multiple rounds of replication and segregation of linear chromosomes. Most human cancer cells express telomerase whereas the other cells utilize the alternative lengthening of telomeres (ALT) pathway to elongate telomere DNA. It is suggested that ALT depends on the recombination between telomere repetitive DNAs. However, the molecular details remain unknown. Recent...

  12. Telomere length is inherited with resetting of the telomere set-point

    OpenAIRE

    Chiang, Y. Jeffrey; Calado, Rodrigo T.; Karen S Hathcock; Lansdorp, Peter M.; Young, Neal S; Richard J Hodes

    2010-01-01

    We have studied models of telomerase haploinsufficiency in humans and mice to analyze regulation of telomere length and the significance of “set points” in inheritance of telomere length. In three families with clinical syndromes associated with short telomeres resulting from haploinsufficient mutations in TERT, the gene encoding telomerase reverse transcriptase, we asked whether restoration of normal genotypes in offspring of affected individuals would elongate inherited short telomeres. Tel...

  13. Telomere Length Correlates with Life Span of Dog Breeds

    OpenAIRE

    Laura J. Fick; Gordon H. Fick; Zichen Li; Eric Cao; Bo Bao; Doug Heffelfinger; Heidi G. Parker; Elaine A. Ostrander; Karl Riabowol

    2012-01-01

    Telomeric DNA repeats are lost as normal somatic cells replicate. When telomeres reach a critically short length, a DNA damage signal is initiated, inducing cell senescence. Some studies have indicated that telomere length correlates with mortality, suggesting that telomere length contributes to human life span; however, other studies report no correlation, and thus the issue remains controversial. Domestic dogs show parallels in telomere biology to humans, with similar telomere length, telom...

  14. Telomere behavior in a hybrid yeast

    Institute of Scientific and Technical Information of China (English)

    Ona C Martin; Christopher G De Sevo; Benjamin Z Guo; Douglas E Koshland; Maiterya J Dunham; Yixian Zheng

    2009-01-01

    @@ Dear Editor, Telomeres and the protein/RNA complexes involved in maintaining them are rapidly evolving systems across eukaryotes.Using two Saccharomyces species, among S.cerevisiae and S.bayanus, we provide evidence that the telomere systems of these two closely related yeasts have evolved significantly apart and that the gene in one spe-cies cannot maintain the set-point of telomere length of the other soecies in the hybrid.

  15. ATRX represses alternative lengthening of telomeres

    OpenAIRE

    Napier, Christine E.; Huschtscha, Lily I.; Harvey, Adam; Bower, Kylie; Noble, Jane R.; Hendrickson, Eric A.; Reddel, Roger R

    2015-01-01

    The unlimited proliferation of cancer cells requires a mechanism to prevent telomere shortening. Alternative Lengthening of Telomeres (ALT) is an homologous recombination-mediated mechanism of telomere elongation used in tumors, including osteosarcomas, soft tissue sarcoma subtypes, and glial brain tumors. Mutations in the ATRX/DAXX chromatin remodeling complex have been reported in tumors and cell lines that use the ALT mechanism, suggesting that ATRX may be an ALT repressor. We show here th...

  16. Identification of telomere dysfunction in Friedreich ataxia

    OpenAIRE

    Anjomani Virmouni, Sara; Al-Mahdawi, Sahar; Sandi, Chiranjeevi; Yasaei, Hemad; Giunti, Paola; Slijepcevic, Predrag; Mark A. Pook

    2015-01-01

    Background Friedreich ataxia (FRDA) is a progressive inherited neurodegenerative disorder caused by mutation of the FXN gene, resulting in decreased frataxin expression, mitochondrial dysfunction and oxidative stress. A recent study has identified shorter telomeres in FRDA patient leukocytes as a possible disease biomarker. Results Here we aimed to investigate both telomere structure and function in FRDA cells. Our results confirmed telomere shortening in FRDA patient leukocytes and identifie...

  17. Stress and Telomere Biology: A Lifespan Perspective

    OpenAIRE

    Shalev, Idan; Entringer, Sonja; Pathik D Wadhwa; Wolkowitz, Owen M.; Puterman, Eli; Lin, Jue; Epel, Elissa S.

    2013-01-01

    In the past decade, the growing field of telomere science has opened exciting new avenues for understanding the cellular and molecular substrates of stress and stress-related aging processes ver the lifespan. Shorter telomere length is associated with advancing chronological age and also increased disease morbidity and mortality. Emerging studies suggest that stress accelerates the erosion of telomeres from very early in life and possibly even influences the initial (newborn) setting of telom...

  18. Telomeric circles are abundant in the stn1-M1 mutant that maintains its telomeres through recombination

    OpenAIRE

    Evelina Y Basenko; Cesare, Anthony J.; Iyer, Shilpa; Griffith, Jack D.; McEachern, Michael J.

    2009-01-01

    Some human cancers maintain their telomeres using the alternative lengthening of telomeres (ALT) mechanism; a process thought to involve recombination. Different types of recombinational telomere elongation pathways have been identified in yeasts. In senescing yeast telomerase deletion (ter1-Δ) mutants with very short telomeres, it has been hypothesized that copying a tiny telomeric circle (t-circle) by a rolling circle mechanism is the key event in telomere elongation. In other cases more cl...

  19. Paternal age and telomere length in twins

    DEFF Research Database (Denmark)

    Hjelmborg, Jacob B; Dalgård, Christine; Mangino, Massimo; Spector, Tim D; Halekoh, Ulrich; Möller, Sören; Kimura, Masayuki; Horvath, Kent; Kark, Jeremy D; Christensen, Kaare; Kyvik, Kirsten O; Aviv, Abraham

    2015-01-01

    Telomere length, a highly heritable trait, is longer in offspring of older fathers. This perplexing feature has been attributed to the longer telomeres in sperm of older men and it might be an 'epigenetic' mechanism through which paternal age plays a role in telomere length regulation in humans....... Based on two independent (discovery and replication) twin studies, comprising 889 twin pairs, we show an increase in the resemblance of leukocyte telomere length between dizygotic twins of older fathers, which is not seen in monozygotic twins. This phenomenon might result from a paternal age...

  20. Leukocyte telomere dynamics in the elderly

    DEFF Research Database (Denmark)

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

    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 of the...... years, assuming a 340 bp attrition during this period. This was not significantly different from the empirical observation of 7.5 % of individuals showing LTL elongation. We conclude that accumulation of ultra-short telomeres in leukocytes of the elderly reflects a shift toward shorter telomeres in the...

  1. Application of primed in situ DNA synthesis (PRINS) with telomere human commercial kit in molecular cytogenetics of Equus caballus and Sus scrofa scrofa.

    OpenAIRE

    Maciej Wnuk; Monika Bugno; Ewa Slota

    2008-01-01

    Recently, molecular techniques have become an indispensable tools for cytogenetic research. Especially, development of in situ techniques made possible detection at the chromosomal level, genes as well as repetitive sequences like telomeres or the DNA component of telomeres. One of these methods is primed in situ DNA synthesis (PRINS) using an oligonucleotide primer complementary to the specific DNA sequence. In this report we described application of PRINS technique with telomere human comme...

  2. CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection.

    OpenAIRE

    FLETCHER, JEAN

    2010-01-01

    PUBLISHED BACKGROUND & AIMS: Increasing age is associated with impaired immune function and in chronic HCV infection specifically, with progressive fibrosis, liver failure, HCC and impaired responses to antiviral therapy. T-lymphocyte telomere length declines with age. We hypothesised that shorter T-lymphocyte telomere length would be associated with poor clinical outcome in HCV infection. METHODS: Circulating T-lymphocyte telomere length, an objective measure of immune senescence, was...

  3. 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

  4. Origin and Evolution of Telomeres

    Czech Academy of Sciences Publication Activity Database

    Fajkus, Jiří; Leitch, A.R.; Chester, M.; Sýkorová, Eva

    Austin : Landes Bioscience, 2008 - (Nosek, J.; Tomáška, L.), s. 114-127 ISBN 978-1-58706-309-1 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 : evolution * telomere * plant Subject RIV: BO - Biophysics

  5. Telomere length correlates with life span of dog breeds.

    Science.gov (United States)

    Fick, Laura J; Fick, Gordon H; Li, Zichen; Cao, Eric; Bao, Bo; Heffelfinger, Doug; Parker, Heidi G; Ostrander, Elaine A; Riabowol, Karl

    2012-12-27

    Telomeric DNA repeats are lost as normal somatic cells replicate. When telomeres reach a critically short length, a DNA damage signal is initiated, inducing cell senescence. Some studies have indicated that telomere length correlates with mortality, suggesting that telomere length contributes to human life span; however, other studies report no correlation, and thus the issue remains controversial. Domestic dogs show parallels in telomere biology to humans, with similar telomere length, telomere attrition, and absence of somatic cell telomerase activity. Using this model, we find that peripheral blood mononuclear cell (PBMC) telomere length is a strong predictor of average life span among 15 different breeds (p Dogs lose telomeric DNA ~10-fold faster than humans, which is similar to the ratio of average life spans between these species. Breeds with shorter mean telomere lengths show an increased probability of death from cardiovascular disease, which was previously correlated with short telomere length in humans. PMID:23260664

  6. SUMO-Dependent Relocalization of Eroded Telomeres to Nuclear Pore Complexes Controls Telomere Recombination

    Directory of Open Access Journals (Sweden)

    Dmitri Churikov

    2016-05-01

    Full Text Available In budding yeast, inactivation of telomerase and ensuing telomere erosion cause relocalization of telomeres to nuclear pore complexes (NPCs. However, neither the mechanism of such relocalization nor its significance are understood. We report that proteins bound to eroded telomeres are recognized by the SUMO (small ubiquitin-like modifier-targeted ubiquitin ligase (STUbL Slx5-Slx8 and become increasingly SUMOylated. Recruitment of Slx5-Slx8 to eroded telomeres facilitates telomere relocalization to NPCs and type II telomere recombination, a counterpart of mammalian alternative lengthening of telomeres (ALT. Moreover, artificial tethering of a telomere to a NPC promotes type II telomere recombination but cannot bypass the lack of Slx5-Slx8 in this process. Together, our results indicate that SUMOylation positively contributes to telomere relocalization to the NPC, where poly-SUMOylated proteins that accumulated over time have to be removed. We propose that STUbL-dependent relocalization of telomeres to NPCs constitutes a pathway in which excessively SUMOylated proteins are removed from “congested” intermediates to ensure unconventional recombination.

  7. SUMO-Dependent Relocalization of Eroded Telomeres to Nuclear Pore Complexes Controls Telomere Recombination.

    Science.gov (United States)

    Churikov, Dmitri; Charifi, Ferose; Eckert-Boulet, Nadine; Silva, Sonia; Simon, Marie-Noelle; Lisby, Michael; Géli, Vincent

    2016-05-10

    In budding yeast, inactivation of telomerase and ensuing telomere erosion cause relocalization of telomeres to nuclear pore complexes (NPCs). However, neither the mechanism of such relocalization nor its significance are understood. We report that proteins bound to eroded telomeres are recognized by the SUMO (small ubiquitin-like modifier)-targeted ubiquitin ligase (STUbL) Slx5-Slx8 and become increasingly SUMOylated. Recruitment of Slx5-Slx8 to eroded telomeres facilitates telomere relocalization to NPCs and type II telomere recombination, a counterpart of mammalian alternative lengthening of telomeres (ALT). Moreover, artificial tethering of a telomere to a NPC promotes type II telomere recombination but cannot bypass the lack of Slx5-Slx8 in this process. Together, our results indicate that SUMOylation positively contributes to telomere relocalization to the NPC, where poly-SUMOylated proteins that accumulated over time have to be removed. We propose that STUbL-dependent relocalization of telomeres to NPCs constitutes a pathway in which excessively SUMOylated proteins are removed from "congested" intermediates to ensure unconventional recombination. PMID:27134164

  8. Single-Cell Telomere-Length Quantification Couples Telomere Length to Meristem Activity and Stem Cell Development in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Mary-Paz González-García

    2015-05-01

    Full Text Available 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.

  9. 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. PMID:25937286

  10. Effect of the anatomical site on telomere length and pref-1 gene expression in bovine adipose tissues

    International Nuclear Information System (INIS)

    Adipose tissue growth is associated with preadipocyte proliferation and differentiation. Telomere length is a biological marker for cell proliferation. Preadipocyte factor-1 (pref-1) is specifically expressed in preadipocytes and acts as a molecular gatekeeper of adipogenesis. In the present study, we investigated the fat depot-specific differences in telomere length and pref-1 gene expression in various anatomical sites (subcutaneous, intramuscular and visceral) of fattening Wagyu cattle. Visceral adipose tissue expressed higher pref-1 mRNA than did subcutaneous and intramuscular adipose tissues. The telomere length in visceral adipose tissue tended to be longer than that of subcutaneous and intramuscular adipose tissues. The telomere length of adipose tissue was not associated with adipocyte size from three anatomical sites. No significant correlation was found between the pref-1 mRNA level and the subcutaneous adipocyte size. In contrast, the pref-1 mRNA level was negatively correlated with the intramuscular and visceral adipocyte size. These results suggest that anatomical sites of adipose tissue affect the telomere length and expression pattern of the pref-1 gene in a fat depot-specific manner. - Highlights: • Visceral adipose tissue express higher pref-1 mRNA than other anatomical sites. • Telomere length in visceral adipose tissue is longer than other anatomical sites. • Telomere length of adipose tissue is not associated with adipocyte size. • Pref-1 mRNA is negatively correlated with intramuscular and visceral adipocyte size

  11. Effect of the anatomical site on telomere length and pref-1 gene expression in bovine adipose tissues

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Tomoya, E-mail: toyamada@affrc.go.jp; Higuchi, Mikito; Nakanishi, Naoto

    2015-08-07

    Adipose tissue growth is associated with preadipocyte proliferation and differentiation. Telomere length is a biological marker for cell proliferation. Preadipocyte factor-1 (pref-1) is specifically expressed in preadipocytes and acts as a molecular gatekeeper of adipogenesis. In the present study, we investigated the fat depot-specific differences in telomere length and pref-1 gene expression in various anatomical sites (subcutaneous, intramuscular and visceral) of fattening Wagyu cattle. Visceral adipose tissue expressed higher pref-1 mRNA than did subcutaneous and intramuscular adipose tissues. The telomere length in visceral adipose tissue tended to be longer than that of subcutaneous and intramuscular adipose tissues. The telomere length of adipose tissue was not associated with adipocyte size from three anatomical sites. No significant correlation was found between the pref-1 mRNA level and the subcutaneous adipocyte size. In contrast, the pref-1 mRNA level was negatively correlated with the intramuscular and visceral adipocyte size. These results suggest that anatomical sites of adipose tissue affect the telomere length and expression pattern of the pref-1 gene in a fat depot-specific manner. - Highlights: • Visceral adipose tissue express higher pref-1 mRNA than other anatomical sites. • Telomere length in visceral adipose tissue is longer than other anatomical sites. • Telomere length of adipose tissue is not associated with adipocyte size. • Pref-1 mRNA is negatively correlated with intramuscular and visceral adipocyte size.

  12. Telomere biology in healthy aging and disease

    NARCIS (Netherlands)

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

    2010-01-01

    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 nucleoti

  13. Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma

    International Nuclear Information System (INIS)

    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

  14. Long telomeres: too much of a good thing

    NARCIS (Netherlands)

    Chang, Michael

    2012-01-01

    Telomeres, the physical ends of linear eukaryotic chromosomes, protect chromosome ends from end fusions and degradation. Telomere length is tightly regulated to ensure that telomeres are neither too short nor too long. Short telomeres are preferentially elongated by the enzyme telomerase. In the abs

  15. 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.

  16. Telomere Length Reprogramming in Embryos and Stem Cells

    Directory of Open Access Journals (Sweden)

    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.

  17. An increase in telomere sister chromatid exchange in murine embryonic stem cells possessing critically shortened telomeres

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yisong [ORNL; Giannone, Richard J [ORNL; Wu, Jun [ORNL; Gomez, Marla V [ORNL; Liu, Yie [ORNL

    2005-01-01

    Telomerase deficiency leads to a progressive loss of telomeric DNA that eventually triggers cell apoptosis in human primary cells during prolonged growth in culture. Rare survivors can maintain telomere length through either activation of telomerase or recombination-based telomere lengthening, and thus proliferate indefinitely. We have explored the possibility that telomeres may be maintained through telomere sister chromatid exchange (T-SCE) in murine telomere reverse transcriptase-deficient (mTert -/-) splenocytes and ES cells. Because telomerase deficiency leads to gradual loss of telomeric DNA in mTert -/- splenocytes and ES cells and eventually to chromosomes with telomere signal-free ends (SFEs), we examined these cell types for evidence of sister chromatid exchange at telomeres, and observed an increase in T-SCEs only in a subset of mTert -/- splenocytes or ES cells that possessed multiple SFEs. Furthermore, T-SCEs were more often detected in ES cells than in splenocytes that harbored a similar frequency of SFEs. In mTert heterozygous (mTert +/-) ES cells or splenocytes, which are known to exhibit a decrease in average telomere length but no SFEs, no increase in T-SCE was observed. In addition to T-SCE, other genomic rearrangements (i.e., SCE) were also significantly increased in mTert -/- ES cells possessing critically short telomeres, but not in splenocytes. Our results suggest that animals and cell culture differ in their ability to carry out genomic rearrangements as a means of maintaining telomere integrity when telomeres become critically shortened.

  18. Alternative lengthening of telomeres in normal mammalian somatic cells

    OpenAIRE

    Neumann, Axel A.; Watson, Catherine M.; Noble, Jane R.; Hilda A Pickett; Tam, Patrick P.L.; Reddel, Roger R

    2013-01-01

    Alternative lengthening of telomeres (ALT), a mechanism involving the replication of new telomeric DNA from a DNA template, is used by some cancer cells to lengthen their telomeres. Reddel and colleagues now show that ALT activity exists in normal somatic tissues as well. A telomere with a DNA tag is found to be intertelomerically copied in normal somatic cells but not germline cells, providing important implications for understanding telomere maintenance and its evolution.

  19. Interchromosomal Homology Searches Drive Directional ALT Telomere Movement and Synapsis

    OpenAIRE

    Cho, Nam Woo; Dilley, Robert L.; Lampson, Michael A.; Greenberg, Roger A.

    2014-01-01

    Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, approximately 10-15% employ a recombination-dependent telomere maintenance pathway known as Alternative Lengthening of Telomeres (ALT) that is characterized by multi-telomere clusters and associated promyelocytic leukemia protein bodies. Here, we show that a DNA double-strand break (DSB) response at ALT telomeres triggers long-ran...

  20. Telomere Length Reprogramming in Embryos and Stem Cells

    OpenAIRE

    Keri Kalmbach; LeRoy G. Robinson; Fang Wang; Lin Liu; David Keefe

    2014-01-01

    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 re...

  1. RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells

    OpenAIRE

    Arora, Rajika; Lee, Yongwoo; Wischnewski, Harry; Brun, Catherine M.; Schwarz, Tobias; Azzalin, Claus M.

    2014-01-01

    A fraction of cancer cells maintain telomeres through the telomerase-independent, ‘Alternative Lengthening of Telomeres’ (ALT) pathway. ALT relies on homologous recombination (HR) between telomeric sequences; yet, what makes ALT telomeres recombinogenic remains unclear. Here we show that the RNA endonuclease RNaseH1 regulates the levels of RNA–DNA hybrids between telomeric DNA and the long noncoding RNA TERRA, and is a key mediator of telomere maintenance in ALT cells. RNaseH1 associated to t...

  2. Long Telomeres are Preferentially Extended During Recombination-Mediated Telomere Maintenance

    OpenAIRE

    Chang, Michael; Dittmar, John C; Rothstein, Rodney

    2011-01-01

    Most human somatic cells do not express telomerase. Consequently, with each cell division their telomeres progressively shorten until replicative senescence is induced. Approximately 15% of human cancers maintain their telomeres using telomerase-independent, recombination-based mechanisms collectively termed Alternative Lengthening of Telomeres (ALT). In the yeast Saccharomyces cerevisiae, ALT cells are referred to as “survivors”. One type of survivor (type II) resembles human ALT cells in th...

  3. Reduced Fetal Telomere Length in Gestational Diabetes

    OpenAIRE

    Xu, Jian; Ye, Junyi; Wu, Yanting; Zhang, Hong; Luo, Qiong; Han, Cong; Ye, Xiaoqun; Wang, Hanzhi; Jing HE; Huang, Hefeng; Liu, Yun; Dong, Minyue

    2014-01-01

    Gestational diabetes mellitus (GDM) is an important complication of pregnancy that poses significant threats to women and their offspring. Telomere length shortens as cellular damage increases and is associated with metabolic diseases. Telomere length in fetal leucocytes was determined in 82 infants of women with GDM (N = 82) and 65 normal pregnant women (N = 65). Women with preeclampsia (N = 45) and gestational hypertension (N = 23) were also studied. In the GDM group, telomere length was si...

  4. Selective recognition and stabilization of new ligands targeting the potassium form of the human telomeric G-quadruplex DNA

    Science.gov (United States)

    Lin, Yi-Hwa; Chuang, Show-Mei; Wu, Pei-Ching; Chen, Chun-Liang; Jeyachandran, Sivakamavalli; Lo, Shou-Chen; Huang, Hsu-Shan; Hou, Ming-Hon

    2016-01-01

    The development of a ligand that is capable of distinguishing among the wide variety of G-quadruplex structures and targeting telomeres to treat cancer is particularly challenging. In this study, the ability of two anthraquinone telomerase inhibitors (NSC749235 and NSC764638) to target telomeric G-quadruplex DNA was probed. We found that these ligands specifically target the potassium form of telomeric G-quadruplex DNA over the DNA counterpart. The characteristic interaction with the telomeric G-quadruplex DNA and the anticancer activities of these ligands were also explored. The results of this present work emphasize our understanding of the binding selectivity of anthraquinone derivatives to G-quadruplex DNA and assists in future drug development for G-quadruplex-specific ligands. PMID:27511133

  5. Ataxia telangiectasia mutated (Atm) is not required for telomerase-mediated elongation of short telomeres

    OpenAIRE

    Feldser, David; Strong, Margaret A.; Greider, Carol W

    2006-01-01

    Telomerase-mediated telomere addition counteracts telomere shortening due to incomplete DNA replication. Short telomeres are the preferred substrate for telomere addition by telomerase; however, the mechanism by which telomerase recognizes short telomeres is unclear. In yeast, the Ataxia telangiectasia mutated (Atm) homolog, Tel1, is necessary for normal telomere length regulation likely by altering telomere structure, allowing telomerase recruitment to short telomeres. To examine the role of...

  6. A preclinical mouse model of glioma with an alternative mechanism of telomere maintenance (ALT).

    Science.gov (United States)

    Jeitany, Maya; Pineda, Jose Ramon; Liu, Qingyuan; Porreca, Rosa Maria; Hoffschir, Françoise; Desmaze, Chantal; Silvestre, David C; Mailliet, Patrick; Junier, Marie-Pierre; Londoño-Vallejo, Arturo; Ségal-Bendirdjian, Evelyne; Chneiweiss, Hervé; Boussin, François D

    2015-04-01

    Glioblastoma multiforme is the most aggressive primary tumor of the central nervous system. Glioma stem cells (GSCs), a small population of tumor cells with stem-like properties, are supposedly responsible for glioblastoma multiforme relapse after current therapies. In approximately thirty percent of glioblastoma multiforme tumors, telomeres are not maintained by telomerase but through an alternative mechanism, termed alternative lengthening of telomere (ALT), suggesting potential interest in developing specific therapeutic strategies. However, no preclinical model of ALT glioma was available until the isolation of TG20 cells from a human ALT glioma. Herein, we show that TG20 cells exhibit a high level of telomeric recombination but a stable karyotype, indicating that their telomeres retain their protective function against chromosomal instability. TG20 cells possess all of the characteristic features of GSCs: the expression of neural stem cell markers, the generation of intracerebral tumors in NOD-SCID-IL2Rγ (NSG) mice as well as in nude mice, and the ability to sustain serial intracerebral transplantations without expressing telomerase, demonstrating the stability of the ALT phenotype in vivo. Furthermore, we also demonstrate that 360B, a G-quadruplex ligand of the pyridine derivative series that impairs telomere replication and mitotic progression in cancer cells, prevents the development of TG20 tumors. Together, our results show that intracerebral grafts of TG20 cells in immunodeficient mice constitute an efficient preclinical model of ALT glioblastoma multiforme and that G-quadruplex ligands are a potential therapy for this specific type of tumor. PMID:25175359

  7. The telomere bouquet regulates meiotic centromere assembly.

    Science.gov (United States)

    Klutstein, Michael; Fennell, Alex; Fernández-Álvarez, Alfonso; Cooper, Julia Promisel

    2015-04-01

    The role of the conserved meiotic telomere bouquet has been enigmatic for over a century. We showed previously that disruption of the fission yeast bouquet impairs spindle formation in approximately half of meiotic cells. Surprisingly, bouquet-deficient meiocytes with functional spindles harbour chromosomes that fail to achieve spindle attachment. Kinetochore proteins and the centromeric histone H3 variant Cnp1 fail to localize to those centromeres that exhibit spindle attachment defects in the bouquet's absence. The HP1 orthologue Swi6 also fails to bind these centromeres, suggesting that compromised pericentromeric heterochromatin underlies the kinetochore defects. We find that centromeres are prone to disassembly during meiosis, but this is reversed by localization of centromeres to the telomere-proximal microenvironment, which is conducive to heterochromatin formation and centromere reassembly. Accordingly, artificially tethering a centromere to a telomere rescues the tethered centromere but not other centromeres. These results reveal an unanticipated level of control of centromeres by telomeres. PMID:25774833

  8. Frequent changes in subtelomeric DNA methylation patterns and its relevance to telomere regulation during human hepatocarcinogenesis.

    Science.gov (United States)

    Oh, Bong-Kyeong; Um, Tae-Hee; Choi, Gi Hong; Park, Young Nyun

    2011-02-15

    Subtelomeric chromatin modifications are important regulators of telomere length. We examined the subtelomeric DNA methylation status of 7q, 8q, 17q, 18p, 21q and XpYp in 32 pairs of hepatocellular carcinomas (HCCs) and their adjacent non-HCCs via methylation-specific PCR (quantified as methylation ratio). In addition, 10q was subjected to bisulfite-genomic-sequencing. Telomere length was determined by Southern hybridization. In all cases, the relationship between methylation ratio and telomere length was determined. High levels of methylation ratio were found on chromosomes 7q, 18p and XpYp, whereas 8q 17q and 21q were less methylated in both HCCs and non-HCCs. Compared to non-HCCs, HCCs exhibited a higher methylation ratio on 18p and 21q, and a wider distribution of methylation ratio on 7q, 21q and 10q (p telomere length of HCCs, respectively (p HCC to HCC were found at 47 sites and hypomethylation changes at 31 sites. Changes in methylation pattern were observed at three to four sites among six chromosomal sites in 15 patients (47%). There was a tendency toward hypomethylation changes at 7q (p = 0.013) and hypermethylation changes at 21q (p = 0.057) when telomere lengthened from non-HCCs to HCCs. In summary, subtelomeric methylation patterns dynamically changed during hepatocarcinogenesis. Subtelomeric methylation at certain regions was related to telomere lengthening or shortening, suggesting an association between subtelomeric chromatin structure and telomere length regulation in human hepatocarcinogenesis. PMID:20473888

  9. Loss of Wild-Type ATRX Expression in Somatic Cell Hybrids Segregates with Activation of Alternative Lengthening of Telomeres

    OpenAIRE

    Kylie Bower; Napier, Christine E.; Cole, Sara L.; Dagg, Rebecca A.; Lau, Loretta M. S.; Duncan, Emma L; Moy, Elsa L.; Reddel, Roger R

    2012-01-01

    Alternative Lengthening of Telomeres (ALT) is a non-telomerase mechanism of telomere lengthening that occurs in about 10% of cancers overall and is particularly common in astrocytic brain tumors and specific types of sarcomas. Somatic cell hybridization analyses have previously shown that normal telomerase-negative fibroblasts and telomerase-positive immortalized cell lines contain repressors of ALT activity, indicating that activation of ALT results from loss of one or more unidentified repr...

  10. The G-quadruplex ligand telomestatin impairs binding of topoisomerase IIIalpha to G-quadruplex-forming oligonucleotides and uncaps telomeres in ALT cells.

    Directory of Open Access Journals (Sweden)

    Nassima Temime-Smaali

    Full Text Available In Alternative Lengthening of Telomeres (ALT cell lines, specific nuclear bodies called APBs (ALT-associated PML bodies concentrate telomeric DNA, shelterin components and recombination factors associated with telomere recombination. Topoisomerase IIIalpha (Topo III is an essential telomeric-associated factor in ALT cells. We show here that the binding of Topo III to telomeric G-overhang is modulated by G-quadruplex formation. Topo III binding to G-quadruplex-forming oligonucleotides was strongly inhibited by telomestatin, a potent and specific G-quadruplex ligand. In ALT cells, telomestatin treatment resulted in the depletion of the Topo III/BLM/TRF2 complex and the disruption of APBs and led to the segregation of PML, shelterin components and Topo III. Interestingly, a DNA damage response was observed at telomeres in telomestatin-treated cells. These data indicate the importance of G-quadruplex stabilization during telomere maintenance in ALT cells. The function of TRF2/Topo III/BLM in the resolution of replication intermediates at telomeres is discussed.

  11. Telomere lengthening to antagonize myocardial aging

    OpenAIRE

    Cottage, Christopher Travis

    2012-01-01

    Aging is associated with onset and progression of cardiovascular disease resulting from changes at both cellular and molecular levels. Accumulation of senescent cells in the myocardium has been implicated in deterioration of hemodynamic performance and impaired reparative processes. Cellular senescence can be linked to oxidative stress and repeated cellular divisions, both of which lead to telomeric shortening. Telomeres are the distal ends of chromosomes that consist of nucleotide repeats th...

  12. Chromatid interchanges at intrachromosomal telomeric DNA sequences

    International Nuclear Information System (INIS)

    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)

  13. [Telomere Recombination in Normal Mammalian Cells].

    Science.gov (United States)

    Zhdanova, N S; Rubtsov, N B

    2016-01-01

    Two mechanisms of telomere length maintenance are known to date. The first includes the use of a special enzymatic telomerase complex to solve the problems that arise during the replication of linear DNA in a normal diploid and part of tumor cells. Alternative lengthening of telomeres (ALT), which is based on the homologous recombination of telomere DNA, represents the second mechanism. Until recently, ALT was assumed to be expressed only in 15-20% of tumors lacking active telomerase and, together with telomerase reactivation represented one of two possibilities to overcome the replicative senescence observed in somatic mammalian cells due to aging or during cell culturing in vitro. Previously described sporadic cases of combinations of the two mechanisms of telomere length maintenance in several cell lines in vitro were attributed to the experimental design rather than to a real biological phenomenon, since active cellular division without active telomerase was considered to be the "gold standard" of ALT. The present review describes the morphological and functional reorganizations of mammalian telomeres observed with ALT activation, as well as recently observed,and well-documented cases of combinations between ALT-like and telomerase-dependent mechanisms in mammalian cells. The possible role of telomere recombination in telomerase-dependent cells is discussed. PMID:27183789

  14. Telomere--the twilight to immortality.

    Science.gov (United States)

    Shukla, Samarth; Acharya, Sourya; Rajput, Devendra; Vagha, S; Grover, Shobha

    2010-09-01

    Besides forming a very important component of the chromosome, the telomeres have extremely significant modes of action and functions, right from maintaining a basic infrastructure and integrity of the chromosome vis a vis the other chromosomes, telomeres are responsible for the cell divisions and replicative senescence of the cell. The number of mitotic divisions which a cell will go through in its life span while passing through the cell cycle is governed inturn by these telomeres, the crux of the entire functioning of these chromosomal components suggests that they are the ticking clocks of the cell and when they diminish or are worn out so does the cell reach it's senility at the fag end of it's replicative life--resulting fate being--the cell is sent to it's grave yard (the final destination). Clinical implications include--regulation of cell life spans, regulating the cell's replicative behavior and it's utility in forming cells which usually are impossible to divide or replicate, telomeres regulate the cloning process,the telomeres play a major role in predicting the fate of a neoplastic cell and finally enhancing the life span of a single cell, the organ, the body as a whole by enzymes which expand the telomeres--the telomerase. PMID:21391375

  15. Conventional anticancer therapeutics and telomere maintenance mechanisms.

    Science.gov (United States)

    Uziel, Orit; Lahav, Meir

    2014-01-01

    The telomere-telomerase system has a unique role in the biology of cancer. Telomere maintenance, mostly affected by the up regulation of telomerase activity, is a prerequisite for perpetuation of malignant cells. This fundamental biologic feature defines telomere maintenance as an attractive therapeutic target for most types of cancer. This review summarizes some critical aspects of telomere biology with special emphasis on the connection to anticancer therapy. In particular, the effects on the telomere - telomerase system of conventional anticancer treatments, including various cytotoxic drugs, targeted biological agents and radiotherapy, and their possible combination with telomerase-directed therapy are discussed. Several potential problems, including side effects and complications inherent to perturbations of telomere biology in normal cells, are also highlighted. In spite of significant progress in this field, there are still several issues that have to be addressed and ultimately resolved in order to obtain a better characterization of the pros and cons of telomerase-directed therapies and, consequently, their clinical relevance. PMID:24975606

  16. Unique C. elegans telomeric overhang structures reveal the evolutionarily conserved properties of telomeric DNA.

    Science.gov (United States)

    Školáková, Petra; Foldynová-Trantírková, Silvie; Bednářová, Klára; Fiala, Radovan; Vorlíčková, Michaela; Trantírek, Lukáš

    2015-05-19

    There are two basic mechanisms that are associated with the maintenance of the telomere length, which endows cancer cells with unlimited proliferative potential. One mechanism, referred to as alternative lengthening of telomeres (ALT), accounts for approximately 10-15% of all human cancers. Tumours engaged in the ALT pathway are characterised by the presence of the single stranded 5'-C-rich telomeric overhang (C-overhang). This recently identified hallmark of ALT cancers distinguishes them from healthy tissues and renders the C-overhang as a clear target for anticancer therapy. We analysed structures of the 5'-C-rich and 3'-G-rich telomeric overhangs from human and Caenorhabditis elegans, the recently established multicellular in vivo model of ALT tumours. We show that the telomeric DNA from C. elegans and humans forms fundamentally different secondary structures. The unique structural characteristics of C. elegans telomeric DNA that are distinct not only from those of humans but also from those of other multicellular eukaryotes allowed us to identify evolutionarily conserved properties of telomeric DNA. Differences in structural organisation of the telomeric DNA between the C. elegans and human impose limitations on the use of the C. elegans as an ALT tumour model. PMID:25855805

  17. Multicolor FISH analysis of rDNA and telomere on spinach

    Institute of Scientific and Technical Information of China (English)

    Tianying LAN; Bo LIU; Fengping DONG; Ruiyang CHEN; Xiulan LI; Chengbin CHEN

    2008-01-01

    In this study,multicolor fluorescence in situ hybridization (FISH) analysis on metaphase chromosomes of spinach with biotin-labeled 25S rDNA,DIG-labeled telomere sequences and biotin-labeled and DIG-labeled 5S rDNA was performed.There were six 25S rDNA loci located on the satellites of the third,the fifth and the sixth chromosomes,and four 5S rDNA loci located on the long arms of the third and the fifth chromosomes.The telomere loci were located on the end of the sixth chromosome and also on both the end and centromeric regions of other chromosomes.This study is an important complement to both traditional karyotype analysis and FISH karyotype analysis in spinach.

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

    Science.gov (United States)

    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

  19. Disrupted lymphocyte homeostasis in hepatitis-associated acquired aplastic anemia is associated with short telomeres.

    Science.gov (United States)

    Babushok, Daria V; Grignon, Anne-Laure; Li, Yimei; Atienza, Jamie; Xie, Hongbo M; Lam, Ho-Sun; Hartung, Helge; Bessler, Monica; Olson, Timothy S

    2016-02-01

    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. PMID:26615915

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

    Science.gov (United States)

    Bender, Hannah S; Murchison, Elizabeth P; Pickett, Hilda A; Deakin, Janine E; Strong, Margaret A; Conlan, Carly; McMillan, Daniel A; Neumann, Axel A; Greider, Carol W; Hannon, Gregory J; Reddel, Roger R; Graves, Jennifer A Marshall

    2012-01-01

    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. PMID:23049977

  1. 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.

  2. Mice with Pulmonary Fibrosis Driven by Telomere Dysfunction

    Directory of Open Access Journals (Sweden)

    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.

  3. SMARCAL1 Resolves Replication Stress at ALT Telomeres.

    Science.gov (United States)

    Cox, Kelli E; Maréchal, Alexandre; Flynn, Rachel Litman

    2016-02-01

    Cancer cells overcome replicative senescence by exploiting mechanisms of telomere elongation, a process often accomplished by reactivation of the enzyme telomerase. However, a subset of cancer cells lack telomerase activity and rely on the alternative lengthening of telomeres (ALT) pathway, a recombination-based mechanism of telomere elongation. Although the mechanisms regulating ALT are not fully defined, chronic replication stress at telomeres might prime these fragile regions for recombination. Here, we demonstrate that the replication stress response protein SMARCAL1 is a critical regulator of ALT activity. SMARCAL1 associates with ALT telomeres to resolve replication stress and ensure telomere stability. In the absence of SMARCAL1, persistently stalled replication forks at ALT telomeres deteriorate into DNA double-strand breaks promoting the formation of chromosome fusions. Our studies not only define a role for SMARCAL1 in ALT telomere maintenance, but also demonstrate that resolution of replication stress is a crucial step in the ALT mechanism. PMID:26832416

  4. SMARCAL1 Resolves Replication Stress at ALT Telomeres

    Directory of Open Access Journals (Sweden)

    Kelli E. Cox

    2016-02-01

    Full Text Available Cancer cells overcome replicative senescence by exploiting mechanisms of telomere elongation, a process often accomplished by reactivation of the enzyme telomerase. However, a subset of cancer cells lack telomerase activity and rely on the alternative lengthening of telomeres (ALT pathway, a recombination-based mechanism of telomere elongation. Although the mechanisms regulating ALT are not fully defined, chronic replication stress at telomeres might prime these fragile regions for recombination. Here, we demonstrate that the replication stress response protein SMARCAL1 is a critical regulator of ALT activity. SMARCAL1 associates with ALT telomeres to resolve replication stress and ensure telomere stability. In the absence of SMARCAL1, persistently stalled replication forks at ALT telomeres deteriorate into DNA double-strand breaks promoting the formation of chromosome fusions. Our studies not only define a role for SMARCAL1 in ALT telomere maintenance, but also demonstrate that resolution of replication stress is a crucial step in the ALT mechanism.

  5. Spectroscopic investigation on the telomeric DNA base sequence repeat

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Telomeres are protein-DNA complexes at the terminals of linear chromosomes, which protect chromosomal integrity and maintain cellular replicative capacity.From single-cell organisms to advanced animals and plants,structures and functions of telomeres are both very conservative. In cells of human and vertebral animals, telomeric DNA base sequences all are (TTAGGG)n. In the present work, we have obtained absorption and fluorescence spectra measured from seven synthesized oligonucleotides to simulate the telomeric DNA system and calculated their relative fluorescence quantum yields on which not only telomeric DNA characteristics are predicted but also possibly the shortened telomeric sequences during cell division are imrelative fluorescence quantum yield and remarkable excitation energy innerconversion, which tallies with the telomeric sequence of (TTAGGG)n. This result shows that telomeric DNA has a strong non-radiative or innerconvertible capability.``

  6. Localization-Dependent and -Independent Roles of SLX4 in Regulating Telomeres

    OpenAIRE

    Jamie S.J. Wilson; Agueda M. Tejera; Dennis Castor; Rachel Toth; Maria A. Blasco; John Rouse

    2013-01-01

    Summary SLX4, a scaffold for structure-specific DNA repair nucleases, is important for several types of DNA repair. Many repair proteins bind to sites of DNA damage, resulting in subnuclear “foci,” but SLX4 forms foci in human cells even without DNA damage. Using several approaches, we show that most, but not all, SLX4 foci localize to telomeres in a range of human cell lines irrespective of the mechanisms used to maintain telomere length. The SLX1 Holliday-junction-processing enzyme is recru...

  7. 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

  8. Telomeres, Early-Life Stress and Mental Illness

    OpenAIRE

    Ridout, Samuel J.; Ridout, Kathryn K.; Kao, Hung-Teh; Carpenter, Linda L.; Philip, Noah S.; Tyrka, Audrey R.; Price, Lawrence H.

    2015-01-01

    Telomeres are structures of tandem TTAGGG repeats at the ends of chromosomes which preserve the encoding DNA by serving as a disposable brake to terminate DNA duplication during chromosome replication. In this process, the telomere itself shortens with each cell division, and can consequently be thought of as a cellular “clock” reflecting the age of a cell and the time until senescence. Telomere shortening, and changes in levels of telomerase, the enzyme that maintains telomeres, occur in the...

  9. Telomere reprogramming and maintenance in porcine iPS cells.

    Directory of Open Access Journals (Sweden)

    Guangzhen Ji

    Full Text Available Telomere reprogramming and silencing of exogenous genes have been demonstrated in mouse and human induced pluripotent stem cells (iPS cells. Pigs have the potential to provide xenotransplant for humans, and to model and test human diseases. We investigated the telomere length and maintenance in porcine iPS cells generated and cultured under various conditions. Telomere lengths vary among different porcine iPS cell lines, some with telomere elongation and maintenance, and others telomere shortening. Porcine iPS cells with sufficient telomere length maintenance show the ability to differentiate in vivo by teratoma formation test. IPS cells with short or dysfunctional telomeres exhibit reduced ability to form teratomas. Moreover, insufficient telomerase and incomplete telomere reprogramming and/or maintenance link to sustained activation of exogenous genes in porcine iPS cells. In contrast, porcine iPS cells with reduced expression of exogenous genes or partial exogene silencing exhibit insufficient activation of endogenous pluripotent genes and telomerase genes, accompanied by telomere shortening with increasing passages. Moreover, telomere doublets, telomere sister chromatid exchanges and t-circles that presumably are involved in telomere lengthening by recombination also are found in porcine iPS cells. These data suggest that both telomerase-dependent and telomerase-independent mechanisms are involved in telomere reprogramming during induction and passages of porcine iPS cells, but these are insufficient, resulting in increased telomere damage and shortening, and chromosomal instability. Active exogenes might compensate for insufficient activation of endogenous genes and incomplete telomere reprogramming and maintenance of porcine iPS cells. Further understanding of telomere reprogramming and maintenance may help improve the quality of porcine iPS cells.

  10. Swi1Timeless Prevents Repeat Instability at Fission Yeast Telomeres.

    Science.gov (United States)

    Gadaleta, Mariana C; Das, Mukund M; Tanizawa, Hideki; Chang, Ya-Ting; Noma, Ken-ichi; Nakamura, Toru M; Noguchi, Eishi

    2016-03-01

    Genomic instability associated with DNA replication stress is linked to cancer and genetic pathologies in humans. If not properly regulated, replication stress, such as fork stalling and collapse, can be induced at natural replication impediments present throughout the genome. The fork protection complex (FPC) is thought to play a critical role in stabilizing stalled replication forks at several known replication barriers including eukaryotic rDNA genes and the fission yeast mating-type locus. However, little is known about the role of the FPC at other natural impediments including telomeres. Telomeres are considered to be difficult to replicate due to the presence of repetitive GT-rich sequences and telomere-binding proteins. However, the regulatory mechanism that ensures telomere replication is not fully understood. Here, we report the role of the fission yeast Swi1(Timeless), a subunit of the FPC, in telomere replication. Loss of Swi1 causes telomere shortening in a telomerase-independent manner. Our epistasis analyses suggest that heterochromatin and telomere-binding proteins are not major impediments for telomere replication in the absence of Swi1. Instead, repetitive DNA sequences impair telomere integrity in swi1Δ mutant cells, leading to the loss of repeat DNA. In the absence of Swi1, telomere shortening is accompanied with an increased recruitment of Rad52 recombinase and more frequent amplification of telomere/subtelomeres, reminiscent of tumor cells that utilize the alternative lengthening of telomeres pathway (ALT) to maintain telomeres. These results suggest that Swi1 ensures telomere replication by suppressing recombination and repeat instability at telomeres. Our studies may also be relevant in understanding the potential role of Swi1(Timeless) in regulation of telomere stability in cancer cells. PMID:26990647

  11. Swi1Timeless Prevents Repeat Instability at Fission Yeast Telomeres.

    Directory of Open Access Journals (Sweden)

    Mariana C Gadaleta

    2016-03-01

    Full Text Available Genomic instability associated with DNA replication stress is linked to cancer and genetic pathologies in humans. If not properly regulated, replication stress, such as fork stalling and collapse, can be induced at natural replication impediments present throughout the genome. The fork protection complex (FPC is thought to play a critical role in stabilizing stalled replication forks at several known replication barriers including eukaryotic rDNA genes and the fission yeast mating-type locus. However, little is known about the role of the FPC at other natural impediments including telomeres. Telomeres are considered to be difficult to replicate due to the presence of repetitive GT-rich sequences and telomere-binding proteins. However, the regulatory mechanism that ensures telomere replication is not fully understood. Here, we report the role of the fission yeast Swi1(Timeless, a subunit of the FPC, in telomere replication. Loss of Swi1 causes telomere shortening in a telomerase-independent manner. Our epistasis analyses suggest that heterochromatin and telomere-binding proteins are not major impediments for telomere replication in the absence of Swi1. Instead, repetitive DNA sequences impair telomere integrity in swi1Δ mutant cells, leading to the loss of repeat DNA. In the absence of Swi1, telomere shortening is accompanied with an increased recruitment of Rad52 recombinase and more frequent amplification of telomere/subtelomeres, reminiscent of tumor cells that utilize the alternative lengthening of telomeres pathway (ALT to maintain telomeres. These results suggest that Swi1 ensures telomere replication by suppressing recombination and repeat instability at telomeres. Our studies may also be relevant in understanding the potential role of Swi1(Timeless in regulation of telomere stability in cancer cells.

  12. SMARCAL1 Resolves Replication Stress at ALT Telomeres

    OpenAIRE

    Kelli E. Cox; Alexandre Maréchal; Rachel Litman Flynn

    2016-01-01

    Cancer cells overcome replicative senescence by exploiting mechanisms of telomere elongation, a process often accomplished by reactivation of the enzyme telomerase. However, a subset of cancer cells lack telomerase activity and rely on the alternative lengthening of telomeres (ALT) pathway, a recombination-based mechanism of telomere elongation. Although the mechanisms regulating ALT are not fully defined, chronic replication stress at telomeres might prime these fragile regions for recombina...

  13. Drug addiction is associated with leukocyte telomere length

    OpenAIRE

    Yang, Zhaoyang; Ye, Junyi; Li, Candong; Zhou, Daizhan; Shen, Qin; Wu, Ji; Cao, Lan; Wang, Ting; Cui, Daxiang; He, Shigang; Qi, Guoyang; He, Lin; Liu, Yun

    2013-01-01

    Telomeres are protective chromosomal structures that play a key role in preserving genomic stability. Telomere length is known to be associated with ageing and age-related diseases. To study the impairment of telomeres induced by drug abuse, we conducted an association study in the Chinese Han population. Multivariate linear regression analyses were performed to evaluate the correlation of leukocyte telomere length (LTL) with addiction control status adjusted for age and gender. The results s...

  14. Alternative mechanisms of telomere lengthening: Permissive mutations, DNA repair proteins and tumorigenic progression

    Energy Technology Data Exchange (ETDEWEB)

    Gocha, April Renee Sandy; Harris, Julia [Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, OH 43210 (United States); Groden, Joanna, E-mail: joanna.groden@osumc.edu [Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, OH 43210 (United States)

    2013-03-15

    Highlights: ► Neoplastic cells maintain telomeres by telomerase or ALT. ► Genetic mutations in p53, ATRX, DAXX or H3F3A may activate ALT. ► Many DNA repair proteins are involved in ALT. ► Tumor progression is favored by telomerase expression. - Abstract: Telomeres protect chromosome termini to maintain genomic stability and regulate cellular lifespan. Maintenance of telomere length is required for neoplastic cells after the acquisition of mutations that deregulate cell cycle control and increase cellular proliferation, and can occur through expression of the enzyme telomerase or in a telomerase-independent manner termed alternative lengthening of telomeres (ALT). The precise mechanisms that govern the activation of ALT or telomerase in tumor cells are unknown, although cellular origin may favor one or the other mechanisms. ALT pathways are incompletely understood to date; however, recent publications have increasingly broadened our understanding of how ALT is activated, how it proceeds, and how it influences tumor growth. Specific mutational events influence ALT activation, as mutations in genes that suppress recombination and/or alterations in the regulation of telomerase expression are associated with ALT. Once engaged, ALT uses DNA repair proteins to maintain telomeres in the absence of telomerase; experiments that manipulate the expression of specific proteins in cells using ALT are illuminating some of its mechanisms. Furthermore, ALT may influence tumor growth, as experimental and clinical data suggest that telomerase expression may favor tumor progression. This review summarizes recent findings in mammalian cells and models, as well as clinical data, that identify the genetic mutations permissive to ALT, the DNA repair proteins involved in ALT mechanisms and the importance of telomere maintenance mechanisms for tumor progression. A comprehensive understanding of the mechanisms that permit tumor cell immortalization will be important for identifying

  15. Telomere Length Correlates with Life Span of Dog Breeds

    Directory of Open Access Journals (Sweden)

    Laura J. Fick

    2012-12-01

    Full Text Available Telomeric DNA repeats are lost as normal somatic cells replicate. When telomeres reach a critically short length, a DNA damage signal is initiated, inducing cell senescence. Some studies have indicated that telomere length correlates with mortality, suggesting that telomere length contributes to human life span; however, other studies report no correlation, and thus the issue remains controversial. Domestic dogs show parallels in telomere biology to humans, with similar telomere length, telomere attrition, and absence of somatic cell telomerase activity. Using this model, we find that peripheral blood mononuclear cell (PBMC telomere length is a strong predictor of average life span among 15 different breeds (p < 0.0001, consistent with telomeres playing a role in life span determination. Dogs lose telomeric DNA ∼10-fold faster than humans, which is similar to the ratio of average life spans between these species. Breeds with shorter mean telomere lengths show an increased probability of death from cardiovascular disease, which was previously correlated with short telomere length in humans.

  16. Telomere length in human liver diseases.

    Science.gov (United States)

    Urabe, Y; Nouso, K; Higashi, T; Nakatsukasa, H; Hino, N; Ashida, K; Kinugasa, N; Yoshida, K; Uematsu, S; Tsuji, T

    1996-10-01

    To determine the role of telomere-mediated gene stability in hepatocarcinogenesis, we examined the telomere length of human liver with or without chronic liver diseases and hepatocellular carcinomas (HCC). The mean telomere restriction fragment (TRF) length of normal liver (n = 13), chronic hepatitis (n = 11), liver cirrhosis (n = 24) and HCC (n = 24) was 7.8 +/- 0.2, 7.1 +/- 0.3, 6.4 +/- 0.2 and 5.2 +/- 0.2 kb, respectively (mean +/- standard error). TRF length decreased with a progression of chronic liver diseases and that in HCC was significantly shorter than that in other chronic liver diseases (p HCC to that of corresponding surrounding liver of well differentiated (n = 7), moderately differentiated (n = 10) and poorly differentiated (n = 4) HCCs were 0.83 +/- 0.06, 0.75 +/- 0.05 and 0.98 +/- 0.09, respectively. The ratio of poorly differentiated HCC was significantly higher than that of moderately differentiated HCC (p telomere length ratio of moderately differentiated HCCs revealed a decrease of the ratio with size until it reached 50 mm in diameter. In contrast, the ratio increased as the size enlarged over 50 mm. These findings suggest that the gene stability of the liver cells mediated by the telomere is reduced as chronic liver disease progresses and that telomerase is activated in poorly differentiated HCC and moderately differentiated HCC over 50 mm in diameter. PMID:8938628

  17. Telomere dysfunction and activation of alternative lengthening of telomeres in B-lymphocytes infected by Epstein–Barr virus

    OpenAIRE

    Kamranvar, S A; Chen, X; Masucci, M G

    2013-01-01

    Malignant cells achieve replicative immortality by two alternative mechanisms, a common one dependent on de novo synthesis of telomeric DNA by telomerase, and a rare one based on telomere recombination known as alternative lengthening of telomeres (ALT). Epstein–Barr virus (EBV) transforms human B-lymphocytes into lymphoblastoid cell lines with unlimited growth potential in vitro and in vivo. Here we show that newly EBV-infected cells exhibit multiple signs of telomere dysfunction, including ...

  18. Presence of alternative lengthening of telomeres associated circular extrachromosome telomere repeats in primary leukemia cells of chronic myeloid leukemia

    OpenAIRE

    Samassekou, Oumar; Malina, Abba; Hébert, Josée; Yan, Ju

    2013-01-01

    Background The predominant mechanism by which human tumors maintain telomere length is via telomerase. In ~10% of tumor samples, however, telomere length is conserved, despite no detectable telomerase activity, in part through activation of the alternative lengthening of telomeres (ALT) pathway. Methods We studied the circular extra-chromosomal telomeric repeat (ECTR), an ALT hallmark, and telomerase activity in 24 chronic myeloid leukemia (CML) patients in chronic phase (CP). Results We iden...

  19. TERRA-reinforced association of LSD1 with MRE11 promotes processing of uncapped telomeres

    OpenAIRE

    Antonio Porro; Sascha Feuerhahn; Joachim Lingner

    2014-01-01

    Telomeres protect chromosome ends from being recognized as sites of DNA damage. Upon telomere shortening or telomere uncapping induced by loss of telomeric repeat-binding factor 2 (TRF2), telomeres elicit a DNA-damage response leading to cellular senescence. Here, we show that following TRF2 depletion, the levels of the long noncoding RNA TERRA increase and LSD1, which binds TERRA, is recruited to telomeres. At uncapped telomeres, LSD1 associates with MRE11, one of the nucleases implicated in...

  20. Alternative Lengthening of Telomeres-An Enhanced Chromosomal Instability in Aggressive Non-MYCN Amplified and Telomere Elongated Neuroblastomas

    NARCIS (Netherlands)

    G. Lundberg; D. Sehic; J.K. Lansberg; I. Ora; A. Frigyesi; V. Castel; S. Navarro; M. Piqueras; T. Martinsson; R. Noguera; D. Gisselsson

    2011-01-01

    Telomere length alterations are known to cause genomic instability and influence clinical course in several tumor types, but have been little investigated in neuroblastoma (NB), one of the most common childhood tumors. In the present study, telomere-dependent chromosomal instability and telomere len

  1. 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.

  2. Suv4-20h deficiency results in telomere elongation and derepression of telomere recombination

    OpenAIRE

    Benetti, Roberta; Gonzalo, Susana; Jaco, Isabel; Schotta, Gunnar; Klatt, Peter; Jenuwein, Thomas; Blasco, María A.

    2007-01-01

    Mammalian telomeres have heterochromatic features, including trimethylated histone H3 at lysine 9 (H3K9me3) and trimethylated histone H4 at lysine 20 (H4K20me3). In addition, subtelomeric DNA is hypermethylated. The enzymatic activities responsible for these modifications at telomeres are beginning to be characterized. In particular, H4K20me3 at telomeres could be catalyzed by the novel Suv4-20h1 and Suv4-20h2 histone methyltransferases (HMTases). In this study, we demonstrate that the Suv4-2...

  3. Functional diversification of yeast telomere associated protein, Rif1, in higher eukaryotes

    Directory of Open Access Journals (Sweden)

    Sreesankar Easwaran

    2012-06-01

    Full Text Available Abstract Background Telomeres are nucleoprotein complexes at the end of linear eukaryotic chromosomes which maintain the genome integrity by regulating telomere length, preventing recombination and end to end fusion events. Multiple proteins associate with telomeres and function in concert to carry out these functions. Rap1 interacting factor 1 (Rif1, was identified as a protein involved in telomere length regulation in yeast. Rif1 is conserved upto mammals but its function has diversified from telomere length regulation to maintenance of genome integrity. Results We have carried out detailed bioinformatic analyses and identified Rif1 homologues in 92 organisms from yeast to human. We identified Rif1 homologues in Drosophila melanogaster, even though fly telomeres are maintained by a telomerase independent pathway. Our analysis shows that Drosophila Rif1 (dRif1 sequence is phylogenetically closer to the one of vertebrates than yeast and has identified a few Rif1 specific motifs conserved through evolution. This includes a Rif1 family specific conserved region within the HEAT repeat domain and a motif involved in protein phosphatase1 docking. We show that dRif1 is nuclear localized with a prominent heterochromatin association and unlike human Rif1, it does not respond to DNA damage by localizing to damaged sites. To test the evolutionary conservation of dRif1 function, we expressed the dRif1 protein in yeast and HeLa cells. In yeast, dRif1 did not perturb yeast Rif1 (yRif1 functions; and in HeLa cells it did not colocalize with DNA damage foci. Conclusions Telomeres are maintained by retrotransposons in all Drosophila species and consequently, telomerase and many of the telomere associated protein homologues are absent, including Rap1, which is the binding partner of Rif1. We found that a homologue of yRif1 protein is present in fly and dRif1 has evolutionarily conserved motifs. Functional studies show that dRif1 responds differently to DNA

  4. A cloned DNA segment from the telomeric region of human chromosome 4p is not detectably rearranged in Huntington disease patients.

    OpenAIRE

    Pritchard, C; Casher, D; Bull, L; Cox, D R; Myers, R.M.

    1990-01-01

    Genetic linkage studies have mapped the Huntington disease (HD) mutation to the distal region of the short arm of human chromosome 4. Analysis of recombination events in this region has produced contradictory locations for HD. One possible location is in the region distal to the D4S90 marker, which is located within 300 kilobases of the telomere. Other crossover events predict a more centromeric position for HD. Here we analyze the telomeric region of 4p in detail. Cloned DNA segments were de...

  5. Modulation of Telomeres in Alternative Lengthening of Telomeres Type I Like Human Cells by the Expression of Werner Protein and Telomerase

    OpenAIRE

    Aisha Siddiqa; David Cavazos; Jeffery Chavez; Linda Long; Marciniak, Robert A.

    2012-01-01

    The alternative lengthening of telomeres (ALT) is a recombination-based mechanism of telomere maintenance activated in 5–20% of human cancers. In Saccharomyces cerevisiae, survivors that arise after inactivation of telomerase can be classified as type I or type II ALT. In type I, telomeres have a tandem array structure, with each subunit consisting of a subtelomeric Y′ element and short telomere sequence. Telomeres in type II have only long telomere repeats and require Sgs1, the S. cerevisiae...

  6. Robotic arm

    Science.gov (United States)

    Kwech, Horst

    1989-04-18

    A robotic arm positionable within a nuclear vessel by access through a small diameter opening and having a mounting tube supported within the vessel and mounting a plurality of arm sections for movement lengthwise of the mounting tube as well as for movement out of a window provided in the wall of the mounting tube. An end effector, such as a grinding head or welding element, at an operating end of the robotic arm, can be located and operated within the nuclear vessel through movement derived from six different axes of motion provided by mounting and drive connections between arm sections of the robotic arm. The movements are achieved by operation of remotely-controllable servo motors, all of which are mounted at a control end of the robotic arm to be outside the nuclear vessel.

  7. Robotic arm

    International Nuclear Information System (INIS)

    A robotic arm positionable within a nuclear vessel by access through a small diameter opening and having a mounting tube supported within the vessel and mounting a plurality of arm sections for movement lengthwise of the mounting tube as well as for movement out of a window provided in the wall of the mounting tube is disclosed. An end effector, such as a grinding head or welding element, at an operating end of the robotic arm, can be located and operated within the nuclear vessel through movement derived from six different axes of motion provided by mounting and drive connections between arm sections of the robotic arm. The movements are achieved by operation of remotely-controllable servo motors, all of which are mounted at a control end of the robotic arm to be outside the nuclear vessel. 23 figs

  8. Actions of human telomerase beyond telomeres

    Institute of Scientific and Technical Information of China (English)

    Yusheng Cong; Jerry W Shay

    2008-01-01

    Telomerase has fundamental roles in bypassing cellular aging and in cancer progression by maintaining telomere homeostasis and integrity. However, recent studies have led some investigators to suggest novel biochemical properties of telomerase in several essential cell signaling pathways without apparent involvement of its well established function in telomere maintenance. These observations may further enhance our understanding of the molecular actions of telomerase in aging and cancer. This review will provide an update on the extracurricular activities of telomerase in apoptosis, DNA repair, stem cell function, and in the regulation of gene expression.

  9. The role of telomere dynamics in aging and cancer

    Science.gov (United States)

    Blagoev, Krastan; Goodwin, Edwin

    2006-03-01

    Telomere length changes are far more dynamic than previously thought. In addition to a gradual loss of ˜100 base pairs per telomere in each cell division, losses as well as gains may occur within a single cell cycle. We are investigating how telomere exchange, extension, and deletion affect the proliferative potential of telomerase-negative somatic cells. Experimental techniques are being devised to detect dynamic telomere processes and quantify both the frequency and length changes of each. In parallel, a ``dynamic telomere model'' is being used that incorporates telomere dynamics to study how the telomere size distribution evolves with time. This is an essential step towards understanding the role that telomere dynamics play in the normal aging of tissues and organisms. The model casts light on relationships not otherwise easily explained by a deterministic ``mitotic clock,'' or to what extent the shortest initial telomere determines the onset of senescence. We also expect to identify biomarkers that will correlate with aging better than average telomere length and to shed light on the transition to unlimited growth found in telomerase-negative tumor cells having the ALT (alternative lengthening of telomeres) phenotype, and to evaluate strategies to suppress the growth of these tumors.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Identification of Neuroblastoma Subgroups Based on Three-Dimensional Telomere Organization.

    Science.gov (United States)

    Kuzyk, Alexandra; Gartner, John; Mai, Sabine

    2016-08-01

    Using 3D telomere quantitative fluorescence in situ hybridization, we determined the 3D telomere organization of 74 neuroblastoma tissue samples. Hierarchical cluster analysis of the measured telomere parameters identified three subgroups from our patient cohort. These subgroups have unique telomere profiles based on telomere length and nuclear architecture. Subgroups with higher levels of telomere dysfunction were comprised of tumors with greater numbers of telomeres, telomeric aggregates, and short telomeres (Pcell lines with constitutively low MYCN expression induced changes in their telomere profile that were consistent with increased telomere dysfunction; this illustrates a functional relationship between MYCN and 3D telomere organization. This study demonstrates the ability to classify neuroblastomas based on the level of telomere dysfunction, which is a novel approach for this cancer. PMID:27567959

  12. TEL2, an essential gene required for telomere length regulation and telomere position effect in Saccharomyces cerevisiae.

    OpenAIRE

    Runge, K W; Zakian, V A

    1996-01-01

    The DNA-protein complexes at the ends of linear eukaryotic chromosomes are called the telomeres. In Saccharomyces cerevisiae, telomeric DNA consists of a variable length of the short repeated sequence C1-3A. The length of yeast telomeres can be altered by mutation, by changing the levels of telomere binding proteins, or by increasing the amount of C1-3A DNA sequences. Cells bearing the tel1-1 or tel2-1 mutations, known previously to have short telomeres, did not respond to perturbations that ...

  13. Shortened telomere length is associated with increased risk of cancer: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Hongxia Ma

    Full Text Available BACKGROUND: Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting. METHODS: A dataset composed of 11,255 cases and 13,101 controls from 21 publications was included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and the relative telomere length. Heterogeneity among studies and their publication bias were further assessed by the χ(2-based Q statistic test and Egger's test, respectively. RESULTS: The results showed that shorter telomeres were significantly associated with cancer risk (OR = 1.35, 95% CI = 1.14-1.60, compared with longer telomeres. In the stratified analysis by tumor type, the association remained significant in subgroups of bladder cancer (OR = 1.84, 95% CI = 1.38-2.44, lung cancer (OR = 2.39, 95% CI = 1.18-4.88, smoking-related cancers (OR = 2.25, 95% CI = 1.83-2.78, cancers in the digestive system (OR = 1.69, 95% CI = 1.53-1.87 and the urogenital system (OR = 1.73, 95% CI = 1.12-2.67. Furthermore, the results also indicated that the association between the relative telomere length and overall cancer risk was statistically significant in studies of Caucasian subjects, Asian subjects, retrospective designs, hospital-based controls and smaller sample sizes. Funnel plot and Egger's test suggested that there was no publication bias in the current meta-analysis (P = 0.532. CONCLUSIONS: The results of this meta-analysis suggest that the presence of shortened telomeres may be a marker for susceptibility to human cancer, but single larger, well-design prospective studies are warranted to confirm these findings.

  14. Telomere repeat binding proteins are functional components of Arabidopsis telomeres and interact with telomerase

    Czech Academy of Sciences Publication Activity Database

    Schrumpfová, P.; Vychodilová, I.; Dvořáčková, Martina; Majerská, J.; Dokládal, Ladislav; Schorová, Š.; Fajkus, Jiří

    2014-01-01

    Roč. 77, č. 5 (2014), s. 770-781. ISSN 0960-7412 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0068; GA ČR(CZ) GA13-06943S Institutional support: RVO:68081707 Keywords : telomere protein interaction * telomere repeat binding * Arabidopsis thaliana Subject RIV: BO - Biophysics Impact factor: 5.972, year: 2014

  15. ARSENIC EFFECTS ON TELOMERE AND TELOMERASE ACTIVITY

    Science.gov (United States)

    Arsenic effects on telomere and telomerase activity. T-C. Zhang, M. T. Schmitt, J. Mo, J. L. Mumford, National Research Council and U.S Environmental Protection Agency, NHEERL, Research Triangle Park, NC 27711Arsenic is a known carcinogen and also an anticancer agent for acut...

  16. A loopy view of telomere evolution

    Directory of Open Access Journals (Sweden)

    Titia eDe Lange

    2015-10-01

    Full Text Available About a decade ago, I proposed that t-loops, the lariat structures adopted by many eukaryotic telomeres, could explain how the transition from circular to linear chromosomes was successfully negotiated by early eukaryotes. Here I reconsider this loopy hypothesis in the context of the idea that eukaryotes evolved through a period of genome invasion by Group II introns.

  17. Expansion of Interstitial Telomeric Sequences in Yeast.

    Science.gov (United States)

    Aksenova, Anna Y; Han, Gil; Shishkin, Alexander A; Volkov, Kirill V; Mirkin, Sergei M

    2015-11-24

    Telomeric repeats located within chromosomes are called interstitial telomeric sequences (ITSs). They are polymorphic in length and are likely hotspots for initiation of chromosomal rearrangements that have been linked to human disease. Using our S. cerevisiae system to study repeat-mediated genome instability, we have previously shown that yeast telomeric (Ytel) repeats induce various gross chromosomal rearrangements (GCR) when their G-rich strands serve as the lagging strand template for replication (G orientation). Here, we show that interstitial Ytel repeats in the opposite C orientation prefer to expand rather than cause GCR. A tract of eight Ytel repeats expands at a rate of 4 × 10(-4) per replication, ranking them among the most expansion-prone DNA microsatellites. A candidate-based genetic analysis implicates both post-replication repair and homologous recombination pathways in the expansion process. We propose a model for Ytel repeat expansions and discuss its applications for genome instability and alternative telomere lengthening (ALT). PMID:26586439

  18. Twin correlations of telomere length metrics

    DEFF Research Database (Denmark)

    Hjelmborg, Jacob B; Dalgård, Christine; Möller, Sören;

    2015-01-01

    BACKGROUND: Leucocyte telomere length (LTL) is a complex trait associated with ageing and longevity. LTL dynamics are defined by LTL and its age-dependent attrition. Strong, but indirect evidence suggests that LTL at birth and its attrition during childhood largely explains interindividual LTL va...

  19. Quantitative dynamics of telomere bouquet formation.

    Directory of Open Access Journals (Sweden)

    David M Richards

    Full Text Available The mechanism by which homologous chromosomes pair during meiosis, as a prelude to recombination, has long been mysterious. At meiosis, the telomeres in many organisms attach to the nuclear envelope and move together to form the telomere bouquet, perhaps to facilitate the homologous search. It is believed that diffusion alone is not sufficient to account for the formation of the bouquet, and that some directed movement is also required. Here we consider the formation of the telomere bouquet in a wheat-rye hybrid both experimentally and using mathematical modelling. The large size of the wheat nucleus and wheat's commercial importance make chromosomal pairing in wheat a particularly interesting and important process, which may well shed light on pairing in other organisms. We show that, prior to bouquet formation, sister chromatid telomeres are always attached to a hemisphere of the nuclear membrane and tend to associate in pairs. We study a mutant lacking the Ph1 locus, a locus ensuring correct homologous chromosome pairing, and discover that bouquet formation is delayed in the wild type compared to the mutant. Further, we develop a mathematical model of bouquet formation involving diffusion and directed movement, where we show that directed movement alone is sufficient to explain bouquet formation dynamics.

  20. The telomere lengthening conundrum - artifact or biology?

    DEFF Research Database (Denmark)

    Steenstrup, Troels; Hjelmborg, Jacob V B; Kark, Jeremy D;

    2013-01-01

    Recent longitudinal studies of age-dependent leukocyte telomere length (LTL) attrition have reported that variable proportions of individuals experience LTL lengthening. Often, LTL lengthening has been taken at face value, and authors have speculated about the biological causation of this finding...

  1. Telomere homeostasis in mammalian germ cells: a review.

    Science.gov (United States)

    Reig-Viader, Rita; Garcia-Caldés, Montserrat; Ruiz-Herrera, Aurora

    2016-06-01

    Telomeres protect against genome instability and participate in chromosomal movements during gametogenesis, especially in meiosis. Thus, maintaining telomere structure and telomeric length is essential to both cell integrity and the production of germ cells. As a result, alteration of telomere homeostasis in the germ line may result in the generation of aneuploid gametes or gametogenesis disruption, triggering fertility problems. In this work, we provide an overview on fundamental aspects of the literature regarding the organization of telomeres in mammalian germ cells, paying special attention to telomere structure and function, as well as the maintenance of telomeric length during gametogenesis. Moreover, we discuss the different roles recently described for telomerase and TERRA in maintaining telomere functionality. Finally, we review how new findings in the field of reproductive biology underscore the role of telomere homeostasis as a potential biomarker for infertility. Overall, we anticipate that the study of telomere stability and equilibrium will contribute to improve diagnoses of patients; assess the risk of infertility in the offspring; and in turn, find new treatments. PMID:26525972

  2. Activity of telomerase and telomeric length in Apis mellifera.

    Science.gov (United States)

    Korandová, Michala; Frydrychová, Radmila Čapková

    2016-06-01

    Telomerase is an enzyme that adds repeats of DNA sequences to the ends of chromosomes, thereby preventing their shortening. Telomerase activity is associated with proliferative status of cells, organismal development, and aging. We report an analysis of telomerase activity and telomere length in the honeybee, Apis mellifera. Telomerase activity was found to be regulated in a development and caste-specific manner. During the development of somatic tissues of larval drones and workers, telomerase activity declined to 10 % of its level in embryos and remained low during pupal and adult stages but was upregulated in testes of late pupae, where it reached 70 % of the embryo level. Upregulation of telomerase activity was observed in the ovaries of late pupal queens, reaching 160 % of the level in embryos. Compared to workers and drones, queens displayed higher levels of telomerase activity. In the third larval instar of queens, telomerase activity reached the embryo level, and an enormous increase was observed in adult brains of queens, showing a 70-fold increase compared to a brain of an adult worker. Southern hybridization of terminal TTAGG fragments revealed a high variability of telomeric length between different individuals, although the same pattern of hybridization signals was observed in different tissues of each individual. PMID:26490169

  3. Conformational variability of recombination R-triplex formed by the mammalian telomeric sequence.

    Science.gov (United States)

    Shchyolkina, Anna K; Kaluzhny, Dmitry N; Borisova, Olga F; Arndt-Jovin, Donna J; Jovin, Thomas M; Zhurkin, Victor B

    2016-06-01

    Alignment of three nucleic acids strands, in which the third strand is identical to one of the DNA duplex strands, occurs in various cellular systems. In the case of telomeric t-loops, recognition between the DNA duplex and the homologous single strand is likely to be mediated by proteins through formation of the transient recombination-type R-triplex. Earlier, using 2-aminopurine as a fluorescent reporting base, we evaluated the thermodynamic characteristics of intramolecular R-triplex formed by a mixed nucleotide sequence. Here, we used this approach to explore a propensity of the telomeric TTAGGG repeat to form the R-triplex. The circular dichroism spectral changes detected upon formation of the R-triplex suggest that this process is accompanied by specific conformational changes in DNA, including a local destabilization of the target duplex next to a GGG run revealed by the fluorescence of the reporting 2-aminopurine base. Surprisingly, stability of the R-triplex formed by telomeric sequence depends strikingly on the counter ion, being higher for Na(+) than for Li(+). Taken together these findings indicate a significant conformational variability of telomeric DNA in the context of recombination-type R-triplex, a phenomenon of possible biological relevance. PMID:26308235

  4. Cryptic Translocation Identification in Human and Mouse using Several Telomeric Multiplex FISH (TM-FISH) Strategies

    Energy Technology Data Exchange (ETDEWEB)

    Henegariu, O; Artan, S; Greally, J M; Chen, X-N; Korenberg, J R; Vance, G H; Stubbs, L; Bray-Ward, P; Ward, D C

    2003-08-19

    Experimental data published in recent years showed that up to 10% of all cases with mild to severe idiopathic mental retardation may result from small rearrangements of the subtelomeric regions of human chromosomes. To detect such cryptic translocations, we developed a ''telomeric'' multiplex FISH assay, using a set of previously published and commercially available subtelomeric probes. This set of probes includes 41 cosmid/PAC/P1 clones located from less than 100kb to about 1 Mb from the end of the chromosomes. Similarly, a published mouse probe set, comprised of BACs hybridizing to the closest known marker toward the centromere and telomere of each mouse chromosome, was used to develop a mouse-specific ''telomeric'' M-FISH. Three different combinatorial labeling strategies were used to simultaneously detect all human sub-telomeric regions on one slide. The simplest approach uses only three fluors, and can be performed in laboratories lacking sophisticated imaging equipment or personnel highly trained in cytogenetics. A standard fluorescence microscope equipped with only three filters is sufficient. Fluor-dUTPs and labeled probes can be custom-made, thus dramatically reducing costs. Images can be prepared using generic imaging software (Adobe Photoshop), and analysis performed by simple visual inspection.

  5. Telomere Length, Telomerase Activity, and Replicative Potential in HIV Infection: Analysis of CD4+ and CD8+T Cells from HIV-discordant Monozygotic Twins

    OpenAIRE

    Palmer, Larry D.; Weng, Nan-ping; Levine, Bruce L.; June, Carl H; Lane, H. Clifford; Hodes, Richard J.

    1997-01-01

    To address the possible role of replicative senescence in human immunodeficiency virus (HIV) infection, telomere length, telomerase activity, and in vitro replicative capacity were assessed in peripheral blood T cells from HIV+ and HIV− donors. Genetic and age-specific effects on these parameters were controlled by studying HIV-discordant pairs of monozygotic twins. Telomere terminal restriction fragment (TRF) lengths from CD4+ T cells of HIV+ donors were significantly greater than those from...

  6. JBP2, a SWI2/SNF2-like protein, regulates de novo telomeric DNA glycosylation in bloodstream form Trypanosoma brucei.

    Science.gov (United States)

    Kieft, Rudo; Brand, Verena; Ekanayake, Dilrukshi K; Sweeney, Kate; DiPaolo, Courtney; Reznikoff, William S; Sabatini, Robert

    2007-11-01

    Synthesis of the modified thymine base, beta-d-glucosyl-hydroxymethyluracil or J, within telomeric DNA of Trypanosoma brucei correlates with the bloodstream form specific epigenetic silencing of telomeric variant surface glycoprotein genes involved in antigenic variation. In order to analyze the function of base J in the regulation of antigenic variation, we are characterizing the regulatory mechanism of J biosynthesis. We have recently proposed a model in which chromatin remodeling by a SWI2/SNF2-like protein (JBP2) regulates the developmental and de novo site-specific localization of J synthesis within bloodstream form trypanosome DNA. Consistent with this model, we now show that JBP2 (-/-) bloodstream form trypanosomes contain five-fold less base J and are unable to stimulate de novo J synthesis in newly generated telomeric arrays. PMID:17706299

  7. A cloned DNA segment from the telomeric region of human chromosome 4p is not detectably rearranged in Huntington disease patients.

    Science.gov (United States)

    Pritchard, C; Casher, D; Bull, L; Cox, D R; Myers, R M

    1990-09-01

    Genetic linkage studies have mapped the Huntington disease (HD) mutation to the distal region of the short arm of human chromosome 4. Analysis of recombination events in this region has produced contradictory locations for HD. One possible location is in the region distal to the D4S90 marker, which is located within 300 kilobases of the telomere. Other crossover events predict a more centromeric position for HD. Here we analyze the telomeric region of 4p in detail. Cloned DNA segments were derived from this region by utilizing a radiation-induced somatic cell hybrid as a source of DNA combined with preparative pulsed-field gel electrophoresis to enrich for the telomeric fraction. Additional DNA was obtained by using the cloned segments as multiple start points for cosmid walks. This strategy proved to be an effective method for cloning 250 kilobases of DNA in the region telomeric to D4S90. Hybridization analysis with the cloned DNA did not provide any evidence for the presence of rearrangements of 100 base pairs or greater in the DNA of individuals affected with HD. We also found no change in the size or structure of the 4p telomere in these samples. PMID:2144903

  8. The Pif1 Helicase, a Negative Regulator of Telomerase, Acts Preferentially at Long Telomeres

    OpenAIRE

    Jane A Phillips; Angela Chan; Katrin Paeschke; Zakian, Virginia A.

    2015-01-01

    Telomerase, the enzyme that maintains telomeres, preferentially lengthens short telomeres. The S. cerevisiae Pif1 DNA helicase inhibits both telomerase-mediated telomere lengthening and de novo telomere addition at double strand breaks (DSB). Here, we report that the association of the telomerase subunits Est2 and Est1 at a DSB was increased in the absence of Pif1, as it is at telomeres, suggesting that Pif1 suppresses de novo telomere addition by removing telomerase from the break. To determ...

  9. PML is required for telomere stability in non-neoplastic human cells

    OpenAIRE

    Marchesini, M.; Matocci, R; Tasselli, L; Cambiaghi, V; Orleth, A; Furia, L; Marinelli, C.; Lombardi, S.; Sammarelli, G; Aversa, F.; Minucci, S; Faretta, M; Pelicci, P.G.; Grignani, F

    2015-01-01

    Telomeres interact with numerous proteins, including components of the shelterin complex, whose alteration, similarly to proliferation-induced telomere shortening, initiates cellular senescence. In tumors, telomere length is maintained by Telomerase activity or by the Alternative Lengthening of Telomeres mechanism, whose hallmark is the telomeric localization of the promyelocytic leukemia (PML) protein. Whether PML contributes to telomeres maintenance in normal cells is unknown. We show that ...

  10. Distinct Roles of TRF1 in the Regulation of Telomere Structure and Lengthening*S⃞

    OpenAIRE

    Okamoto, Keiji; Iwano, Tomohiko; Tachibana, Makoto; Shinkai, Yoichi

    2008-01-01

    The telomere is a functional chromatin structure that consists of G-rich repetitive sequences and various associated proteins. Telomeres protect chromosomal ends from degradation, provide escape from the DNA damage response, and regulate telomere lengthening by telomerase. Multiple proteins that localize at telomeres form a complex called shelterin/telosome. One component, TRF1, is a double-stranded telomeric DNA binding protein. Inactivation of TRF1 disrupts telomeric...

  11. Variant repeats are interspersed throughout the telomeres and recruit nuclear receptors in ALT cells

    OpenAIRE

    Conomos, Dimitri; Stutz, Michael D.; Hills, Mark; Neumann, Axel A.; Bryan, Tracy M.; Reddel, Roger R; Hilda A Pickett

    2012-01-01

    Telomeres in cells that use the recombination-mediated alternative lengthening of telomeres (ALT) pathway elicit a DNA damage response that is partly independent of telomere length. We therefore investigated whether ALT telomeres contain structural abnormalities that contribute to ALT activity. Here we used next generation sequencing to analyze the DNA content of ALT telomeres. We discovered that variant repeats were interspersed throughout the telomeres of ALT cells. We found that the C-type...

  12. Inter-telomeric recombination is present in telomerase-positive human cells

    OpenAIRE

    Dlaska, Margit; Schöffski, Patrick; Bechter, Oliver E.

    2013-01-01

    Immortal cells require a mechanism of telomere length control in order to divide infinitely. One mechanism is telomerase, an enzyme that compensates the loss of telomeric DNA. The second mechanism is the alternative lengthening of telomeres (ALT) pathway. In ALT pathway cells, homologous recombination between telomeric DNA is the mechanism by which telomere homeostasis is achieved. We developed a novel homologous recombination reporter system that is able to measure inter-telomeric recombinat...

  13. Rif1 Maintains Telomere Length Homeostasis of ESCs by Mediating Heterochromatin Silencing

    OpenAIRE

    Dan, Jiameng; Liu, Yifei; Liu, Na; Chiourea, Maria; Okuka, Maja; Wu, Tao; Ye, Xiaoying; Mou, Chunlin; Wang, Lei; Wang, Lingling; Yin, Yu; Yuan, Jihong; Zuo, Bingfeng; Wang, Fang; Li, Zhiguo

    2014-01-01

    Telomere length homeostasis is essential for genomic stability and unlimited self-renewal of embryonic stem cells (ESCs). We show that telomere-associated protein Rif1 is required to maintain telomere length homeostasis by negatively regulating Zscan4 expression, a critical factor for telomere elongation by recombination. Depletion of Rif1 results in terminal hyperrecombination, telomere length heterogeneity, and chromosomal fusions. Reduction of Zscan4 by shRNA significantly rescues telomere...

  14. At Short Telomeres Tel1 Directs Early Replication and Phosphorylates Rif1

    OpenAIRE

    Sridhar, Akila; Kedziora, Sylwia; Donaldson, Anne D.

    2014-01-01

    The replication time of Saccharomyces cerevisiae telomeres responds to TG1–3 repeat length, with telomeres of normal length replicating late during S phase and short telomeres replicating early. Here we show that Tel1 kinase, which is recruited to short telomeres, specifies their early replication, because we find a tel1Δ mutant has short telomeres that nonetheless replicate late. Consistent with a role for Tel1 in driving early telomere replication, initiation at a replication origin close t...

  15. 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

    2015-01-01

    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. PMID:26382656

  16. Telomerase activity and telomere length in human hepatocellular carcinoma.

    Science.gov (United States)

    Huang, G T; Lee, H S; Chen, C H; Chiou, L L; Lin, Y W; Lee, C Z; Chen, D S; Sheu, J C

    1998-11-01

    Telomerase activity is activated and telomere length altered in various types of cancers, including hepatocellular carcinoma (HCC). A total of 39 HCC tissues and the corresponding non-tumour livers were analysed and correlated with clinical parameters. Telomere length was determined by terminal restriction fragment assay, and telomerase activity was assayed by telomeric repeat amplification protocol. Telomerase activity was positive in 24 of the 39 tumour tissues (1.15-285.13 total product generated (TPG) units) and in six of the 39 non-tumour liver tissues (1.05-1.73 TPG units). In the 28 cases analysed for telomere length, telomere length was shortened in 11 cases, lengthened in six cases, and unaltered in 11 cases compared with non-tumour tissues. Neither telomere length nor telomerase activity was correlated to any clinical parameters. PMID:10023320

  17. Telomeric repeats facilitate CENP-A(Cnp1) incorporation via telomere binding proteins.

    Science.gov (United States)

    Castillo, Araceli G; Pidoux, Alison L; Catania, Sandra; Durand-Dubief, Mickaël; Choi, Eun Shik; Hamilton, Georgina; Ekwall, Karl; Allshire, Robin C

    2013-01-01

    The histone H3 variant, CENP-A, is normally assembled upon canonical centromeric sequences, but there is no apparent obligate coupling of sequence and assembly, suggesting that centromere location can be epigenetically determined. To explore the tolerances and constraints on CENP-A deposition we investigated whether certain locations are favoured when additional CENP-A(Cnp1) is present in fission yeast cells. Our analyses show that additional CENP-A(Cnp1) accumulates within and close to heterochromatic centromeric outer repeats, and over regions adjacent to rDNA and telomeres. The use of minichromosome derivatives with unique DNA sequences internal to chromosome ends shows that telomeres are sufficient to direct CENP-A(Cnp1) deposition. However, chromosome ends are not required as CENP-A(Cnp1) deposition also occurs at telomere repeats inserted at an internal locus and correlates with the presence of H3K9 methylation near these repeats. The Ccq1 protein, which is known to bind telomere repeats and recruit telomerase, was found to be required to induce H3K9 methylation and thus promote the incorporation of CENP-A(Cnp1) near telomere repeats. These analyses demonstrate that at non-centromeric chromosomal locations the presence of heterochromatin influences the sites at which CENP-A is incorporated into chromatin and, thus, potentially the location of centromeres. PMID:23936074

  18. Telomeric repeats facilitate CENP-A(Cnp1 incorporation via telomere binding proteins.

    Directory of Open Access Journals (Sweden)

    Araceli G Castillo

    Full Text Available The histone H3 variant, CENP-A, is normally assembled upon canonical centromeric sequences, but there is no apparent obligate coupling of sequence and assembly, suggesting that centromere location can be epigenetically determined. To explore the tolerances and constraints on CENP-A deposition we investigated whether certain locations are favoured when additional CENP-A(Cnp1 is present in fission yeast cells. Our analyses show that additional CENP-A(Cnp1 accumulates within and close to heterochromatic centromeric outer repeats, and over regions adjacent to rDNA and telomeres. The use of minichromosome derivatives with unique DNA sequences internal to chromosome ends shows that telomeres are sufficient to direct CENP-A(Cnp1 deposition. However, chromosome ends are not required as CENP-A(Cnp1 deposition also occurs at telomere repeats inserted at an internal locus and correlates with the presence of H3K9 methylation near these repeats. The Ccq1 protein, which is known to bind telomere repeats and recruit telomerase, was found to be required to induce H3K9 methylation and thus promote the incorporation of CENP-A(Cnp1 near telomere repeats. These analyses demonstrate that at non-centromeric chromosomal locations the presence of heterochromatin influences the sites at which CENP-A is incorporated into chromatin and, thus, potentially the location of centromeres.

  19. Longer telomeres associated with higher survival in birds

    OpenAIRE

    Haussmann, Mark F.; Winkler, David W.; Vleck, Carol M

    2005-01-01

    Differences in individual quality and survival within species are a major focus in evolutionary ecology, but we know very little about the underlying physiological mechanisms that determine these differences. Telomere shortening associated with cellular senescence and ageing may be one such mechanism. To date, however, there is little evidence linking telomere length and survival. Here, we show that tree swallows (Tachycineta bicolor) with relatively short telomeres at the age of 1 year have ...

  20. Telomere Q-PNA-FISH - Reliable Results from Stochastic Signals

    OpenAIRE

    Ćukušić Kalajžić, Andrea; Škrobot Vidaček, Nikolina; Huzak, Miljenko; Ivanković, Milena; Rubelj, Ivica

    2014-01-01

    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 pop...

  1. Extracting Extra-Telomeric Phenotypes from Telomerase Mouse Models

    OpenAIRE

    Sung, Young Hoon; Ali, Muhammad; Lee, Han-Woong

    2013-01-01

    Telomerase reverse transcriptase (TERT) is the protein component of telomerase and combined with an RNA molecule, telomerase RNA component, forms the telomerase enzyme responsible for telomere elongation. Telomerase is essential for maintaining telomere length from replicative attrition and thus contributes to the preservation of genome integrity. Although diverse mouse models have been developed and studied to prove the physiological roles of telomerase as a telomere-elongating enzyme, recen...

  2. The many facets of homologous recombination at telomeres

    OpenAIRE

    Clémence Claussin; Michael Chang

    2015-01-01

    The ends of linear chromosomes are capped by nucleoprotein structures called telomeres. A dysfunctional telomere may resemble a DNA double-strand break (DSB), which is a severe form of DNA damage. The presence of one DSB is sufficient to drive cell cycle arrest and cell death. Therefore cells have evolved mechanisms to repair DSBs such as homologous recombination (HR). HR-mediated repair of telomeres can lead to genome instability, a hallmark of cancer cells, wh...

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

    OpenAIRE

    Jin Gao; Munch, Stephan B.

    2015-01-01

    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 ...

  4. Air Pollution Stress and the Aging Phenotype: The Telomere Connection.

    Science.gov (United States)

    Martens, Dries S; Nawrot, Tim S

    2016-09-01

    Aging is a complex physiological phenomenon. The question why some subjects grow old while remaining free from disease whereas others prematurely die remains largely unanswered. We focus here on the role of air pollution in biological aging. Hallmarks of aging can be grouped into three main categories: genomic instability, telomere attrition, and epigenetic alterations leading to altered mitochondrial function and cellular senescence. At birth, the initial telomere length of a person is largely determined by environmental factors. Telomere length shortens with each cell division and exposure to air pollution as well as low residential greens space exposure is associated with shorter telomere length. Recent studies show that the estimated effects of particulate air pollution exposure on the telomere mitochondrial axis of aging may play an important role in chronic health effects of air pollution. The exposome encompasses all exposures over an entire life. As telomeres can be considered as the cellular memories of exposure to oxidative stress and inflammation, telomere maintenance may be a proxy for assessing the "exposome". If telomeres are causally related to the aging phenotype and environmental air pollution is an important determinant of telomere length, this might provide new avenues for future preventive strategies. PMID:27357566

  5. 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...

  6. SMARCAL1 maintains telomere integrity during DNA replication.

    Science.gov (United States)

    Poole, Lisa A; Zhao, Runxiang; Glick, Gloria G; Lovejoy, Courtney A; Eischen, Christine M; Cortez, David

    2015-12-01

    The SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent, regulator of chromatin, subfamily A-like 1) DNA translocase is one of several related enzymes, including ZRANB3 (zinc finger, RAN-binding domain containing 3) and HLTF (helicase-like transcription factor), that are recruited to stalled replication forks to promote repair and restart replication. These enzymes can perform similar biochemical reactions such as fork reversal; however, genetic studies indicate they must have unique cellular activities. Here, we present data showing that SMARCAL1 has an important function at telomeres, which present an endogenous source of replication stress. SMARCAL1-deficient cells accumulate telomere-associated DNA damage and have greatly elevated levels of extrachromosomal telomere DNA (C-circles). Although these telomere phenotypes are often found in tumor cells using the alternative lengthening of telomeres (ALT) pathway for telomere elongation, SMARCAL1 deficiency does not yield other ALT phenotypes such as elevated telomere recombination. The activity of SMARCAL1 at telomeres can be separated from its genome-maintenance activity in bulk chromosomal replication because it does not require interaction with replication protein A. Finally, this telomere-maintenance function is not shared by ZRANB3 or HLTF. Our results provide the first identification, to our knowledge, of an endogenous source of replication stress that requires SMARCAL1 for resolution and define differences between members of this class of replication fork-repair enzymes. PMID:26578802

  7. Cancer and aging: The importance of telomeres in genome maintenance

    Energy Technology Data Exchange (ETDEWEB)

    Rodier, Francis; Kim, Sahn-ho; Nijjar, Tarlochan; Yaswen, Paul; Campisi, Judith

    2004-10-01

    Telomeres are the specialized DNA-protein structures that cap the ends of linear chromosomes, thereby protecting them from degradation and fusion by cellular DNA repair processes. In vertebrate cells, telomeres consist of several kilobase pairs of DNA having the sequence TTAGGG, a few hundred base pairs of single-stranded DNA at the 3' end of the telomeric DNA tract, and a host of proteins that organize the telomeric double and single stranded DNA into a protective structure. Functional telomeres are essential for maintaining the integrity and stability of genomes. When combined with loss of cell cycle checkpoint controls, telomere dysfunction can lead to genomic instability, a common cause and hallmark of cancer. Consequently, normal mammalian cells respond to dysfunctional telomeres by undergoing apoptosis (programmed cell death) or cellular senescence (permanent cell cycle arrest), two cellular tumor suppressor mechanisms. These tumor suppressor mechanisms are potent suppressors of cancer, but recent evidence suggests that they can antagonistically also contribute to aging phenotypes. Here, we review what is known about the structure and function of telomeres in mammalian cells, particularly human cells, and how telomere dysfunction may arise and contribute to cancer and aging phenotypes.

  8. Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers.

    Science.gov (United States)

    Walsh, Kyle M; Whitehead, Todd P; de Smith, Adam J; Smirnov, Ivan V; Park, Minsun; Endicott, Alyson A; Francis, Stephen S; Codd, Veryan; Samani, Nilesh J; Metayer, Catherine; Wiemels, Joseph L

    2016-06-01

    Aberrant telomere lengthening is an important feature of cancer cells in adults and children. In addition to somatic mutations, germline polymorphisms in telomere maintenance genes impact telomere length. Whether these telomere-associated polymorphisms affect risk of childhood malignancies remains largely unexplored. We collected genome-wide data from three groups with pediatric malignancies [neuroblastoma (N = 1516), acute lymphoblastic leukemia (ALL) (N = 958) and osteosarcoma (N = 660)] and three control populations (N = 6892). Using case-control comparisons, we analyzed eight single nucleotide polymorphisms (SNPs) in genes definitively associated with interindividual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208 and RTEL1 Six of these SNPs were associated (P < 0.05) with neuroblastoma risk, one with leukemia risk and one with osteosarcoma risk. The allele associated with longer LTL increased cancer risk for all these significantly associated SNPs. Using a weighted linear combination of the eight LTL-associated SNPs, we observed that neuroblastoma patients were predisposed to longer LTL than controls, with each standard deviation increase in genotypically estimated LTL associated with a 1.15-fold increased odds of neuroblastoma (95%CI = 1.09-1.22; P = 7.9×10(-7)). This effect was more pronounced in adolescent-onset neuroblastoma patients (OR = 1.46; 95%CI = 1.03-2.08). A one standard deviation increase in genotypically estimated LTL was more weakly associated with osteosarcoma risk (OR = 1.10; 95%CI = 1.01-1.19; P = 0.017) and leukemia risk (OR = 1.07; 95%CI = 1.00-1.14; P = 0.044), specifically for leukemia patients who relapsed (OR = 1.19; 95%CI = 1.01-1.40; P = 0.043). These results indicate that genetic predisposition to longer LTL is a newly identified risk factor for neuroblastoma and potentially for other cancers of childhood. PMID:27207662

  9. The pif1 helicase, a negative regulator of telomerase, acts preferentially at long telomeres.

    Directory of Open Access Journals (Sweden)

    Jane A Phillips

    2015-04-01

    Full Text Available Telomerase, the enzyme that maintains telomeres, preferentially lengthens short telomeres. The S. cerevisiae Pif1 DNA helicase inhibits both telomerase-mediated telomere lengthening and de novo telomere addition at double strand breaks (DSB. Here, we report that the association of the telomerase subunits Est2 and Est1 at a DSB was increased in the absence of Pif1, as it is at telomeres, suggesting that Pif1 suppresses de novo telomere addition by removing telomerase from the break. To determine how the absence of Pif1 results in telomere lengthening, we used the single telomere extension assay (STEX, which monitors lengthening of individual telomeres in a single cell cycle. In the absence of Pif1, telomerase added significantly more telomeric DNA, an average of 72 nucleotides per telomere compared to the 45 nucleotides in wild type cells, and the fraction of telomeres lengthened increased almost four-fold. Using an inducible short telomere assay, Est2 and Est1 no longer bound preferentially to a short telomere in pif1 mutant cells while binding of Yku80, a telomere structural protein, was unaffected by the status of the PIF1 locus. Two experiments demonstrate that Pif1 binding is affected by telomere length: Pif1 (but not Yku80 -associated telomeres were 70 bps longer than bulk telomeres, and in the inducible short telomere assay, Pif1 bound better to wild type length telomeres than to short telomeres. Thus, preferential lengthening of short yeast telomeres is achieved in part by targeting the negative regulator Pif1 to long telomeres.

  10. The pif1 helicase, a negative regulator of telomerase, acts preferentially at long telomeres.

    Science.gov (United States)

    Phillips, Jane A; Chan, Angela; Paeschke, Katrin; Zakian, Virginia A

    2015-04-01

    Telomerase, the enzyme that maintains telomeres, preferentially lengthens short telomeres. The S. cerevisiae Pif1 DNA helicase inhibits both telomerase-mediated telomere lengthening and de novo telomere addition at double strand breaks (DSB). Here, we report that the association of the telomerase subunits Est2 and Est1 at a DSB was increased in the absence of Pif1, as it is at telomeres, suggesting that Pif1 suppresses de novo telomere addition by removing telomerase from the break. To determine how the absence of Pif1 results in telomere lengthening, we used the single telomere extension assay (STEX), which monitors lengthening of individual telomeres in a single cell cycle. In the absence of Pif1, telomerase added significantly more telomeric DNA, an average of 72 nucleotides per telomere compared to the 45 nucleotides in wild type cells, and the fraction of telomeres lengthened increased almost four-fold. Using an inducible short telomere assay, Est2 and Est1 no longer bound preferentially to a short telomere in pif1 mutant cells while binding of Yku80, a telomere structural protein, was unaffected by the status of the PIF1 locus. Two experiments demonstrate that Pif1 binding is affected by telomere length: Pif1 (but not Yku80) -associated telomeres were 70 bps longer than bulk telomeres, and in the inducible short telomere assay, Pif1 bound better to wild type length telomeres than to short telomeres. Thus, preferential lengthening of short yeast telomeres is achieved in part by targeting the negative regulator Pif1 to long telomeres. PMID:25906395

  11. Telomere Elongation and Naive Pluripotent Stem Cells Achieved from Telomerase Haplo-Insufficient Cells by Somatic Cell Nuclear Transfer

    Directory of Open Access Journals (Sweden)

    Li-Ying Sung

    2014-12-01

    Full Text Available Haplo-insufficiency of telomerase genes in humans leads to telomere syndromes such as dyskeratosis congenital and idiopathic pulmonary fibrosis. Generation of pluripotent stem cells from telomerase haplo-insufficient donor cells would provide unique opportunities toward the realization of patient-specific stem cell therapies. Recently, pluripotent human embryonic stem cells (ntESCs have been efficiently achieved by somatic cell nuclear transfer (SCNT. We tested the hypothesis that SCNT could effectively elongate shortening telomeres of telomerase haplo-insufficient cells in the ntESCs with relevant mouse models. Indeed, telomeres of telomerase haplo-insufficient (Terc+/− mouse cells are elongated in ntESCs. Moreover, ntESCs derived from Terc+/− cells exhibit naive pluripotency as evidenced by generation of Terc+/− ntESC clone pups by tetraploid embryo complementation, the most stringent test of naive pluripotency. These data suggest that SCNT could offer a powerful tool to reprogram telomeres and to discover the factors for robust restoration of telomeres and pluripotency of telomerase haplo-insufficient somatic cells.

  12. Schizosaccharomyces pombe Hat1 (Kat1) is associated with Mis16 and is required for telomeric silencing.

    Science.gov (United States)

    Tong, Kevin; Keller, Thomas; Hoffman, Charles S; Annunziato, Anthony T

    2012-09-01

    The Hat1 histone acetyltransferase has been implicated in the acetylation of histone H4 during chromatin assembly. In this study, we have characterized the Hat1 complex from the fission yeast Schizosaccharomyces pombe and have examined its role in telomeric silencing. Hat1 is found associated with the RbAp46 homologue Mis16, an essential protein. The Hat1 complex acetylates lysines 5 and 12 of histone H4, the sites that are acetylated in newly synthesized H4 in a wide range of eukaryotes. Deletion of hat1 in S. pombe is itself sufficient to cause the loss of silencing at telomeres. This is in contrast to results obtained with an S. cerevisiae hat1Δ strain, which must also carry mutations of specific acetylatable lysines in the H3 tail domain for loss of telomeric silencing to occur. Notably, deletion of hat1 from S. pombe resulted in an increase of acetylation of histone H4 in subtelomeric chromatin, concomitant with derepression of this region. A similar loss of telomeric silencing was also observed after growing cells in the presence of the deacetylase inhibitor trichostatin A. However, deleting hat1 did not cause loss of silencing at centromeres or the silent mating type locus. These results point to a direct link between Hat1, H4 acetylation, and the establishment of repressed telomeric chromatin in fission yeast. PMID:22771823

  13. Extreme Telomere Length Dimorphism in the Tasmanian Devil and Related Marsupials Suggests Parental Control of Telomere Length

    OpenAIRE

    Bender, Hannah S.; Murchison, Elizabeth P.; Pickett, Hilda A.; Deakin, Janine E.; Strong, Margaret A.; Conlan, Carly; McMillan, Daniel A; Neumann, Axel A.; Greider, Carol W.; Hannon, Gregory J.; Reddel, Roger R; Graves, Jennifer A. Marshall

    2012-01-01

    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...

  14. Replication protein A prevents accumulation of single-stranded telomeric DNA in cells that use alternative lengthening of telomeres

    OpenAIRE

    Grudic, Amra; Jul-Larsen, Åsne; Haring, SJ; Wold, MS; Lønning, Per Eystein; Bjerkvig, Rolf; Bøe, Stig Ove

    2007-01-01

    The activation of a telomere maintenance mechanism is required for cancer development in humans. While most tumors achieve this by expressing the enzyme telomerase, a fraction (5–15%) employs a recombination-based mechanism termed alternative lengthening of telomeres (ALT). Here we show that loss of the single-stranded DNA-binding protein replication protein A (RPA) in human ALT cells, but not in telomerase-positive cells, causes increased exposure of single-stranded G-rich telomeric DNA, cel...

  15. The telomere-associated homeobox-containing protein TAH1/HMBOX1 participates in telomere maintenance in ALT cells

    OpenAIRE

    Feng, Xuyang; Luo, Zhenhua; Jiang, Shuai; Li, Feng; Han, Xin; Hu, Yang; Wang, Dan; Zhao, Yong; Ma, Wenbin; Liu, Dan; Huang, Junjiu; Songyang, Zhou

    2013-01-01

    The majority of cancer cells rely on elevated telomerase expression and activity for rapid growth and proliferation. Telomerase-negative cancer cells, by contrast, often employ the alternative lengthening of telomeres (ALT) pathway to maintain telomeres. ALT cells are characterized by long and dynamic telomeres and the presence of ALT-associated promyelocytic leukemia (PML) bodies (APBs). Previous work has shown the importance of APBs to the ALT pathway, but their formation and precise role r...

  16. The Pif1 family helicase Pfh1 facilitates telomere replication and has an RPA-dependent role during telomere lengthening

    OpenAIRE

    McDonald, Karin R.; Sabouri, Nasim; Webb, Christopher J.; Zakian, Virginia A.

    2014-01-01

    Pif1 family helicases are evolutionary conserved 5′ to 3′ DNA helicases. Pfh1, the sole S. pombe Pif1 family DNA helicase, is essential for maintenance of both nuclear and mitochondrial DNAs. Here we show that its nuclear functions include roles in telomere replication and telomerase action. Pfh1 promoted semi-conservative replication through telomeric DNA, as replication forks moved more slowly through telomeres when Pfh1 levels were reduced. Unlike other organisms, S. pombe cells overexpres...

  17. Telomere-Mediated Plasmid Segregation in Saccharomyces Cerevisiae Involves Gene Products Required for Transcriptional Repression at Silencers and Telomeres

    OpenAIRE

    Longtine, M. S.; Enomoto, S.; Finstad, S L; Berman, J

    1993-01-01

    Plasmids that contain Saccharomyces cerevisiae TG(1-3) telomere repeat sequences (TRS plasmids) segregate efficiently during mitosis. Mutations in histone H4 reduce the efficiency of TRS-mediated plasmid segregation, suggesting that chromatin structure is involved in this process. Sir2, Sir3 and Sir4 are required for the transcriptional repression of genes located at the silent mating type loci (HML and HMR) and at telomeres (telomere position effect) and are also involved in the segregation ...

  18. Assignment of Atlantic salmon (Salmo salar) Linkage Groups to Specific Chromosomes: Conservation of Large Syntenic Blocks Corresponding to Whole Chromosome Arms in Rainbow Trout (Oncorhynchus mykiss)

    OpenAIRE

    Phillips, Ruth; Keatley, Kimberly; Morasch, Matthew; Ventura, Abigail; Lubieniecki, Krzysztof; Koop, Ben; Danzmann, Roy; Davidson, William

    2009-01-01

    Background: Most teleost species, especially freshwater groups such as the Esocidae which are theclosest relatives of salmonids, have a karyotype comprising 25 pairs of acrocentric chromosomes and 48–52 chromosome arms. After the common ancestor of salmonids underwent a whole genome duplication,its karyotype would have 100 chromosome arms, and this is reflected in the modal range of 96–104 seenin extant salmonids (e.g., rainbow trout). The Atlantic salmon is an exception among the salmonids a...

  19. Telomere regulation in pluripotent stem cells

    OpenAIRE

    Huang, Yan; Liang, Puping; Liu, Dan; Huang, Junjiu; Songyang, Zhou

    2014-01-01

    Pluripotent stem cells (PSCs) have the potential to produce any types of cells from all three basic germ layers and the capacity to self-renew and proliferate indefinitely in vitro. The two main types of PSCs, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), share common features such as colony morphology, high expression of Oct4 and Nanog, and strong alkaline phosphatase activity. In recent years, increasing evidences suggest that telomere length represents another imp...

  20. Telomere and Telomerase Therapeutics in Cancer

    Science.gov (United States)

    Xu, Yucheng; Goldkorn, Amir

    2016-01-01

    Telomerase is a reverse transcriptase capable of utilizing an integrated RNA component as a template to add protective tandem telomeric single strand DNA repeats, TTAGGG, to the ends of chromosomes. Telomere dysfunction and telomerase reactivation are observed in approximately 90% of human cancers; hence, telomerase activation plays a unique role as a nearly universal step on the path to malignancy. In the past two decades, multiple telomerase targeting therapeutic strategies have been pursued, including direct telomerase inhibition, telomerase interference, hTERT or hTERC promoter driven therapy, telomere-based approaches, and telomerase vaccines. Many of these strategies have entered clinical development, and some have now advanced to phase III clinical trials. In the coming years, one or more of these new telomerase-targeting drugs may be expected to enter the pharmacopeia of standard care. Here, we briefly review the molecular functions of telomerase in cancer and provide an update about the preclinical and clinical development of telomerase targeting therapeutics. PMID:27240403

  1. ATRX represses alternative lengthening of telomeres.

    Science.gov (United States)

    Napier, Christine E; Huschtscha, Lily I; Harvey, Adam; Bower, Kylie; Noble, Jane R; Hendrickson, Eric A; Reddel, Roger R

    2015-06-30

    The unlimited proliferation of cancer cells requires a mechanism to prevent telomere shortening. Alternative Lengthening of Telomeres (ALT) is an homologous recombination-mediated mechanism of telomere elongation used in tumors, including osteosarcomas, soft tissue sarcoma subtypes, and glial brain tumors. Mutations in the ATRX/DAXX chromatin remodeling complex have been reported in tumors and cell lines that use the ALT mechanism, suggesting that ATRX may be an ALT repressor. We show here that knockout or knockdown of ATRX in mortal cells or immortal telomerase-positive cells is insufficient to activate ALT. Notably, however, in SV40-transformed mortal fibroblasts ATRX loss results in either a significant increase in the proportion of cell lines activating ALT (instead of telomerase) or in a significant decrease in the time prior to ALT activation. These data indicate that loss of ATRX function cooperates with one or more as-yet unidentified genetic or epigenetic alterations to activate ALT. Moreover, transient ATRX expression in ALT-positive/ATRX-negative cells represses ALT activity. These data provide the first direct, functional evidence that ATRX represses ALT. PMID:26001292

  2. Telomere and Telomerase Therapeutics in Cancer

    Directory of Open Access Journals (Sweden)

    Yucheng Xu

    2016-05-01

    Full Text Available Telomerase is a reverse transcriptase capable of utilizing an integrated RNA component as a template to add protective tandem telomeric single strand DNA repeats, TTAGGG, to the ends of chromosomes. Telomere dysfunction and telomerase reactivation are observed in approximately 90% of human cancers; hence, telomerase activation plays a unique role as a nearly universal step on the path to malignancy. In the past two decades, multiple telomerase targeting therapeutic strategies have been pursued, including direct telomerase inhibition, telomerase interference, hTERT or hTERC promoter driven therapy, telomere-based approaches, and telomerase vaccines. Many of these strategies have entered clinical development, and some have now advanced to phase III clinical trials. In the coming years, one or more of these new telomerase-targeting drugs may be expected to enter the pharmacopeia of standard care. Here, we briefly review the molecular functions of telomerase in cancer and provide an update about the preclinical and clinical development of telomerase targeting therapeutics.

  3. Telomere and Telomerase Therapeutics in Cancer.

    Science.gov (United States)

    Xu, Yucheng; Goldkorn, Amir

    2016-01-01

    Telomerase is a reverse transcriptase capable of utilizing an integrated RNA component as a template to add protective tandem telomeric single strand DNA repeats, TTAGGG, to the ends of chromosomes. Telomere dysfunction and telomerase reactivation are observed in approximately 90% of human cancers; hence, telomerase activation plays a unique role as a nearly universal step on the path to malignancy. In the past two decades, multiple telomerase targeting therapeutic strategies have been pursued, including direct telomerase inhibition, telomerase interference, hTERT or hTERC promoter driven therapy, telomere-based approaches, and telomerase vaccines. Many of these strategies have entered clinical development, and some have now advanced to phase III clinical trials. In the coming years, one or more of these new telomerase-targeting drugs may be expected to enter the pharmacopeia of standard care. Here, we briefly review the molecular functions of telomerase in cancer and provide an update about the preclinical and clinical development of telomerase targeting therapeutics. PMID:27240403

  4. Rapid telomere motions in live human cells analyzed by highly time-resolved microscopy

    Directory of Open Access Journals (Sweden)

    Wang Xueying

    2008-10-01

    Full Text Available Abstract Background Telomeres cap chromosome ends and protect the genome. We studied individual telomeres in live human cancer cells. In capturing telomere motions using quantitative imaging to acquire complete high-resolution three-dimensional datasets every second for 200 seconds, telomere dynamics were systematically analyzed. Results The motility of individual telomeres within the same cancer cell nucleus was widely heterogeneous. One class of internal heterochromatic regions of chromosomes analyzed moved more uniformly and showed less motion and heterogeneity than telomeres. The single telomere analyses in cancer cells revealed that shorter telomeres showed more motion, and the more rapid telomere motions were energy dependent. Experimentally increasing bulk telomere length dampened telomere motion. In contrast, telomere uncapping, but not a DNA damaging agent, methyl methanesulfonate, significantly increased telomere motion. Conclusion New methods for seconds-scale, four-dimensional, live cell microscopic imaging and data analysis, allowing systematic tracking of individual telomeres in live cells, have defined a previously undescribed form of telomere behavior in human cells, in which the degree of telomere motion was dependent upon telomere length and functionality.

  5. Increased brood size leads to persistent eroded telomeres

    Directory of Open Access Journals (Sweden)

    FrançoisCriscuolo

    2014-04-01

    Full Text Available Costs of reproduction can be divided in mandatory costs coming from physiological, metabolic and anatomical changes required to sustain reproduction itself, and in investment-dependent costs that are likely to become apparent when reproductive efforts are exceeding what organisms were prepared to sustain. Interestingly, recent data showed that entering reproduction enhanced breeders’ telomere loss, but no data explored so far the impact of reproductive investment. Telomeres protect the ends of eukaryote chromosomes. Shortened telomeres were associated with shorter lifespan, telomere erosion being then proposed to powerfully quantify life’s insults. Here, we experimentally manipulated brood size in order to modify reproductive investment of adult zebra finches (Taeniopygia guttata below or beyond their (optimal starting investment and tested the consequences of our treatment on parents’ telomere dynamics. We show that an increased brood size led to a reduction in telomere lengths in both parents compared to control and to parents raising a reduced brood. This greater telomere erosion was detected in parents immediately after the reproductive event and the telomere length difference persisted up to one year later. However, we did not detect any effects of brood size manipulation on annual survival of parents kept under laboratory conditions. In addition, telomere lengths at the end of reproduction were not associated with annual survival. Altogether, although our findings highlight that fast telomere erosion can come as a cost of brood size manipulation, they provide mixed correlative support to the emerging hypothesis that telomere erosion could account for the links between high reproductive investment and longevity.

  6. Palladium-Catalyzed Telomerization of Butadiene with Polyols: From Mono to Polysaccharides

    Science.gov (United States)

    Bouquillon, Sandrine; Muzart, Jacques; Pinel, Catherine; Rataboul, Franck

    The telomerization of butadiene with alcohols is an elegant way to synthesize ethers with minimal environmental impact since this reaction is 100% atom efficient. Besides telomerization of butadiene with methanol and water that is industrially developed, the modification of polyols is still under development. Recently, a series of new substrates has been involved in this reaction, including diols, pure or crude glycerol, protected or unprotected monosaccharides, as well as polysaccharides. This opens up the formation of new products having specific physicochemical properties. We will describe recent advances in this field, focusing on the reaction of renewable products and more specifically on saccharides. The efficient catalytic systems as well as the optimized reaction conditions will be described and some physicochemical properties of the products will be reported.

  7. Telomerase and telomeres : From basic biology to cancer treatment

    NARCIS (Netherlands)

    Helder, MN; Wisman, GBA; van der Zee, AGJ

    2002-01-01

    The limited capacity to divide is one of the major differences between normal somatic cells and cancerous cells. This finite life span' of somatic cells is closely linked to loss of telomeric DNA at telomeres, the 'chromosome caps' consisting of repeated (TTAGGG) sequences. In more than 85% of advan

  8. The many facets of homologous recombination at telomeres

    NARCIS (Netherlands)

    Claussin, Clémence; Chang, Michael

    2015-01-01

    The ends of linear chromosomes are capped by nucleoprotein structures called telomeres. A dysfunctional telomere may resemble a DNA double-strand break (DSB), which is a severe form of DNA damage. The presence of one DSB is sufficient to drive cell cycle arrest and cell death. Therefore cells have e

  9. Telomerase-null survivor screening identifies novel telomere recombination regulators.

    Directory of Open Access Journals (Sweden)

    Yan Hu

    Full Text Available Telomeres are protein-DNA structures found at the ends of linear chromosomes and are crucial for genome integrity. Telomeric DNA length is primarily maintained by the enzyme telomerase. Cells lacking telomerase will undergo senescence when telomeres become critically short. In Saccharomyces cerevisiae, a very small percentage of cells lacking telomerase can remain viable by lengthening telomeres via two distinct homologous recombination pathways. These "survivor" cells are classified as either Type I or Type II, with each class of survivor possessing distinct telomeric DNA structures and genetic requirements. To elucidate the regulatory pathways contributing to survivor generation, we knocked out the telomerase RNA gene TLC1 in 280 telomere-length-maintenance (TLM gene mutants and examined telomere structures in post-senescent survivors. We uncovered new functional roles for 10 genes that affect the emerging ratio of Type I versus Type II survivors and 22 genes that are required for Type II survivor generation. We further verified that Pif1 helicase was required for Type I recombination and that the INO80 chromatin remodeling complex greatly affected the emerging frequency of Type I survivors. Finally, we found the Rad6-mediated ubiquitination pathway and the KEOPS complex were required for Type II recombination. Our data provide an independent line of evidence supporting the idea that these genes play important roles in telomere dynamics.

  10. The many facets of homologous recombination at telomeres

    Directory of Open Access Journals (Sweden)

    Clémence Claussin

    2015-07-01

    Full Text Available The ends of linear chromosomes are capped by nucleoprotein structures called telomeres. A dysfunctional telomere may resemble a DNA double-strand break (DSB, which is a severe form of DNA damage. The presence of one DSB is sufficient to drive cell cycle arrest and cell death. Therefore cells have evolved mechanisms to repair DSBs such as homologous recombination (HR. HR-mediated repair of telomeres can lead to genome instability, a hallmark of cancer cells, which is why such repair is normally inhibited. However, some HR-mediated processes are required for proper telomere function. The need for some recombination activities at telomeres but not others necessitates careful and complex regulation, defects in which can lead to catastrophic consequences. Furthermore, some cell types can maintain telomeres via telomerase-independent, recombination-mediated mechanisms. In humans, these mechanisms are called alternative lengthening of telomeres (ALT and are used in a subset of human cancer cells. In this review, we summarize the different recombination activities occurring at telomeres and discuss how they are regulated. Much of the current knowledge is derived from work using yeast models, which is the focus of this review, but relevant studies in mammals are also included.

  11. 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: 4.041, year: 2014

  12. Structural evaluation of tandem hairpin pyrrole-imidazole polyamides recognizing human telomeres.

    Science.gov (United States)

    Hirata, Akiyoshi; Nokihara, Kiyoshi; Kawamoto, Yusuke; Bando, Toshikazu; Sasaki, Asuka; Ide, Satoru; Maeshima, Kazuhiro; Kasama, Takeshi; Sugiyama, Hiroshi

    2014-08-13

    A polyamide containing N-methylpyrrole (Py) and N-methylimidazole (Im), designated PIPA, binds with high affinity and specificity to specific nucleotide sequences in the minor groove of double-helical DNA. Based on a recent report of the synthesis of PIPA for telomere visualization, the present paper focused on the size of the connecting part (hinge region) of two PIPA segments of the tandem hairpin PIPA, Dab(Im-Im-Py)-Py-Py-Py-Im-[Hinge]-Dab(Im-Im-Py)-Py-Py-Py-Im-βAla-NH(CH2)3N(CH3)-(CH2)3NH-[Dye]. The present paper also describes the characterization of binding by measuring the thermal melting temperature and surface plasmon resonance and by specific staining of telomeres (TTAGGG)n in human cells. Microheterogeneity was also investigated by high-resolution mass spectrometry. We found that the optimal compound as the hinge segment for telomere staining was [-NH(C2H4O)2(C2H4)CO-] with tetramethylrhodamine as the fluorescent dye. PMID:25036716

  13. Allium telomeres unmasked: the unusual telomeric sequence (CTCGGTTATGGG)(n) is synthesized by telomerase

    Czech Academy of Sciences Publication Activity Database

    Fajkus, Petr; Peška, Vratislav; Sitová, Z.; Fulnečková, Jana; Dvořáčková, Martina; Gogola, M.; Sýkorová, Eva; Hapala, J.; Fajkus, J.

    2016-01-01

    Roč. 85, č. 3 (2016), s. 337-347. ISSN 0960-7412 R&D Projects: GA ČR(CZ) GP13-10948P Institutional support: RVO:68081707 Keywords : Allium * unusual telomere * telomerase Subject RIV: BO - Biophysics Impact factor: 5.972, year: 2014

  14. Assembly of telomeric chromatin to create ALTernative endings.

    Science.gov (United States)

    O'Sullivan, Roderick J; Almouzni, Genevieve

    2014-11-01

    Circumvention of the telomere length-dependent mechanisms that control the upper boundaries of cellular proliferation is necessary for the unlimited growth of cancer. Most cancer cells achieve cellular immortality by up-regulating the expression of telomerase to extend and maintain their telomere length. However, a small but significant number of cancers do so via the exchange of telomeric DNA between chromosomes in a pathway termed alternative lengthening of telomeres, or ALT. Although it remains to be clarified why a cell chooses the ALT pathway and how ALT is initiated, recently identified mutations in factors that shape the chromatin and epigenetic landscape of ALT telomeres are shedding light on these mechanisms. In this review, we examine these recent findings and integrate them into the current models of the ALT mechanism. PMID:25172551

  15. TELOMERE SHORTENING IN MONOCYTES OF THE PATIENTS WITH RHEUMATOID ARTHRITIS

    Directory of Open Access Journals (Sweden)

    V. I. Borisov

    2006-01-01

    Full Text Available Abstract. Present study deals with size measurements of telomeric DNA from the human peripheral mononuclear immune cells in rheumatoid arthritis (RA. A method for measuring the relative telomere length by in situ hybridization followed by flow cytometric analysis (flow-FISH was used. Relative telomere length (RTL in monocytes was estimated as mean fluorescence intensity (MFI of test cells divided by MFI values of internal control cells. Hybridization conditions for analysis of telomere length in monocytes have been optimized in advance. It has been shown that RTL of monocytes was significantly lower in RA patients compared to donors. Significant differences in telomere length of monocytes between RA patients and donors were revealed for the young persons under 30 years old. The findings obtained may be considered as an additional argument confirming the hypothesis on genetic defects of hematopoietic stem cells determining RA development.

  16. Telomere Length – a New Biomarker in Medicine

    Directory of Open Access Journals (Sweden)

    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.

  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. Keeping It in the Family: ATRX Loss Promotes Persistent Sister Telomere Cohesion in ALT Cancer Cells.

    Science.gov (United States)

    Roake, Caitlin M; Artandi, Steven E

    2015-09-14

    In this issue of Cancer Cell, Ramamoorthy and Smith report that cancer cells that maintain their chromosome ends through alternative lengthening of telomeres (ALT) display persistent sister telomere cohesion. This delayed resolution of sister telomere cohesion depends upon the loss of ATRX and its histone-sequestering function and is associated with increased recombination between sister telomeres. PMID:26373274

  19. 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

    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 as import...

  20. Characterization of the telomere complex, TERF1 and TERF2 genes in muntjac species with fusion karyotypes

    International Nuclear Information System (INIS)

    The telomere binding proteins TRF1 and TRF2 maintain and protect chromosome ends and confer karyotypic stability. Chromosome evolution in the genus Muntiacus is characterized by numerous tandem (end-to-end) fusions. To study TRF1 and TRF2 telomere binding proteins in Muntiacus species, we isolated and characterized the TERF1 and -2 genes from Indian muntjac (Muntiacus muntjak vaginalis; 2n = 6 female) and from Chinese muntjac (Muntiacus reveesi; 2n = 46). Expression analysis revealed that both genes are ubiquitously expressed and sequence analysis identified several transcript variants of both TERF genes. Control experiments disclosed a novel testis-specific splice variant of TERF1 in human testes. Amino acid sequence comparisons demonstrate that Muntiacus TRF1 and in particular TRF2 are highly conserved between muntjac and human. In vivo TRF2-GFP and immuno-staining studies in muntjac cell lines revealed telomeric TRF2 localization, while deletion of the DNA binding domain abrogated this localization, suggesting muntjac TRF2 represents a functional telomere protein. Finally, expression analysis of a set of telomere-related genes revealed their presence in muntjac fibroblasts and testis tissue, which suggests the presence of a conserved telomere complex in muntjacs. However, a deviation from the common theme was noted for the TERT gene, encoding the catalytic subunit of telomerase; TERT expression could not be detected in Indian or Chinese muntjac cDNA or genomic DNA using a series of conserved primers, while TRAP assay revealed functional telomerase in Chinese muntjac testis tissues. This suggests muntjacs may harbor a diverged telomerase sequence

  1. Integration of Telomere Length Dynamics into Systems Biology Framework: A Review.

    Science.gov (United States)

    Nersisyan, Lilit

    2016-01-01

    Telomere length dynamics plays a crucial role in regulation of cellular processes and cell fate. In contrast to epidemiological studies revealing the association of telomere length with age, age-related diseases, and cancers, the role of telomeres in regulation of transcriptome and epigenome and the role of genomic variations in telomere lengthening are not extensively analyzed. This is explained by the fact that experimental assays for telomere length measurement are resource consuming, and there are very few studies where high-throughput genomics, transcriptomics, and/or epigenomics experiments have been coupled with telomere length measurements. Recent development of computational approaches for assessment of telomere length from whole genome sequencing data pave a new perspective on integration of telomeres into high-throughput systems biology analysis framework. Herein, we review existing methodologies for telomere length measurement and compare them to computational approaches, as well as discuss their applications in large-scale studies on telomere length dynamics. PMID:27346946

  2. Inhibition of the mitotic exit network in response to damaged telomeres.

    Directory of Open Access Journals (Sweden)

    Mauricio Valerio-Santiago

    Full Text Available When chromosomal DNA is damaged, progression through the cell cycle is halted to provide the cells with time to repair the genetic material before it is distributed between the mother and daughter cells. In Saccharomyces cerevisiae, this cell cycle arrest occurs at the G2/M transition. However, it is also necessary to restrain exit from mitosis by maintaining Bfa1-Bub2, the inhibitor of the Mitotic Exit Network (MEN, in an active state. While the role of Bfa1 and Bub2 in the inhibition of mitotic exit when the spindle is not properly aligned and the spindle position checkpoint is activated has been extensively studied, the mechanism by which these proteins prevent MEN function after DNA damage is still unclear. Here, we propose that the inhibition of the MEN is specifically required when telomeres are damaged but it is not necessary to face all types of chromosomal DNA damage, which is in agreement with previous data in mammals suggesting the existence of a putative telomere-specific DNA damage response that inhibits mitotic exit. Furthermore, we demonstrate that the mechanism of MEN inhibition when telomeres are damaged relies on the Rad53-dependent inhibition of Bfa1 phosphorylation by the Polo-like kinase Cdc5, establishing a new key role of this kinase in regulating cell cycle progression.

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

    Directory of Open Access Journals (Sweden)

    Lisa A Boardman

    Full Text Available INTRODUCTION: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

  4. Relative Telomere Length and Cognitive Decline in the Nurses’ Health Study

    OpenAIRE

    Devore, Elizabeth E.; Prescott, Jennifer; De Vivo, Immaculata; Grodstein, Francine

    2011-01-01

    Telomeres are short DNA repeats on the ends of mammalian chromosomes, which can undergo incomplete replication leading to gradual shortening with each cell cycle. Age and oxidative stress are contributors to telomere shortening; thus, telomere length may be a composite measure of biologic aging, and a potential predictor of health status in older adults. We evaluated whether relative telomere length (the proportion of telomere repeat copy number to single gene copy number, using a real-time P...

  5. DNA-directed Polymerase Subunits Play a Vital Role in Human Telomeric Overhang Processing

    OpenAIRE

    Diotti, Raffaella; Kalan, Sampada; Matveyenko, Anastasiya; Loayza, Diego

    2014-01-01

    Telomeres consist of TTAGGG repeats bound by the shelterin complex and end with a 3' overhang. In humans, telomeres shorten at each cell division, unless telomerase (TERT) is expressed and able to add telomeric repeats. For effective telomere maintenance, the DNA strand complementary to that made by telomerase must be synthesized. Recent studies have discovered a link between different activities necessary to process telomeres in the S-phase of the cell cycle in order to ref...

  6. Deletion of the major peroxiredoxin Tsa1 alters telomere length homeostasis

    OpenAIRE

    LU, Jian; Vallabhaneni, Haritha; Yin, Jinhu; Liu, Yie

    2013-01-01

    Reactive oxygen species (ROS) are proposed to play a major role in telomere length alterations during aging. The mechanisms by which ROS disrupt telomeres remain unclear. In Saccharomyces cerevisiae, telomere DNA consists of TG(1-3) repeats, which are maintained primarily by telomerase. Telomere length maintenance can be modulated by the expression level of telomerase subunits and telomerase activity. Additionally, telomerase-mediated telomere repeat addition is negatively modulated by the le...

  7. A role for monoubiquitinated FANCD2 at telomeres in ALT cells

    OpenAIRE

    Fan, Qiang; Zhang, Fan; Barrett, Briana; Ren, Keqin; Andreassen, Paul R.

    2009-01-01

    Both Fanconi anemia (FA) and telomere dysfunction are associated with chromosome instability and an increased risk of cancer. Because of these similarities, we have investigated whether there is a relationship between the FA protein, FANCD2 and telomeres. We find that FANCD2 nuclear foci colocalize with telomeres and PML bodies in immortalized telomerase-negative cells. These cells maintain telomeres by alternative lengthening of telomeres (ALT). In contrast, FANCD2 does not colocalize with t...

  8. Alternative lengthening of telomeres (ALT) in cancer stem cells in vivo

    OpenAIRE

    Bojovic, Bojana; Booth, Ryan E.; Jin, Yi; Zhou, Xiaofeng; Crowe, David L.

    2014-01-01

    Chromosome ends are protected by telomeres which prevent DNA damage response and degradation. Telomerase expression extends telomeres and inhibits DNA damage response. Telomeres are also maintained by the recombination based alternative lengthening pathway. Telomerase is believed to be the sole mechanism for telomere maintenance in epidermis. We show that basal cells in epidermis maintain telomeres both by telomerase and ALT mechanisms in vivo. ALT was detected in epidermal stem cells in Terc...

  9. Dynamics of Telomeres and Promyelocytic Leukemia Nuclear Bodies in a Telomerase-negative Human Cell Line

    OpenAIRE

    Jegou, Thibaud; Chung, Inn; Heuvelman, Gerrit; Wachsmuth, Malte; Görisch, Sabine M.; Greulich-Bode, Karin M.; Boukamp, Petra; Lichter, Peter; Rippe, Karsten

    2009-01-01

    Telomerase-negative tumor cells maintain their telomeres via an alternative lengthening of telomeres (ALT) mechanism. This process involves the association of telomeres with promyelocytic leukemia nuclear bodies (PML-NBs). Here, the mobility of both telomeres and PML-NBs as well as their interactions were studied in human U2OS osteosarcoma cells, in which the ALT pathway is active. A U2OS cell line was constructed that had lac operator repeats stably integrated adjacent to the telomeres of ch...

  10. Control of telomere length by a trimming mechanism that involves generation of t-circles

    OpenAIRE

    Hilda A Pickett; Cesare, Anthony J.; Johnston, Rebecca L; Neumann, Axel A.; Reddel, Roger R

    2009-01-01

    Telomere lengths are maintained in many cancer cells by the ribonucleoprotein enzyme telomerase but can be further elongated by increasing telomerase activity through the overexpression of telomerase components. We report here that increased telomerase activity results in increased telomere length that eventually reaches a plateau, accompanied by the generation of telomere length heterogeneity and the accumulation of extrachromosomal telomeric repeat DNA, principally in the form of telomeric ...

  11. Telomere length as a quantitative trait: genome-wide survey and genetic mapping of telomere length-control genes in yeast.

    Directory of Open Access Journals (Sweden)

    Tonibelle Gatbonton

    2006-03-01

    Full Text Available Telomere length-variation in deletion strains of Saccharomyces cerevisiae was used to identify genes and pathways that regulate telomere length. We found 72 genes that when deleted confer short telomeres, and 80 genes that confer long telomeres relative to those of wild-type yeast. Among identified genes, 88 have not been previously implicated in telomere length control. Genes that regulate telomere length span a variety of functions that can be broadly separated into telomerase-dependent and telomerase-independent pathways. We also found 39 genes that have an important role in telomere maintenance or cell proliferation in the absence of telomerase, including genes that participate in deoxyribonucleotide biosynthesis, sister chromatid cohesion, and vacuolar protein sorting. Given the large number of loci identified, we investigated telomere lengths in 13 wild yeast strains and found substantial natural variation in telomere length among the isolates. Furthermore, we crossed a wild isolate to a laboratory strain and analyzed telomere length in 122 progeny. Genome-wide linkage analysis among these segregants revealed two loci that account for 30%-35% of telomere length-variation between the strains. These findings support a general model of telomere length-variation in outbred populations that results from polymorphisms at a large number of loci. Furthermore, our results laid the foundation for studying genetic determinants of telomere length-variation and their roles in human disease.

  12. Breakage-fusion-bridge cycles and de novo telomere formation on broken chromosomes in maize callus cultures.

    Science.gov (United States)

    Santos-Serejo, Janay A; Aguiar-Perecin, Margarida L R

    2016-06-01

    Breakpoints involved in chromosome alterations associated with heterochromatin have been detected in maize plants regenerated from callus culture. A cytogenetic analysis of plants regenerated from a maize callus was performed aiming to analyze the stability of a chromosome 7 bearing a deficiency-duplication (Df-Dp), which was interpreted as derived from a chromatid type breakage-fusion-bridge (BFB) cycle. The Df-Dp chromosome 7 was stable in mitotic and meiotic cells of the regenerated plants. Fluorescence in situ hybridization showed signals of telomeric sequences on the broken chromosome arm and provided evidence of de novo telomere formation. The stability of two types of altered chromosome 7 was investigated in C-banded metaphases from samples of the original callus that were collected during a period of 30-42 months after culture initiation. New alterations involving heterochromatic knobs of chromosomes 7 and 9 were observed. The aberrant chromosomes were stable in the subcultures, thus providing evidence of broken chromosome healing. The examination of anaphases showed the presence of bridges, which was consistent with the occurrence of BFB cycles. De novo telomere formation occurred in euchromatic and heterochromatic chromosome termini. The results point to events of chromosomal evolution that might occur in plants. PMID:27203556

  13. A model of a patient-derived IDH1 mutant anaplastic astrocytoma with alternative lengthening of telomeres.

    Science.gov (United States)

    Borodovsky, Alexandra; Meeker, Alan K; Kirkness, Ewen F; Zhao, Qi; Eberhart, Charles G; Gallia, Gary L; Riggins, Gregory J

    2015-02-01

    Mutations in isocitrate dehydrogenase 1 (IDH1) have been found in the vast majority of low grade and progressive infiltrating gliomas and are characterized by the production of 2-hydroxyglutarate from α-ketoglutarate. Recent investigations of malignant gliomas have identified additional genetic and chromosomal abnormalities which cluster with IDH1 mutations into two distinct subgroups. The astrocytic subgroup was found to have frequent mutations in ATRX, TP53 and displays alternative lengthening of telomeres. The second subgroup with oligodendrocytic morphology has frequent mutations in CIC or FUBP1, and is linked to co-deletion of the 1p/19q arms. These mutations reflect the development of two distinct molecular pathways representing the majority of IDH1 mutant gliomas. Unfortunately, due to the scarcity of endogenously derived IDH1 mutant models, there is a lack of accurate models to study mechanism and develop new therapy. Here we report the generation of an endogenous IDH1 anaplastic astrocytoma in vivo model with concurrent mutations in TP53, CDKN2A and ATRX. The model has a similar phenotype and histopathology as the original patient tumor, expresses the IDH1 (R132H) mutant protein and exhibits an alternative lengthening of telomeres phenotype. The JHH-273 model is characteristic of anaplastic astrocytoma and represents a valuable tool for investigating the pathogenesis of this distinct molecular subset of gliomas and for preclinical testing of compounds targeting IDH1 mutations or alternative lengthening of telomeres. PMID:25471051

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

    Science.gov (United States)

    Stone, Rivka C; Horvath, Kent; Kark, Jeremy D; Susser, Ezra; Tishkoff, Sarah A; Aviv, Abraham

    2016-07-01

    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. PMID:27386863

  15. Telomere Length and the Cancer–Atherosclerosis Trade-Off

    Science.gov (United States)

    Stone, Rivka C.; Horvath, Kent; Kark, Jeremy D.; Susser, Ezra; Tishkoff, Sarah A.; Aviv, Abraham

    2016-01-01

    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. PMID:27386863

  16. Mathematical model of alternative mechanism of telomere length maintenance

    Science.gov (United States)

    Kollár, Richard; Bod'ová, Katarína; Nosek, Jozef; Tomáška, L'ubomír

    2014-03-01

    Biopolymer length regulation is a complex process that involves a large number of biological, chemical, and physical subprocesses acting simultaneously across multiple spatial and temporal scales. An illustrative example important for genomic stability is the length regulation of telomeres—nucleoprotein structures at the ends of linear chromosomes consisting of tandemly repeated DNA sequences and a specialized set of proteins. Maintenance of telomeres is often facilitated by the enzyme telomerase but, particularly in telomerase-free systems, the maintenance of chromosomal termini depends on alternative lengthening of telomeres (ALT) mechanisms mediated by recombination. Various linear and circular DNA structures were identified to participate in ALT, however, dynamics of the whole process is still poorly understood. We propose a chemical kinetics model of ALT with kinetic rates systematically derived from the biophysics of DNA diffusion and looping. The reaction system is reduced to a coagulation-fragmentation system by quasi-steady-state approximation. The detailed treatment of kinetic rates yields explicit formulas for expected size distributions of telomeres that demonstrate the key role played by the J factor, a quantitative measure of bending of polymers. The results are in agreement with experimental data and point out interesting phenomena: an appearance of very long telomeric circles if the total telomere density exceeds a critical value (excess mass) and a nonlinear response of the telomere size distributions to the amount of telomeric DNA in the system. The results can be of general importance for understanding dynamics of telomeres in telomerase-independent systems as this mode of telomere maintenance is similar to the situation in tumor cells lacking telomerase activity. Furthermore, due to its universality, the model may also serve as a prototype of an interaction between linear and circular DNA structures in various settings.

  17. Depressive symptoms are not associated with leukocyte telomere length: findings from the Nova Scotia Health Survey (NSHS95, a population-based study.

    Directory of Open Access Journals (Sweden)

    Jonathan A Shaffer

    Full Text Available BACKGROUND: Premature shortening of leukocyte telomere length has been proposed as a novel mechanism by which depression may confer increased risk of adverse cardiovascular events. Prior studies demonstrating associations of depression and depressive symptoms with shorter leukocyte telomere length were small, included selected psychiatric outpatients, were based on convenience samples, and/or adjusted for a limited number of possible confounding factors. METHODS AND FINDINGS: We examined the associations of depressive symptoms, probable depressive disorder, and specific depressive symptom clusters, as assessed by the Center for Epidemiological Studies--Depression (CES-D scale, with leukocyte telomere length, measured by using a real-time PCR method, in 2,225 apparently healthy participants from the 1995 Nova Scotia Health Survey population-based study. The mean age was 48.2 ± 18.9 years; 49.9% of participants were female; and the mean CES-D score was 7.4 ± 7.9. The mean telomere length was 5,301 ± 587 base pairs. In an unadjusted model, depressive symptoms were significantly associated with longer leukocyte telomere length (B = 27.6 base pairs per standard deviation increase in CES-D, 95% confidence interval [CI] = 3.1-52.1, p = 0.027. This association was no longer significant after adjustment for age and sex (B = 9.5, 95% CI = -14.6-33.6, p = 0.44 or after further adjustment for body mass index, Framingham risk score and previous history of ischemic heart disease (all p's ≥ 0.37. Neither probable depressive disorder nor specific depressive symptom clusters were independently associated with leukocyte telomere length. CONCLUSIONS: Concurrent depressive symptoms were not associated with leukocyte telomere length in a large, representative, population-based study.

  18. Tandem isomerization/telomerization of long chain dienes

    Directory of Open Access Journals (Sweden)

    Laura eTorrente Murciano

    2014-06-01

    Full Text Available The first example of a tandem reaction involving double-bond migration in combination with telomerization is reported. Homogeneous and heterogeneous Ru catalysts were employed as isomerisation catalysts, and telomerization was realized using a homogeneous Pd(0 precursor complex with a N-heterocyclic carbene (IMes ligand. Overall conversions approaching 60 % were achieved with the best selectivity to telomerization products of 91% attained at 11 % conversion. Conversion was markedly higher in the presence of longer-chain alcohol (1-butanol as the nucleophile (telogen.

  19. Mec1p associates with functionally compromised telomeres

    OpenAIRE

    Hector, Ronald E; Ray, Alo; Chen, Bo-Ruei; Shtofman, Rebecca; Berkner, Kathleen L.; Runge, Kurt W.

    2012-01-01

    In many organisms, telomere DNA consists of simple sequence repeat tracts that are required to protect the chromosome end. In the yeast Saccharomyces cerevisiae, tract maintenance requires two checkpoint kinases of the ATM family, Tel1p and Mec1p. Previous work has shown that Tel1p is recruited to functional telomeres with shorter repeat tracts to promote telomerase-mediated repeat addition, but the role of Mec1p is unknown. We found that Mec1p telomere association was detected as cells senes...

  20. Sex-Specific Effects of Gonadectomy and Hormone Treatment on Acquisition of a 12-Arm Radial Maze Task by Sprague Dawley Rats

    OpenAIRE

    Gibbs, Robert B; Johnson, David A.

    2008-01-01

    The effects of gonadectomy and hormone treatment on spatial learning were evaluated in adult male and female rats using a modified version of a 12-arm radial maze task. In this version, procedures were used to minimize the effectiveness of strategies less reliant on working and reference memory. Results demonstrate significant sex differences favoring male performance on the working memory component of the task. In contrast, females performed slightly better than males on the reference memory...

  1. Telomere Lengths and Telomerase Activity in Dog Tissues: A Potential Model System to Study Human Telomere and Telomerase Biology

    Directory of Open Access Journals (Sweden)

    Lubna Nasir

    2001-01-01

    Full Text Available Studies on telomere and telomerase biology are fundamental to the understanding of aging and age-related diseases such as cancer. However, human studies have been hindered by differences in telomere biology between humans and the classical murine animal model system. In this paper, we describe basic studies of telomere length and telomerase activity in canine normal and neoplastic tissues and propose the dog as an alternative model system. Briefly, telomere lengths were measured in normal canine peripheral blood mononuclear cells (PBMCs, a range of normal canine tissues, and in a panel of naturally occurring soft tissue tumours by terminal restriction fragment (TRF analysis. Further, telomerase activity was measured in canine cell lines and multiple canine tissues using a combined polymerase chain reaction/enzyme-linked immunosorbent assay method. TRF analysis in canine PBMCs and tissues demonstrated mean TRF lengths to range between 12 and 23 kbp with heterogeneity in telomere lengths being observed in a range of normal somatic tissues. In soft tissue sarcomas, two subgroups were identified with mean TRFs of 22.2 and 18.2 kbp. Telomerase activity in canine tissue was present in tumour tissue and testis with little or no activity in normal somatic tissues. These results suggest that the dog telomere biology is similar to that in humans and may represent an alternative model system for studying telomere biology and telomerase-targeted anticancer therapies.

  2. Old Fathers and Long-Telomered Offspring: Elongation of Telomeres in the Testes of Older Men Versus Transgenerational Erosion of Germline Telomeres

    OpenAIRE

    Reinhard Stindl

    2011-01-01

    There have been several reports of a significant positive correlation between paternal age and chromosome telomere length in offspring. Moreover, the telomeres in sperm cells of older men tend to be longer than in young men, and it has been concluded that telomeres lengthen in the testes during adulthood. This would be the first evidence of an increasing biological advantage with age, and therefore contradicts current models in which telomere shortening is a biomarker of aging. Instead, an al...

  3. Up-Regulation of Telomere-Binding Proteins, TRF1, TRF2, and TIN2 Is Related to Telomere Shortening during Human Multistep Hepatocarcinogenesis

    OpenAIRE

    Oh, Bong-Kyeong; Kim, Young-Joo; Park, Chanil; Park, Young Nyun

    2005-01-01

    The telomeric repeat-binding factor 1 (TRF1), TRF2, and the TRF1-interacting nuclear protein 2 (TIN2) are involved in telomere maintenance. We describe the regulation of expression of these genes along with their relationship to telomere length in hepatocarcinogenesis. The transcriptional expression of these genes, TRF1 protein, and telomere length was examined in 9 normal livers, 14 chronic hepatitis, 24 liver cirrhosis, 5 large regenerative nodules, 14 low-grade dysplastic nodules (DNs), 7 ...

  4. NEK6-mediated phosphorylation of human TPP1 regulates telomere length through telomerase recruitment.

    Science.gov (United States)

    Hirai, Yugo; Tamura, Miki; Otani, Junji; Ishikawa, Fuyuki

    2016-08-01

    Shelterin component TPP1 plays critical roles in chromosome end protection and telomere length regulation. Specifically, TPP1 contains an OB-fold domain that provides an interface to recruit telomerase. However, it remains largely unknown how telomerase recruitment is regulated by cell cycle regulators. We show that TPP1 interacts with the cell cycle regulator kinase NEK6 in human cells. We found that NEK6-mediated phosphorylation of TPP1 Ser255 in G2/M phase regulates the association between telomerase activity and TPP1. Furthermore, we found evidence that POT1 negatively regulates TPP1 phosphorylation because the level of Ser255 phosphorylation was elevated when telomeres were elongated by a POT1 mutant lacking its OB-fold domains. Ser255 is located in the intervening region between the telomerase-recruiting OB-fold and the POT1 recruitment domains. Ser255 and the surrounding amino acids are conserved among vertebrates. These observations suggest that a region adjacent to the OB-fold domain of TPP1 is involved in telomere length regulation via telomerase recruitment. PMID:27396482

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

    DEFF Research Database (Denmark)

    Kimura, Masayuki; Cherkas, Lynn F; Kato, Bernet S; Demissie, Serkalem; Hjelmborg, Jacob B; Brimacombe, Michael; Cupples, Adrienne; Hunkin, Janice L; Gardner, Jefferey P; Lu, Xiaobin; Cao, Xiaojian; Sastrasinh, Malinee; Province, Michael A; Hunt, Steven C; Christensen, Kaare; Levy, Daniel; Spector, Tim D; Aviv, Abraham

    2008-01-01

    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...... cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18-94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring....... 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...

  6. Modulation of Telomeres in Alternative Lengthening of Telomeres Type I Like Human Cells by the Expression of Werner Protein and Telomerase

    Directory of Open Access Journals (Sweden)

    Aisha Siddiqa

    2012-01-01

    Full Text Available The alternative lengthening of telomeres (ALT is a recombination-based mechanism of telomere maintenance activated in 5–20% of human cancers. In Saccharomyces cerevisiae, survivors that arise after inactivation of telomerase can be classified as type I or type II ALT. In type I, telomeres have a tandem array structure, with each subunit consisting of a subtelomeric Y′ element and short telomere sequence. Telomeres in type II have only long telomere repeats and require Sgs1, the S. cerevisiae RecQ family helicase. We previously described the first human ALT cell line, AG11395, that has a telomere structure similar to type I ALT yeast cells. This cell line lacks the activity of the Werner syndrome protein, a human RecQ helicase. The telomeres in this cell line consist of tandem repeats containing SV40 DNA, including the origin of replication, and telomere sequence. We investigated the role of the SV40 origin of replication and the effects of Werner protein and telomerase on telomere structure and maintenance in AG11395 cells. We report that the expression of Werner protein facilitates the transition in human cells of ALT type I like telomeres to type II like telomeres in some aspects. These findings have implications for the diagnosis and treatment of cancer.

  7. Defective repair of uracil causes telomere defects in mouse hematopoietic cells.

    Science.gov (United States)

    Vallabhaneni, Haritha; Zhou, Fang; Maul, Robert W; Sarkar, Jaya; Yin, Jinhu; Lei, Ming; Harrington, Lea; Gearhart, Patricia J; Liu, Yie

    2015-02-27

    Uracil in the genome can result from misincorporation of dUTP instead of dTTP during DNA synthesis, and is primarily removed by uracil DNA glycosylase (UNG) during base excision repair. Telomeres contain long arrays of TTAGGG repeats and may be susceptible to uracil misincorporation. Using model telomeric DNA substrates, we showed that the position and number of uracil substitutions of thymine in telomeric DNA decreased recognition by the telomere single-strand binding protein, POT1. In primary mouse hematopoietic cells, uracil was detectable at telomeres, and UNG deficiency further increased uracil loads and led to abnormal telomere lengthening. In UNG-deficient cells, the frequencies of sister chromatid exchange and fragility in telomeres also significantly increased in the absence of telomerase. Thus, accumulation of uracil and/or UNG deficiency interferes with telomere maintenance, thereby underscoring the necessity of UNG-initiated base excision repair for the preservation of telomere integrity. PMID:25572391

  8. Loss of wild-type ATRX expression in somatic cell hybrids segregates with activation of Alternative Lengthening of Telomeres.

    Directory of Open Access Journals (Sweden)

    Kylie Bower

    Full Text Available Alternative Lengthening of Telomeres (ALT is a non-telomerase mechanism of telomere lengthening that occurs in about 10% of cancers overall and is particularly common in astrocytic brain tumors and specific types of sarcomas. Somatic cell hybridization analyses have previously shown that normal telomerase-negative fibroblasts and telomerase-positive immortalized cell lines contain repressors of ALT activity, indicating that activation of ALT results from loss of one or more unidentified repressors. More recently, ATRX or DAXX was shown to be mutated both in tumors with telomere lengths suggestive of ALT activity and in ALT cell lines. Here, an ALT cell line was separately fused to each of four telomerase-positive cell lines, and four or five independent hybrid lines from each fusion were examined for expression of ATRX and DAXX and for telomere lengthening mechanism. The hybrid lines expressed either telomerase or ALT, with the other mechanism being repressed. DAXX was expressed normally in all parental cell lines and in all of the hybrids. ATRX was expressed normally in each of the four telomerase-positive parental cell lines and in every telomerase-positive hybrid line, and was abnormal in the ALT parental cells and in all but one of the ALT hybrids. This correlation between ALT activity and loss of ATRX expression is consistent with ATRX being a repressor of ALT.

  9. Specifications

    International Nuclear Information System (INIS)

    As part of the Danish RERTR Program, three fuel elements with LEU U3O8-Al fuel and three fuel elements with LEU U3Si2-Al fuel were manufactured by NUKEM for irradiation testing in the DR-3 reactor at the Risoe National Laboratory in Denmark. The specifications for the elements with U3O8-Al fuel are presented here as an illustration only. Specifications for the elements with U3Si2-Al fuel were very similar. In this example, materials, material numbers, documents numbers, and drawing numbers specific to a single fabricator have been deleted. (author)

  10. Telomere end processing: unexpected complexity at the end game

    OpenAIRE

    Lundblad, Victoria

    2012-01-01

    Lundblad provides perspective on the recent work by Wright and colleagues (this issue) that reveals a tightly choreographed sequence of events that occur during telomere replication and end processing.

  11. Different patterns of evolution in the centromeric and telomeric regions of group A and B haplotypes of the human killer cell Ig-like receptor locus.

    Directory of Open Access Journals (Sweden)

    Chul-Woo Pyo

    Full Text Available The fast evolving human KIR gene family encodes variable lymphocyte receptors specific for polymorphic HLA class I determinants. Nucleotide sequences for 24 representative human KIR haplotypes were determined. With three previously defined haplotypes, this gave a set of 12 group A and 15 group B haplotypes for assessment of KIR variation. The seven gene-content haplotypes are all combinations of four centromeric and two telomeric motifs. 2DL5, 2DS5 and 2DS3 can be present in centromeric and telomeric locations. With one exception, haplotypes having identical gene content differed in their combinations of KIR alleles. Sequence diversity varied between haplotype groups and between centromeric and telomeric halves of the KIR locus. The most variable A haplotype genes are in the telomeric half, whereas the most variable genes characterizing B haplotypes are in the centromeric half. Of the highly polymorphic genes, only the 3DL3 framework gene exhibits a similar diversity when carried by A and B haplotypes. Phylogenetic analysis and divergence time estimates, point to the centromeric gene-content motifs that distinguish A and B haplotypes having emerged ~6 million years ago, contemporaneously with the separation of human and chimpanzee ancestors. In contrast, the telomeric motifs that distinguish A and B haplotypes emerged more recently, ~1.7 million years ago, before the emergence of Homo sapiens. Thus the centromeric and telomeric motifs that typify A and B haplotypes have likely been present throughout human evolution. The results suggest the common ancestor of A and B haplotypes combined a B-like centromeric region with an A-like telomeric region.

  12. Early Telomerase Inactivation Accelerates Aging Independently of Telomere Length

    OpenAIRE

    Xie, Zhengwei; Jay, Kyle A.; Smith, Dana L.; Zhang, Yi; Liu, Zairan; Zheng, Jiashun; Tian, Ruilin; Li, Hao; Blackburn, Elizabeth

    2015-01-01

    Telomerase is required for long-term telomere maintenance and protection. Using single budding yeast mother cell analyses we found that, even Early after Telomerase Inactivation (ETI), yeast mother cells show transient DNA Damage Response (DDR) episodes, stochastically altered cell cycle dynamics, and accelerated mother cell aging. The acceleration of ETI mother cell aging was not explained by increased reactive oxygen species (ROS), Sir protein perturbation, or deprotected telomeres. ETI occ...

  13. Photosensitized damage to telomere overhang and telomerase RNA by riboflavin

    Institute of Scientific and Technical Information of China (English)

    Yuxia Liu; Fuqiang Du; Weizhen Lin; Tiecheng Tu; Wenxin Li; Nianyun Lin

    2008-01-01

    By ESR spin elimination and photodeavage assay, the mechanisms of one-electron oxidation damage of oligonucleotides by excited triplet state of riboflavin (Rb) have been elucidated. The results demonstrate that Rb, an endogenous photosensitizer, is capable of cleaving single-stranded telomeric overhang and the template region of telomerase RNA under UVA irradiation, resulting in blocking of reverse transcription of telomeric DNA which leads to the apoptosis of cancer cells ultimately.

  14. Telomere maintenance through recruitment of internal genomic regions

    OpenAIRE

    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

    2015-01-01

    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 chromoso...

  15. Mathematical model of alternative mechanism of telomere length maintenance

    OpenAIRE

    Kollár, Richard; Bodova, Katarina; Nosek, Jozef; Tomaska, Lubomir

    2014-01-01

    Biopolymer length regulation is a complex process that involves a large number of subprocesses acting simultaneously across multiple spatial and temporal scales. An illustrative example important for genomic stability is the length regulation of telomeres---nucleo-protein structures at the ends of linear chromosomes. Maintenance of telomeres is often facilitated by the enzyme telomerase but, particularly in telomerase-free systems, the maintenance of chromosomal termini depends on alternative...

  16. Telomere dynamics and homeostasis in a transmissible cancer.

    Directory of Open Access Journals (Sweden)

    Beata Ujvari

    Full Text Available BACKGROUND: 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". METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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

  17. Genetics of Leukocyte Telomere Length and its Role in Atherosclerosis

    OpenAIRE

    Aviv, Abraham

    2011-01-01

    Humans display a large inter-individual variation in leukocyte telomere length (LTL), which is influenced by heredity, sex, race/ethnicity, paternal age at conception and environmental exposures. LTL dynamics (birth LTL and its age-dependent attrition thereafter) mirror telomere dynamics in hematopoietic stem cells (HSCs). LTL at birth is evidently a major determinant of LTL throughout the human lifespan, such that individuals endowed with short (or long) LTL at birth probably have short (or ...

  18. Human Rap1 modulates TRF2 attraction to telomeric DNA

    OpenAIRE

    Janoušková Eliška; Nečasová Ivona; Pavloušková Jana; Zimmermann Michal; Hluchý Milan; Marini Palomeque María Victoria; Nováková Monika; Hofr Ctirad

    2015-01-01

    More than two decades of genetic research have identified and assigned main biological functions of shelterin proteins that safeguard telomeres. However, a molecular mechanism of how each protein subunit contributes to the protecting function of the whole shelterin complex remains elusive. Human Repressor activator protein 1 (Rap1) forms a multifunctional complex with Telomeric Repeat binding Factor 2 (TRF2). Rap1-TRF2 complex is a critical part of shelterin as it suppresses homology-directed...

  19. Telomere Transcripts Target Telomerase in Human Cancer Cells.

    Science.gov (United States)

    Kreilmeier, Theresa; Mejri, Doris; Hauck, Marlene; Kleiter, Miriam; Holzmann, Klaus

    2016-01-01

    Long non-coding transcripts from telomeres, called telomeric repeat-containing RNA (TERRA), were identified as blocking telomerase activity (TA), a telomere maintenance mechanism (TMM), in tumors. We expressed recombinant TERRA transcripts in tumor cell lines with TA and with alternative lengthening of telomeres (ALT) to study effects on TMM and cell growth. Adeno- and lentivirus constructs (AV and LV) were established for transient and stable expression of approximately 130 units of telomere hexanucleotide repeats under control of cytomegalovirus (CMV) and human RNase P RNA H1 (hH1) promoters with and without polyadenylation, respectively. Six human tumor cell lines either using telomerase or ALT were infected and analyzed for TA levels. Pre-infection cells using telomerase had 1%-3% of the TERRA expression levels of ALT cells. AV and LV expression of recombinant TERRA in telomerase positive cells showed a 1.3-2.6 fold increase in TERRA levels, and a decrease in TA of 25%-58%. Dominant-negative or small hairpin RNA (shRNA) viral expression against human telomerase reverse transcriptase (hTERT) results in senescence, not induced by TERRA expression. Population doubling time, cell viability and TL (telomere length) were not impacted by ectopic TERRA expression. Clonal growth was reduced by TERRA expression in TA but not ALT cell lines. ALT cells were not affected by treatments applied. Established cell models and tools may be used to better understand the role of TERRA in the cell, especially for targeting telomerase. PMID:27537914

  20. The heritability of leucocyte telomere length dynamics

    Science.gov (United States)

    Hjelmborg, Jacob B; Dalgård, Christine; Möller, Soren; Steenstrup, Troels; Kimura, Masayuki; Christensen, Kaare; Kyvik, Kirsten O; Aviv, Abraham

    2015-01-01

    Background Leucocyte telomere length (LTL) is a complex trait associated with ageing and longevity. LTL dynamics are defined by LTL and its age-dependent attrition. Strong, but indirect evidence suggests that LTL at birth and its attrition during childhood largely explains interindividual LTL variation among adults. A number of studies have estimated the heritability of LTL, but none has assessed the heritability of age-dependent LTL attrition. Methods We examined the heritability of LTL dynamics based on a longitudinal evaluation (an average follow-up of 12 years) in 355 monozygotic and 297 dizygotic same-sex twins (aged 19–64 years at baseline). Results Heritability of LTL at baseline was estimated at 64% (95% CI 39% to 83%) with 22% (95% CI 6% to 49%) of shared environmental effects. Heritability of age-dependent LTL attrition rate was estimated at 28% (95% CI 16% to 44%). Individually unique environmental factors, estimated at 72% (95% CI 56% to 84%) affected LTL attrition rate with no indication of shared environmental effects. Conclusions This is the first study that estimated heritability of LTL and also its age-dependent attrition. As LTL attrition is much slower in adults than in children and given that having a long or a short LTL is largely determined before adulthood, our findings suggest that heritability and early life environment are the main determinants of LTL throughout the human life course. Thus, insights into factors that influence LTL at birth and its dynamics during childhood are crucial for understanding the role of telomere genetics in human ageing and longevity. PMID:25770094

  1. 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

  2. Telomere-Binding Protein TPP1 Modulates Telomere Homeostasis and Confers Radioresistance to Human Colorectal Cancer Cells

    OpenAIRE

    Lei Yang; Wenbo Wang; Liu Hu; Xiaoxi Yang; Juan Zhong; Zheng Li; Hui Yang; Han Lei; Haijun Yu; ZhengKai Liao; Fuxiang Zhou; Conghua Xie; Yunfeng Zhou

    2013-01-01

    BACKGROUND: Radiotherapy is one of the major therapeutic strategies in cancer treatment. The telomere-binding protein TPP1 is an important component of the shelterin complex at mammalian telomeres. Our previous reports showed that TPP1 expression was elevated in radioresistant cells, but the exact effects and mechanisms of TPP1 on radiosensitivity is unclear. PRINCIPAL FINDINGS: In this study, we found that elevated TPP1 expression significantly correlated with radioresistance and longer telo...

  3. Telomere-Binding Protein TPP1 Modulates Telomere Homeostasis and Confers Radioresistance to Human Colorectal Cancer Cells

    OpenAIRE

    Yang, Lei; Wang, Wenbo; Hu, Liu; Yang, Xiaoxi; Zhong, Juan; Li, Zheng; Yang, Hui; Lei, Han; Yu, Haijun; Liao, Zhengkai; Zhou, Fuxiang; Xie, Conghua; Zhou, Yunfeng

    2013-01-01

    Background Radiotherapy is one of the major therapeutic strategies in cancer treatment. The telomere-binding protein TPP1 is an important component of the shelterin complex at mammalian telomeres. Our previous reports showed that TPP1 expression was elevated in radioresistant cells, but the exact effects and mechanisms of TPP1 on radiosensitivity is unclear. Principal Findings In this study, we found that elevated TPP1 expression significantly correlated with radioresistance and longer telome...

  4. PML is required for telomere stability in non-neoplastic human cells.

    Science.gov (United States)

    Marchesini, M; Matocci, R; Tasselli, L; Cambiaghi, V; Orleth, A; Furia, L; Marinelli, C; Lombardi, S; Sammarelli, G; Aversa, F; Minucci, S; Faretta, M; Pelicci, P G; Grignani, F

    2016-04-01

    Telomeres interact with numerous proteins, including components of the shelterin complex, whose alteration, similarly to proliferation-induced telomere shortening, initiates cellular senescence. In tumors, telomere length is maintained by Telomerase activity or by the Alternative Lengthening of Telomeres mechanism, whose hallmark is the telomeric localization of the promyelocytic leukemia (PML) protein. Whether PML contributes to telomeres maintenance in normal cells is unknown. We show that in normal human fibroblasts the PML protein associates with few telomeres, preferentially when they are damaged. Proliferation-induced telomere attrition or their damage due to alteration of the shelterin complex enhances the telomeric localization of PML, which is increased in human T-lymphocytes derived from patients genetically deficient in telomerase. In normal fibroblasts, PML depletion induces telomere damage, nuclear and chromosomal abnormalities, and senescence. Expression of the leukemia protein PML/RARα in hematopoietic progenitors displaces PML from telomeres and induces telomere shortening in the bone marrow of pre-leukemic mice. Our work provides a novel view of the physiologic function of PML, which participates in telomeres surveillance in normal cells. Our data further imply that a diminished PML function may contribute to cell senescence, genomic instability, and tumorigenesis. PMID:26119943

  5. Shortened leukocyte telomere length in type 2 diabetes mellitus: genetic polymorphisms in mitochondrial uncoupling proteins and telomeric pathways.

    Science.gov (United States)

    Zhou, Yuling; Ning, Zhixin; Lee, Yvonne; Hambly, Brett D; McLachlan, Craig S

    2016-12-01

    Current debate in type 2 diabetes (T2DM) has focused on shortened leukocyte telomere length (LTL) as the result of a number of possible causes, including polymorphisms in mitochondrial uncoupling proteins (UCPs) leading to oxidative stress, telomere regulatory pathway gene polymorphisms, or as a direct result of associated cardiovascular complications inducing tissue organ inflammation and oxidative stress. There is evidence that a heritable shorter telomere trait is a risk factor for development of T2DM. This review discusses the contribution and balance of genetic regulation of UCPs and telomere pathways in the context of T2DM. We discuss genotypes that are well known to influence the shortening of LTL, in particular OBFC1 and telomerase genotypes such as TERC. Interestingly, the interaction between short telomeres and T2DM risk appears to involve mitochondrial dysfunction as an intermediate process. A hypothesis is presented that genetic heterogeneity within UCPs may directly affect oxidative stress that feeds back to influence the fine balance of telomere regulation, cell cycle regulation and diabetes risk and/or metabolic disease progression. PMID:26951191

  6. Depleting components of the THO complex causes increased telomere length by reducing the expression of the telomere-associated protein Rif1p.

    Directory of Open Access Journals (Sweden)

    Tai-Yuan Yu

    Full Text Available Telomere length is regulated mostly by proteins directly associated with telomeres. However, genome-wide analysis of Saccharomyces cerevisiae mutants has revealed that deletion of Hpr1p, a component of the THO complex, also affects telomere length. The THO complex comprises four protein subunits, namely, Tho2p, Hpr1p, Mft1p, and Thp2p. These subunits interplay between transcription elongation and co-transcriptional assembly of export-competent mRNPs. Here we found that the deletion of tho2 or hpr1 caused telomere lengthening by ∼50-100 bps, whereas that of mft1 or thp2 did not affect telomere length. Since the THO complex functions in transcription elongation, we analyzed the expression of telomere-associated proteins in mutants depleted of complex components. We found that both the mRNA and protein levels of RIF1 were decreased in tho2 and hpr1 cells. RIF1 encodes a 1917-amino acid polypeptide that is involved in regulating telomere length and the formation of telomeric heterochromatin. Hpr1p and Tho2p appeared to affect telomeres through Rif1p, as increased Rif1p levels suppressed the telomere lengthening in tho2 and hpr1 cells. Moreover, yeast cells carrying rif1 tho2 or rif1 hpr1 double mutations showed telomere lengths and telomere silencing effects similar to those observed in the rif1 mutant. Thus, we conclude that mutations of components of the THO complex affect telomere functions by reducing the expression of a telomere-associated protein, Rif1p.

  7. Soleus Hoffmann reflex amplitudes are specifically modulated by cutaneous inputs from the arms and opposite leg during walking but not standing.

    Science.gov (United States)

    Suzuki, Shinya; Nakajima, Tsuyoshi; Futatsubashi, Genki; Mezzarane, Rinaldo A; Ohtsuka, Hiroyuki; Ohki, Yukari; Zehr, E Paul; Komiyama, Tomoyoshi

    2016-08-01

    Electrical stimulation of cutaneous nerves innervating heteronymous limbs (the arms or contralateral leg) modifies the excitability of soleus Hoffmann (H-) reflexes. The differences in the sensitivities of the H-reflex pathway to cutaneous afferents from different limbs and their modulation during the performance of motor tasks (i.e., standing and walking) are not fully understood. In the present study, we investigated changes in soleus H-reflex amplitudes induced by electrical stimulation of peripheral nerves. Selected targets for conditioning stimulation included the superficial peroneal nerve, which innervates the foot dorsum in the contralateral ankle (cSP), and the superficial radial nerve, which innervates the dorsum of the hand in the ipsilateral (iSR) or contralateral wrist (cSR). Stimulation and subsequent reflex assessment took place during the standing and early-stance phase of treadmill walking in ten healthy subjects. Cutaneous stimulation produced long-latency inhibition (conditioning-test interval of ~100 ms) of the H-reflex during the early-stance phase of walking, and the inhibition was stronger following cSP stimulation compared with iSR or cSR stimulation. In contrast, although similar conditioning stimulation significantly facilitated the H-reflex during standing, this effect remained constant irrespective of the different conditioning sites. These findings suggest that cutaneous inputs from the arms and contralateral leg had reversible effects on the H-reflex amplitudes, including inhibitions with different sensitivities during the early-stance phase of walking and facilitation during standing. Furthermore, the differential sensitivities of the H-reflex modulations were expressed only during walking when the locations of the afferent inputs were functionally relevant. PMID:27030502

  8. Telomere length homeostasis responds to changes in intracellular dNTP pools

    NARCIS (Netherlands)

    Gupta, Amitabha; Sharma, Sushma; Reichenbach, Patrick; Marjavaara, Lisette; Nilsson, Anna Karin; Lingner, Joachim; Chabes, Andrei; Rothstein, Rodney; Chang, Michael

    2013-01-01

    Telomeres, the ends of linear eukaryotic chromosomes, shorten due to incomplete DNA replication and nucleolytic degradation. Cells counteract this shortening by employing a specialized reverse transcriptase called telomerase, which uses deoxyribonucleoside triphosphates (dNTPs) to extend telomeres.

  9. Loss of ATRX Suppresses Resolution of Telomere Cohesion to Control Recombination in ALT Cancer Cells.

    Science.gov (United States)

    Ramamoorthy, Mahesh; Smith, Susan

    2015-09-14

    The chromatin-remodeler ATRX is frequently lost in cancer cells that use ALT (alternative lengthening of telomeres) for telomere maintenance, but its function in telomere recombination is unknown. Here we show that loss of ATRX suppresses the timely resolution of sister telomere cohesion that normally occurs prior to mitosis. In the absence of ATRX, the histone variant macroH2A1.1 binds to the poly(ADP-ribose) polymerase tankyrase 1, preventing it from localizing to telomeres and resolving cohesion. The resulting persistent telomere cohesion promotes recombination between sister telomeres, while it suppresses inappropriate recombination between non-sisters. Forced resolution of sister telomere cohesion induces excessive recombination between non-homologs, genomic instability, and impaired cell growth, indicating the ATRX-macroH2A1.1-tankyrase axis as a potential therapeutic target in ALT tumors. PMID:26373281

  10. 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.

  11. Telomere shortening may be associated with human keloids

    Directory of Open Access Journals (Sweden)

    Wilson Robert R

    2009-10-01

    Full Text Available Abstract Background Keloids are benign skin tumors that are the effect of a dysregulated wound-healing process in genetically predisposed patients. They are inherited with an autosomal dominant mode with incomplete clinical penetrance and variable expression. Keloids are characterized by formation of excess scar tissue beyond the boundaries of the wound. The exact etiology is still unknown and there is currently no appropriate treatment for keloid disease. Methods We analyzed sample tissues were obtained from 20 patients with keloid skin lesions and normal skin was obtained from 20 healthy donors. The telomeres were measured by Terminal Restriction Fragment (TRF analysis and Real-Time PCR assay. Quantitative Real-Time RT-PCR analysis of hTERT gene expression was performed and intracellular ROS generation was measured. Results In this study, we determined whether telomeric shortening and the expression of human telomerase reverse transcriptase (hTERT occurs in keloid patients. Using Terminal Restriction Fragment (TRF analysis and Real-Time PCR assay, we detected a significant telomere shortening of 30% in keloid specimens compared to normal skin. Using quantitative Real-Time RT-PCR, telomerase activity was found absent in the keloid tissues. Moreover, an increase in ROS generation was detected in fibroblasts cell cultures from keloid specimens as more time elapsed compared to fibroblasts from normal skin. Conclusion Telomere shortening has been reported in several metabolic and cardiovascular diseases. We found that telomere shortening can also be associated with human keloids. Chronic oxidative stress plays a major role in the pathophysiology of several chronic inflammatory diseases. Here we found increased ROS generation in fibroblasts from keloid fibroblasts cell cultures when compared to normal skin fibroblasts. Hence we conclude that oxidative stress might be an important modulator of telomere loss in keloid because of the absence of active

  12. Progressive telomere shortening and telomerase reactivation during hepatocellular carcinogenesis.

    Science.gov (United States)

    Miura, N; Horikawa, I; Nishimoto, A; Ohmura, H; Ito, H; Hirohashi, S; Shay, J W; Oshimura, M

    1997-01-01

    Telomeres shorten progressively with age in normal somatic cells in culture and in vivo. The maintenance of telomere length is assumed to be an obligatory step in the progression and immortalization of most human tumor cells. To understand the role of telomere dynamics in the development of hepatocellular carcinoma (HCC), we examined the length of terminal restriction fragment (TRF), as an indicator for telomere length, in HCC and surrounding tissues with chronic active hepatitis (CAH) or liver cirrhosis (LC). The study was performed in 12 hepatitis C virus (HCV) antibody-positive, 12 hepatitis B virus (HBV) antigen-positive tissues, and 4 tissue samples from virus-negative patients with HCC. The peak TRFs in all 3 types of HCC were significantly shorter than those of the surrounding tissues (i.e., LC or CAH). TRFs examined in one patient with atypical adenomatous hyperplasia (AAH) also was shortened. Thus, progressive TRF shortening occurs from normal to CAH to LC to HCC(AAH). Telomerase, an enzyme that adds repeated telomere sequences onto the chromosome ends and stabilizes telomere length in immortal cells, also was examined in tissues and detected in high levels almost exclusively in HCCs. Interestingly, the intensity of telomerase activity in the AAH case was similar to that of HCC. In addition, the telomerase activity of biopsy samples with a fine 21-gauge needle also was examined in 10 HCCs, 2 adenomatous hyperplasias (AHs), 2 LCs, and 2 CAHs. We found strong telomerase activity in all the HCCs and surprisingly in the 2 cases that were pathologically diagnosed as AH. Thus, the findings strongly suggest that persistent cell proliferation or rapid cell turnover through damage of hepatic cells result in a process of multistep hepatocellular carcinogenesis. Thus, progressive shortening of telomeres and the activation of telomerase may be a useful marker for the early detection of malignant progression in liver disease. PMID:9062581

  13. Telomere Length, Current Perceived Stress, and Urinary Stress Hormones in Women

    OpenAIRE

    Parks, Christine G.; Miller, Diane B; McCanlies, Erin C; Cawthon, Richard M; Andrew, Michael E; DeRoo, Lisa A.; Sandler, Dale P.

    2009-01-01

    Telomeres are repetitive DNA sequences that cap and protect the ends of chromosomes; critically short telomeres may lead to cellular senescence or carcinogenic transformation. Previous findings suggest a link between psychosocial stress, shorter telomeres, and chronic disease risk. This cross-sectional study examined relative telomere length in relation to perceived stress and urinary stress hormones in a sample of participants (n = 647) in the National Institute of Environmental Health Scien...

  14. 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.

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

    OpenAIRE

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

    2012-01-01

    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...

  16. Telomere extension by telomerase and ALT generates variant repeats by mechanistically distinct processes

    OpenAIRE

    Lee, Michael; Hills, Mark; Conomos, Dimitri; Stutz, Michael D.; Dagg, Rebecca A.; Lau, Loretta M. S.; Reddel, Roger R; Hilda A Pickett

    2013-01-01

    Telomeres are terminal repetitive DNA sequences on chromosomes, and are considered to comprise almost exclusively hexameric TTAGGG repeats. We have evaluated telomere sequence content in human cells using whole-genome sequencing followed by telomere read extraction in a panel of mortal cell strains and immortal cell lines. We identified a wide range of telomere variant repeats in human cells, and found evidence that variant repeats are generated by mechanistically distinct processes during te...

  17. Telomeric overhang length determines structural dynamics and accessibility to telomerase and ALT associated proteins

    OpenAIRE

    Hwang, Helen; Kreig, Alex; Calvert, Jacob; Lormand, Justin; Kwon, Yongho; Daley, James M.; Sung, Patrick; Opresko, Patricia L.; Myong, Sua

    2014-01-01

    The G-rich single stranded DNA at the 3′ end of human telomeres can self-fold into G-quaduplex (GQ). However, telomere lengthening by telomerase or the recombination-based alternative lengthening of telomere (ALT) mechanism requires protein loading on the overhang. Using single molecule fluorescence spectroscopy we discovered that lengthening the telomeric overhang also increased the rate of dynamic exchanges between structural conformations. Overhangs with five to seven TTAGGG repeats, compa...

  18. Shorter telomere length in peripheral blood leukocytes is associated with childhood autism

    OpenAIRE

    Li, Zongchang; Tang, Jinsong; LI Hong; Chen, Shan; He, Ying; Liao, Yanhui; Wei, Zhen; Wan, Guobin; XIANG, XI; Xia, Kun; Chen, Xiaogang

    2014-01-01

    Telomeres are protective chromosomal structures that play a key role in preserving genomic stability. Epidemiologic studies have shown that the abnormal telomere length in leukocytes is associated with some mental disorders and age-related diseases. However, the association between leukocyte telomere length and autism has not been investigated. Here we investigated the possible association between relative telomere length (RTL) in peripheral blood leukocytes and childhood autism by using an e...

  19. Telomere Length in Human Adults and High Level Natural Background Radiation

    OpenAIRE

    Birajalaxmi Das; Divyalakshmi Saini; Seshadri, M

    2009-01-01

    BACKGROUND: Telomere length is considered as a biomarker of aging, stress, cancer. It has been associated with many chronic diseases such as hypertension and diabetes. Although, telomere shortening due to ionizing radiation has been reported in vitro, no in vivo data is available on natural background radiation and its effect on telomere length. METHODOLOGY/PRINCIPAL FINDINGS: The present investigation is an attempt to determine the telomere length among human adults residing in high level na...

  20. High Phobic Anxiety Is Related to Lower Leukocyte Telomere Length in Women

    OpenAIRE

    Okereke, Olivia Ifeoma; Prescott, Jennifer; Wong, Jason Yat Yang; Han, Jiali; Rexrode, Kathryn Marian; Vivo, Immaculata

    2012-01-01

    Background: 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. Methodology/Principal Findings 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 pa...

  1. Functional diversification of yeast telomere associated protein, Rif1, in higher eukaryotes

    OpenAIRE

    Sreesankar Easwaran; Senthilkumar Ramamoorthy; Bharathi Vellaichamy; Mishra Rakesh K; Mishra Krishnaveni

    2012-01-01

    Abstract Background Telomeres are nucleoprotein complexes at the end of linear eukaryotic chromosomes which maintain the genome integrity by regulating telomere length, preventing recombination and end to end fusion events. Multiple proteins associate with telomeres and function in concert to carry out these functions. Rap1 interacting factor 1 (Rif1), was identified as a protein involved in telomere length regulation in yeast. Rif1 is conserved upto mammals but its function has diversified f...

  2. Role of saccharomyces cerevisiae Rif1 and Rif2 proteins in protection of telomeres

    OpenAIRE

    Anbalagan

    2013-01-01

    Eukaryotic cells distinguish their chromosome ends from accidental DNA double-strand breaks (DSBs) by packaging them into protective structures called telomeres that prevent DNA repair/recombination activities. In this work, we investigated the role of key telomeric proteins in protecting Saccharomyces cerevisiae telomeres from degradation. We show that the shelterin-like proteins Rif1, Rif2, and Rap1 inhibit nucleolytic processing at both de novo and native telomeres during G1 and G2 cell cy...

  3. Altered telomere homeostasis and resistance to skin carcinogenesis in Suv39h1 transgenic mice

    OpenAIRE

    Petti, Eleonora; Jordi, Fabian; Buemi, Valentina; Dinami, Roberto; Benetti, Roberta; Blasco, Maria A.; Schoeftner, Stefan

    2015-01-01

    The Suv39h1 and Suv39h2 H3K9 histone methyltransferases (HMTs) have a conserved role in the formation of constitutive heterochromatin and gene silencing. Using a transgenic mouse model system we demonstrate that elevated expression of Suv39h1 increases global H3K9me3 levels in vivo. More specifically, Suv39h1 overexpression enhances the imposition of H3K9me3 levels at constitutive heterochromatin at telomeric and major satellite repeats in primary mouse embryonic fibroblasts. Chromatin compac...

  4. Stem cell function and maintenance - ends that matter: Role of telomeres and telomerase

    Indian Academy of Sciences (India)

    Hamid Saeed; Mehwish Iqtedar

    2013-09-01

    Stem cell research holds a promise to treat and prevent age-related degenerative changes in humans. Literature is replete with studies showing that stem cell function declines with aging, especially in highly proliferative tissues/organs. Among others, telomerase and telomere damage is one of the intrinsic physical instigators that drive agerelated degenerative changes. In this review we provide brief overview of telomerase-deficient aging affects in diverse stem cells populations. Furthermore, potential disease phenotypes associated with telomerase dysregulation in a specific stem cell population is also discussed in this review. Additionally, the role of telomerase in stem cell driven cancer is also briefly touched upon.

  5. Rif1 supports the function of the CST complex in yeast telomere capping

    OpenAIRE

    S. Anbalagan; Bonetti, D; Lucchini, G; Longhese, MP

    2011-01-01

    Background: Telomere integrity in budding yeast depends on the CST (Cdc13-Stn1-Ten1) and shelterin-like (Rap1-Rif1-Rif2) complexes, which are thought to act independently from each other. Methodology: Here we show that a specific functional interaction indeed exists among components of the two complexes. In particular, unlike RIF2 deletion, the lack of Rif1 is lethal for stn1ΔC cells and causes a dramatic reduction in viability of cdc13-1 and cdc13-5 mutants. This synthetic interaction ...

  6. Dynamic Length Changes of Telomeres and Their Nuclear Organization in Chronic Myeloid Leukemia

    International Nuclear Information System (INIS)

    Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the t(9;22) translocation. As in most cancers, short telomeres are one of the features of CML cells, and telomere shortening accentuates as the disease progresses from the chronic phase to the blastic phase. Although most individual telomeres are short, some of them are lengthened, and long individual telomeres occur non-randomly and might be associated with clonal selection. Telomerase is the main mechanism used to maintain telomere lengths, and its activity increases when CML evolves toward advanced stages. ALT might be another mechanism employed by CML cells to sustain the homeostasis of their telomere lengths and this mechanism seems predominant at the early stage of leukemogenesis. Also, telomerase and ALT might jointly act to maintain telomere lengths at the chronic phase, and as CML progresses, telomerase becomes the major mechanism. Finally, CML cells display an altered nuclear organization of their telomeres which is characterized by the presence of high number of telomeric aggregates, a feature of genomic instability, and differential positioning of telomeres. CML represents a good model to study mechanisms responsible for dynamic changes of individual telomere lengths and the remodeling of telomeric nuclear organization throughout cancer progression

  7. Dynamic Length Changes of Telomeres and Their Nuclear Organization in Chronic Myeloid Leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Samassekou, Oumar [Manitoba Institute of Cell Biology, Cancer Care Manitoba, Department of Physiology, University of Manitoba, Winnipeg, Manitoba R3E 0V9 (Canada)

    2013-08-22

    Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the t(9;22) translocation. As in most cancers, short telomeres are one of the features of CML cells, and telomere shortening accentuates as the disease progresses from the chronic phase to the blastic phase. Although most individual telomeres are short, some of them are lengthened, and long individual telomeres occur non-randomly and might be associated with clonal selection. Telomerase is the main mechanism used to maintain telomere lengths, and its activity increases when CML evolves toward advanced stages. ALT might be another mechanism employed by CML cells to sustain the homeostasis of their telomere lengths and this mechanism seems predominant at the early stage of leukemogenesis. Also, telomerase and ALT might jointly act to maintain telomere lengths at the chronic phase, and as CML progresses, telomerase becomes the major mechanism. Finally, CML cells display an altered nuclear organization of their telomeres which is characterized by the presence of high number of telomeric aggregates, a feature of genomic instability, and differential positioning of telomeres. CML represents a good model to study mechanisms responsible for dynamic changes of individual telomere lengths and the remodeling of telomeric nuclear organization throughout cancer progression.

  8. A high rate of telomeric sister chromatid exchange occurs in chronic lymphocytic leukaemia B-cells.

    Science.gov (United States)

    Medves, Sandrine; Auchter, Morgan; Chambeau, Laetitia; Gazzo, Sophie; Poncet, Delphine; Grangier, Blandine; Verney, Aurélie; Moussay, Etienne; Ammerlaan, Wim; Brisou, Gabriel; Morjani, Hamid; Géli, Vincent; Palissot, Valérie; Berchem, Guy; Salles, Gilles; Wenner, Thomas

    2016-07-01

    Cancer cells protect their telomere ends from erosion through reactivation of telomerase or by using the Alternative Lengthening of Telomere (ALT) mechanism that depends on homologous recombination. Chronic lymphocytic leukaemia (CLL) B cells are characterized by almost no telomerase activity, shelterin deregulation and telomere fusions. To characterize telomeric maintenance mechanisms in B-CLL patients, we measured their telomere length, telomerase expression and the main hallmarks of the ALT activity i.e. C-circle concentration, an extra-chromosomal telomere repeat (ECTR), and the level of telomeric sister chromatid exchange (T-SCE) rate. Patients showed relative homogenous telomere length although almost no TERT transcript and nearly no C-circle were evidenced. Nevertheless, compared with normal B cells, B-CLL cells showed an increase in T-SCE rate that was correlated with a strong down-regulation of the topoisomerase III alpha (TOP3A) expression, involved in the dissolution of Holliday Junctions (HJ), together with an increased expression of SLX1A, SLX4, MUS81 and GEN1, involved in the resolution of HJ. Altogether, our results suggest that the telomere maintenance mechanism of B-CLL cells do not preferentially use telomerase or ALT. Rather, the rupture of the dissolvasome/resolvasome balance may increase telomere shuffling that could homogenize telomere length, slowing telomere erosion in this disease. PMID:26970083

  9. Telomere length abnormalities and telomerase RNA component expression in gastroenteropancreatic neuroendocrine tumors.

    Science.gov (United States)

    Kim, Hee Sung; Lee, Hye Seung; Nam, Kyung Han; Choi, Jiwoon; Kim, Woo Ho

    2015-06-01

    Telomere lengths in normal human cells are tightly regulated within a narrow range. Telomere length abnormalities are prevalent genetic alterations in malignant transformation. We studied telomere length abnormalities, telomerase RNA component (TERC) expression, alpha-thalassemia X-linked mental retardation (ATRX) expression, and death domain-associated protein (DAXX) expression in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We used tissue microarrays to perform telomere fluorescent in situ hybridization (FISH) and TERC in situ hybridization in 327 formalin-fixed paraffin-embedded tissues of GEP-NETs. Telomere length abnormalities were detected in 35% of 253 informative cases by using telomere FISH. Ten cases had altered lengthening of telomeres (ALT), an ALT-positive phenotype (4%), and 79 cases had telomere shortening (31%). The ALT-positive phenotype was significantly associated with tumors of pancreatic origin (7/10) and loss of ATRX or DAXX protein (8/10). Telomere shortening was significantly associated with low TERC expression. In the survival analysis, loss of ATRX or DAXX protein was associated with a decreased overall survival. Multivariate regression analysis showed that lymph node metastasis and high TERC expression were independent prognostic factors of reduced overall survival (OS) for patients with GEP-NETs. Our results showed that telomere lengthening (the ALT-positive phenotype) and telomere shortening accompanied by low TERC levels are two types of clinically significant telomere abnormalities in GEP-NETs. PMID:26026117

  10. Factors that influence telomeric oxidative base damage and repair by DNA glycosylase OGG1

    DEFF Research Database (Denmark)

    Rhee, David B; Ghosh, Avik; Lu, Jian; Bohr, Vilhelm A; Liu, Yie

    2011-01-01

    -telomeric double-stranded substrates. In addition, telomere repeat binding factors TRF1 and TRF2 do not impair OGG1 incision activity. Yet, 8-oxodG in some telomere structures (e.g., fork-opening, 3'-overhang, and D-loop) were less effectively excised by OGG1, depending upon its position in these substrates...

  11. Association of telomere length with authentic pluripotency of ES/iPS cells

    Institute of Scientific and Technical Information of China (English)

    Junjiu Huang; William W Ge; John CM Tsibris; David L Keefe; Lin Liu; Fang Wang; Maja Okuka; Na Liu; Guangzhen Ji; Xiaoying Ye; Bingfeng Zuo; Minshu Li; Ping Liang

    2011-01-01

    Telomerase and telomeres are important for indefinite replication of stem cells. Recently, telomeres of somatic cells were found to be reprogrammed to elongate in induced pluripotent stem cells(iPSCs). The role of telomeres in developmental pluripotency in vivo of embryonic stem cells(ESCs)or iPSCs, however, has not been directly addressed.We show that ESCs with long telomeres exhibit authentic developmental pluripotency, as evidenced by generation of complete ESC pups as well as germline-competent chimeras, the most stringent tests available in rodents. ESCs with short telomeres show reduced teratoma formation and chimera production, and fail to generate complete ESC pups. Telomere lengths are highly correlated(r>0.8)with the developmental pluripotency of ESCs. Short telomeres decrease the proliferative rate or capacity of ESCs, alter the expression of genes related to telomere epigenetics,down-regulate genes important for embryogenesis and disrupt germ cell differentiation. Moreover, iPSCs with longer telomeres generate chimeras with higher efficiency than those with short telomeres. Our data show that functional telomeres are essential for the developmental pluripotency of ESCs/iPSCs and suggest that telomere length may provide a valuable marker to evaluate stem cell pluripotency, particularly when the stringent tests are not feasible.

  12. Old Fathers and Long-Telomered Offspring: Elongation of Telomeres in the Testes of Older Men Versus Transgenerational Erosion of Germline Telomeres

    Directory of Open Access Journals (Sweden)

    Reinhard Stindl

    2011-01-01

    Full Text Available There have been several reports of a significant positive correlation between paternal age and chromosome telomere length in offspring. Moreover, the telomeres in sperm cells of older men tend to be longer than in young men, and it has been concluded that telomeres lengthen in the testes during adulthood. This would be the first evidence of an increasing biological advantage with age, and therefore contradicts current models in which telomere shortening is a biomarker of aging. Instead, an alternative model of telomere erosion between human generations is discussed in which longer germ cell telomeres in old men result from their being members of a previous generation. Based on the well-known correlation between maternal age and the incidence of aneuploid pregnancies, it is hypothesized that telomere erosion predominantly operates in the female germline, leading to a carry-over effect for both sexes into the next generation. This theory fits well with experimental results that maternal age does not correlate with longer telomeres in offspring. An experimental design is presented to distinguish be-tween the two possible scenarios leading to old fathers with long-telomered offspring - namely lifetime lengthening in the testis versus transgenerational germline erosion. Consideration of net loss of telomeric DNA between human generations is supported by recent findings of a large difference in blood telomere length between different Euro-pean populations of the same age, and is likely to have profound consequences for species evolution.

  13. 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.

  14. Therapeutic opportunities: Telomere maintenance in inducible pluripotent stem cells

    International Nuclear Information System (INIS)

    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.

  15. Telomere shortening in the colonial coral Acropora digitifera during development.

    Science.gov (United States)

    Tsuta, Hiroki; Shinzato, Chuya; Satoh, Nori; Hidaka, Michio

    2014-03-01

    To test whether telomere length can be used in estimating the age of colonial corals, we used terminal restriction fragment (TRF) length analysis to compare the telomere lengths of the coral Acropora digitifera at three developmental stages: sperm, planula larvae, and polyps of adult colonies. We also compared the mean TRF lengths between branches at the center and periphery of tabular colonies of A. digitifera. A significant difference was observed in the mean TRF lengths in sperm, planulae, and polyps. The mean TRF length was longest in sperm and shortest in polyps from adult colonies. These results suggest that telomere length decreases during coral development and may be useful for estimating coral age. However, the mean TRF length of branches at the center of a table-form colony tended to be longer than that of peripheral branches, although this difference was not statistically significant. This suggests that both the chronological age of polyps and cell proliferation rate influence telomere length in polyps, and that estimating coral age based on telomere length is not a simple endeavor. PMID:24601774

  16. Sde2: A novel nuclear protein essential for telomeric silencing and genomic stability in Schizosaccharomyces pombe

    Energy Technology Data Exchange (ETDEWEB)

    Sugioka-Sugiyama, Rie [Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577 (Japan); Initiative for the Promotion of Young Scientists' Independent Research, University of Tsukuba, Tsukuba, Ibaraki 305-8577 (Japan); Sugiyama, Tomoyasu, E-mail: sugiyamt@biol.tsukuba.ac.jp [Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577 (Japan); Initiative for the Promotion of Young Scientists' Independent Research, University of Tsukuba, Tsukuba, Ibaraki 305-8577 (Japan); Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012 (Japan)

    2011-03-18

    Research highlights: {yields} Sde2 is essential for telomere silencing. {yields} Sde2 is involved in the maintenance of genomic stability. {yields} Sde2 promotes the recruitment of SHREC, a histone deacetylase complex, to telomeres. -- Abstract: Telomeres, specialized domains assembled at the ends of linear chromosomes, are essential for genomic stability in eukaryotes. The formation and maintenance of telomeres are governed by numerous factors such as telomeric repeats, telomere-binding proteins, heterochromatin proteins, and telomerase. Here, we report Sde2, a novel nuclear protein essential for telomeric silencing and genomic stability in the fission yeast Schizosaccharomyces pombe. A deficiency in sde2 results in the derepression of the ura4{sup +} gene inserted near telomeric repeats, and the noncoding transcripts from telomeric regions accumulate in sde2{Delta} cells. The loss of Sde2 function compromises transcriptional silencing at telomeres, and this silencing defect is accompanied by increased levels of acetylated histone H3K14 and RNA polymerase II occupancy at telomeres as well as reduced recruitment of the SNF2 ATPase/histone deacetylase-containing complex SHREC to telomeres. Deletion of sde2 also leads to a higher frequency of mitotic minichromosome loss, and sde2{Delta} cells often form asci that contain spores in abnormal numbers, shapes, or both. In addition, sde2{Delta} cells are highly sensitive to several stresses, including high/low temperatures, bleomycin, which induces DNA damage, and thiabendazole, a microtubule-destabilizing agent. Furthermore, Sde2 genetically interacts with the telomere regulators Taz1, Pof3, and Ccq1. These findings demonstrate that Sde2 cooperates with other telomere regulators to maintain functional telomeres, thereby preventing genomic instability.

  17. Alternative lengthening of telomeres and loss of ATRX are frequent events in pleomorphic and dedifferentiated liposarcomas.

    Science.gov (United States)

    Lee, Jen-Chieh; Jeng, Yung-Ming; Liau, Jau-Yu; Tsai, Jia-Huei; Hsu, Hung-Han; Yang, Ching-Yao

    2015-08-01

    Telomerase activation and alternative lengthening of telomeres are two major mechanisms of telomere length maintenance. Soft tissue sarcomas appear to use the alternative lengthening of telomeres more frequently. Loss of α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein 6 (DAXX) expression has been implicated in the pathogenesis of alternative telomere lengthening in pancreatic endocrine neoplasm and glioma. The mechanism leading to the alternative lengthening of telomeres in liposarcoma remains unknown. Whereas alternative telomere lengthening was determined to be an indicator of poor prognosis in liposarcomas as a whole, its prognostic power has not been verified in any subtype of liposarcoma. In this study, we characterized the status of alternative telomere lengthening and expression of ATRX and DAXX in 111 liposarcomas (28 well-differentiated, 52 dedifferentiated, 20 myxoid or round cell, and 11 pleomorphic liposarcomas) by telomere fluorescence in situ hybridization and immunohistochemistry, respectively. Alternative lengthening of telomere was observed in 0% (0/16) of well-differentiated, 30% (14/46) of dedifferentiated, 5% (1/19) of myxoid or round cell, and 80% (8/10) of pleomorphic liposarcomas. Eighteen (16%) and one (1%) tumors were negative for ATRX and DAXX immunostaining, respectively. Remarkably, all cases with loss of either ATRX or DAXX expression had alternative lengthening of telomeres, and 83% (19/23) of tumors that had alternative lengthening of telomeres showed loss of either protein. The correlation between loss of either ATRX or DAXX and alternative telomere lengthening was 100% in dedifferentiated liposarcoma. The presence of alternative telomere lengthening in dedifferentiated liposarcoma suggested poor overall survival (hazard ratio=1.954, P=0.077) and was the most significant indicator of short progression-free survival (hazard ratio=3.119, P=0.003). In conclusion, we found that ATRX loss was

  18. Sde2: A novel nuclear protein essential for telomeric silencing and genomic stability in Schizosaccharomyces pombe

    International Nuclear Information System (INIS)

    Research highlights: → Sde2 is essential for telomere silencing. → Sde2 is involved in the maintenance of genomic stability. → Sde2 promotes the recruitment of SHREC, a histone deacetylase complex, to telomeres. -- Abstract: Telomeres, specialized domains assembled at the ends of linear chromosomes, are essential for genomic stability in eukaryotes. The formation and maintenance of telomeres are governed by numerous factors such as telomeric repeats, telomere-binding proteins, heterochromatin proteins, and telomerase. Here, we report Sde2, a novel nuclear protein essential for telomeric silencing and genomic stability in the fission yeast Schizosaccharomyces pombe. A deficiency in sde2 results in the derepression of the ura4+ gene inserted near telomeric repeats, and the noncoding transcripts from telomeric regions accumulate in sde2Δ cells. The loss of Sde2 function compromises transcriptional silencing at telomeres, and this silencing defect is accompanied by increased levels of acetylated histone H3K14 and RNA polymerase II occupancy at telomeres as well as reduced recruitment of the SNF2 ATPase/histone deacetylase-containing complex SHREC to telomeres. Deletion of sde2 also leads to a higher frequency of mitotic minichromosome loss, and sde2Δ cells often form asci that contain spores in abnormal numbers, shapes, or both. In addition, sde2Δ cells are highly sensitive to several stresses, including high/low temperatures, bleomycin, which induces DNA damage, and thiabendazole, a microtubule-destabilizing agent. Furthermore, Sde2 genetically interacts with the telomere regulators Taz1, Pof3, and Ccq1. These findings demonstrate that Sde2 cooperates with other telomere regulators to maintain functional telomeres, thereby preventing genomic instability.

  19. Mathematical model of alternative mechanism of telomere length maintenance

    CERN Document Server

    Kollár, Richard; Nosek, Jozef; Tomaska, Lubomir

    2014-01-01

    Biopolymer length regulation is a complex process that involves a large number of subprocesses acting simultaneously across multiple spatial and temporal scales. An illustrative example important for genomic stability is the length regulation of telomeres---nucleo-protein structures at the ends of linear chromosomes. Maintenance of telomeres is often facilitated by the enzyme telomerase but, particularly in telomerase-free systems, the maintenance of chromosomal termini depends on alternative lengthening of telomeres (ALT) mechanisms mediated by recombination. Various linear and circular DNA structures were identified to participate in ALT, however, dynamics of the whole process is still poorly understood. We propose a chemical kinetics model of ALT with kinetic rates systematically derived from the biophysics of DNA diffusion and looping. The reaction system is reduced to a coagulation-fragmentation system by quasi-steady state approximation. The detailed treatment of kinetic rates yields explicit formulae f...

  20. Telomere length is a biomarker of cumulative oxidative stress, biologic age, and an independent predictor of survival and therapeutic treatment requirement associated with smoking behavior.

    Science.gov (United States)

    Babizhayev, Mark A; Savel'yeva, Ekaterina L; Moskvina, Svetlana N; Yegorov, Yegor E

    2011-11-01

    Globally, tobacco use is associated with 5 million deaths per annum and is regarded as one of the leading causes of premature death. Major chronic disorders associated with smoking include cardiovascular diseases, several types of cancer, and chronic obstructive pulmonary disease (lung problems). Cigarette smoking (CS) generates a cumulative oxidative stress, which may contribute to the pathogenesis of chronic diseases. Mainstream and side stream gas-phase smoke each have about the same concentration of reactive free radical species, about 1 × 10(16) radicals per cigarette (or 5 × 10(14) per puff). This effect is critical in understanding the biologic effects of smoke. Several lines of evidence suggest that cigarette smoke constituents can directly activate vascular reactive oxygen species production. In this work we present multiple evidence that CS provide the important risk factors in many age-related diseases, and is associated with increased cumulative and systemic oxidative stress and inflammation. The cited processes are marked by increased white blood cell (leucocytes, WBCs) turnover. The data suggest an alteration of the circulating WBCs by CS, resulting in increased adherence to endothelial cells. Telomeres are complex DNA-protein structures located at the end of eukaryotic chromosomes. Telomere length shortens with biologic age in all replicating somatic cells. It has been shown that tobacco smoking enhances telomere shortening in circulating human WBCs. Telomere attrition (expressed in WBCs) can serve as a biomarker of the cumulative oxidative stress and inflammation induced by smoking and, consequently, show the pace of biologic aging. We originally propose that patented specific oral formulations of nonhydrolized carnosine and carcinine provide a powerful tool for targeted therapeutic inhibition of cumulative oxidative stress and inflammation and protection of telomere attrition associated with smoking. The longitudinal studies of the clinical

  1. Telomere Transcripts Target Telomerase in Human Cancer Cells

    Directory of Open Access Journals (Sweden)

    Theresa Kreilmeier

    2016-08-01

    Full Text Available Long non-coding transcripts from telomeres, called telomeric repeat-containing RNA (TERRA, were identified as blocking telomerase activity (TA, a telomere maintenance mechanism (TMM, in tumors. We expressed recombinant TERRA transcripts in tumor cell lines with TA and with alternative lengthening of telomeres (ALT to study effects on TMM and cell growth. Adeno- and lentivirus constructs (AV and LV were established for transient and stable expression of approximately 130 units of telomere hexanucleotide repeats under control of cytomegalovirus (CMV and human RNase P RNA H1 (hH1 promoters with and without polyadenylation, respectively. Six human tumor cell lines either using telomerase or ALT were infected and analyzed for TA levels. Pre-infection cells using telomerase had 1%–3% of the TERRA expression levels of ALT cells. AV and LV expression of recombinant TERRA in telomerase positive cells showed a 1.3–2.6 fold increase in TERRA levels, and a decrease in TA of 25%–58%. Dominant-negative or small hairpin RNA (shRNA viral expression against human telomerase reverse transcriptase (hTERT results in senescence, not induced by TERRA expression. Population doubling time, cell viability and TL (telomere length were not impacted by ectopic TERRA expression. Clonal growth was reduced by TERRA expression in TA but not ALT cell lines. ALT cells were not affected by treatments applied. Established cell models and tools may be used to better understand the role of TERRA in the cell, especially for targeting telomerase.

  2. Dimensions of religious involvement and leukocyte telomere length.

    Science.gov (United States)

    Hill, Terrence D; Ellison, Christopher G; Burdette, Amy M; Taylor, John; Friedman, Katherine L

    2016-08-01

    Although numerous studies suggest that religious involvement is associated with a wide range of favorable health outcomes, it is unclear whether this general pattern extends to cellular aging. In this paper, we tested whether leukocyte telomere length varies according to several dimensions of religious involvement. We used cross-sectional data from the Nashville Stress and Health Study (2011-2014), a large probability sample of 1252 black and white adults aged 22 to 69 living in Davidson County, TN, USA. Leukocyte telomere length was measured using the monochrome multiplex quantitative polymerase chain reaction method with albumin as the single-copy reference sequence. Dimensions of religious involvement included religiosity, religious support, and religious coping. Our multivariate analyses showed that religiosity (an index of religious attendance, prayer frequency, and religious identity) was positively associated with leukocyte telomere length, even with adjustments for religious support, religious coping, age, gender, race, education, employment status, income, financial strain, stressful life events, marital status, family support, friend support, depressive symptoms, smoking, heavy drinking, and allostatic load. Unlike religiosity, religious support and religious coping were unrelated to leukocyte telomere length across models. Depressive symptoms, smoking, heavy drinking, and allostatic load failed to explain any of the association between religiosity and telomere length. To our knowledge, this is the first population-based study to link religious involvement and cellular aging. Although our data suggest that adults who frequently attend religious services, pray with regularity, and consider themselves to be religious tend to exhibit longer telomeres than those who attend and pray less frequently and do not consider themselves to be religious, additional research is needed to establish the mechanisms underlying this association. PMID:27174242

  3. Multiple POT1-TPP1 Proteins Coat and Compact Long Telomeric Single-stranded DNA

    OpenAIRE

    Derek J. Taylor; Podell, Elaine R.; Taatjes, Dylan J; Cech, Thomas R.

    2011-01-01

    Telomeres are nucleoprotein complexes that cap and protect the ends of linear chromosomes. In humans, telomeres end in 50 – 300 nucleotides of G-rich single-stranded DNA (ssDNA) overhangs. Protection of telomeres 1 (POT1) binds with nanomolar affinity to the ssDNA overhangs and forms a dimer with another telomere-end binding protein called TPP1. Whereas most previous studies utilized telomeric oligonucleotides comprising single POT1-TPP1 binding sites, here we examined 72 – 144 nucleotide tra...

  4. Dynamic Localization of an Okazaki Fragment Processing Protein Suggests a Novel Role in Telomere Replication

    OpenAIRE

    CHOE, WONCHAE; Budd, Martin; Imamura, Osamu; Hoopes, Laura; Campbell, Judith L.

    2002-01-01

    We have found that the Dna2 helicase-nuclease, thought to be involved in maturation of Okazaki fragments, is a component of telomeric chromatin. We demonstrate a dynamic localization of Dna2p to telomeres that suggests a dual role for Dna2p, one in telomere replication and another, unknown function, perhaps in telomere capping. Both chromatin immunoprecipitation (ChIP) and immunofluorescence show that Dna2p associates with telomeres but not bulk chromosomal DNA in G1 phase, when there is no t...

  5. Regulating telomere length from the inside out: the replication fork model

    Science.gov (United States)

    2016-01-01

    Telomere length is regulated around an equilibrium set point. Telomeres shorten during replication and are lengthened by telomerase. Disruption of the length equilibrium leads to disease; thus, it is important to understand the mechanisms that regulate length at the molecular level. The prevailing protein-counting model for regulating telomerase access to elongate the telomere does not explain accumulating evidence of a role of DNA replication in telomere length regulation. Here I present an alternative model: the replication fork model that can explain how passage of a replication fork and regulation of origin firing affect telomere length. PMID:27401551

  6. PIAS1-mediated sumoylation promotes STUbL-dependent proteasomal degradation of the human telomeric protein TRF2.

    Science.gov (United States)

    Her, Joonyoung; Jeong, Yu Young; Chung, In Kwon

    2015-10-24

    The human telomeric protein TRF2 protects chromosome ends by facilitating their organization into the protective capping structure. Here we show that the stability of TRF2 is regulated via modification by the small ubiquitin-like modifiers (SUMO). TRF2 specifically interacts with and is sumoylated by PIAS1 in mammalian cells. The proteasome inhibitor stabilizes SUMO-conjugated TRF2 without affecting the level of unmodified TRF2, suggesting that SUMO conjugation is required for proteasomal degradation of TRF2. We also show that RNF4, a mammalian SUMO-targeted ubiquitin ligase, interacts with TRF2 in a SUMO-dependent manner and preferentially targets SUMO-conjugated TRF2 for ubiquitination. Collectively, our data demonstrate that the PIAS1-mediated sumoylation status of TRF2 serves as a molecular switch that controls the level of TRF2 at telomeres. PMID:26450775

  7. New prospects for targeting telomerase beyond the telomere.

    Science.gov (United States)

    Arndt, Greg M; MacKenzie, Karen L

    2016-08-01

    Telomerase activity is responsible for the maintenance of chromosome end structures (telomeres) and cancer cell immortality in most human malignancies, making telomerase an attractive therapeutic target. The rationale for targeting components of the telomerase holoenzyme has been strengthened by accumulating evidence indicating that these molecules have extra-telomeric functions in tumour cell survival and proliferation. This Review discusses current knowledge of the biogenesis, structure and multiple functions of telomerase-associated molecules intertwined with recent advances in drug discovery approaches. We also describe the fertile ground available for the pursuit of next-generation small-molecule inhibitors of telomerase. PMID:27339602

  8. A Mutation in the STN1 Gene Triggers an Alternative Lengthening of Telomere-Like Runaway Recombinational Telomere Elongation and Rapid Deletion in Yeast

    OpenAIRE

    Iyer, Shilpa; Chadha, Ashley D.; McEachern, Michael J.

    2005-01-01

    Some human cancer cells achieve immortalization by using a recombinational mechanism termed ALT (alternative lengthening of telomeres). A characteristic feature of ALT cells is the presence of extremely long and heterogeneous telomeres. The molecular mechanism triggering and maintaining this pathway is currently unknown. In Kluyveromyces lactis, we have identified a novel allele of the STN1 gene that produces a runaway ALT-like telomeric phenotype by recombination despite the presence of an a...

  9. Short communication: Telomere lengths in different tissues of dairy cows during early and late lactation.

    Science.gov (United States)

    Laubenthal, L; Hoelker, M; Frahm, J; Dänicke, S; Gerlach, K; Südekum, K-H; Sauerwein, H; Häussler, S

    2016-06-01

    Telomeres create a protective cap on the ends of chromosomes that shorten with cell division and are influenced by stressful conditions. With the onset of lactation, high-yielding dairy cows are exposed to metabolic stress. In the present study, we aimed to analyze telomere length (TL) in key metabolic organs, such as liver, subcutaneous (sc) adipose tissue (AT), and mammary gland, as well as in peripheral blood cells during early and late lactation in German Holstein cows (n=21). Animals were fed according to their requirement, and biopsies from scAT, liver, and mammary gland as well as blood cells were collected in early and late lactation. The relative quantity of telomere products (qT), which is proportional to the average TL, was determined in genomic DNA by multiplex quantitative PCR. In this study, relative qT varied widely in the investigated tissues and blood. In late lactation, slowly proliferating tissues, such as liver and scAT, had the highest qT, whereas peripheral blood cells and in the mammary gland had the lowest qT. Comparing early with late lactation, relative qT attrition was limited to blood and mammary gland. Relationships between relative qT in blood, mammary gland, scAT, and liver suggest that blood qT might serve as a surrogate marker for tissue-specific qT. Cows with high initial qT in tissues and blood in early lactation had greater qT attrition during the course of lactation than cows with lower qT. The determination of qT could be included when phenotyping dairy cattle to test for associations with performance and fitness traits. PMID:26995138

  10. 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.

  11. Suppression of Alternative Lengthening of Telomeres by Sp100-Mediated Sequestration of the MRE11/RAD50/NBS1 Complex

    OpenAIRE

    Jiang, Wei-Qin; Zhong, Ze-Huai; Henson, Jeremy D.; Neumann, Axel A.; Chang, Andy C.-M.; Reddel, Roger R

    2005-01-01

    Approximately 10% of cancers overall use alternative lengthening of telomeres (ALT) instead of telomerase to prevent telomere shortening, and ALT is especially common in astrocytomas and various types of sarcomas. The hallmarks of ALT in telomerase-negative cancer cells include a unique pattern of telomere length heterogeneity, rapid changes in individual telomere lengths, and the presence of ALT-associated promyelocytic leukemia bodies (APBs) containing telomeric DNA and proteins involved in...

  12. Getting it done at the ends: Pif1 family DNA helicases and telomeres.

    Science.gov (United States)

    Geronimo, Carly L; Zakian, Virginia A

    2016-08-01

    It is widely appreciated that the ends of linear DNA molecules cannot be fully replicated by the conventional replication apparatus. Less well known is that semi-conservative replication of telomeric DNA also presents problems for DNA replication. These problems likely arise from the atypical chromatin structure of telomeres, the GC-richness of telomeric DNA that makes it prone to forming DNA secondary structures, and from RNA-DNA hybrids, formed by transcripts of one or both DNA strands. Given the different aspects of telomeres that complicate their replication, it is not surprising that multiple DNA helicases promote replication of telomeric DNA. This review focuses on one such class of DNA helicases, the Pif1 family of 5'-3' DNA helicases. In budding and fission yeasts, Pif1 family helicases impact both telomerase-mediated and semi-conservative replication of telomeric DNA as well as recombination-mediated telomere lengthening. PMID:27233114

  13. 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. PMID:24091626

  14. The paradox of longer sperm telomeres in older men's testes: a birth-cohort effect caused by transgenerational telomere erosion in the female germline.

    Science.gov (United States)

    Stindl, Reinhard

    2016-01-01

    Longer telomeres in the somatic cells of an individual have been regarded as a marker of youth and biological fitness within a population. Yet, several research groups have reported the surprising findings of longer telomeres in the germ cells of older men, which translated into longer leukocyte telomere length in their offspring. Although all these studies were purely cross-sectional, a longitudinal trend in the aging testes of individual males was taken for granted. Recently, a high-profile study reported a negative birth-cohort effect on leukocyte mean telomere length in human populations, namely the progressive loss of telomeric sequence between healthy human generations. This is what I based my theory of telomere-driven macroevolution on, 12 years ago. On the basis of published data on telomere length inheritance, I identified the source of human intergenerational telomere erosion in the female germline. Accordingly, because of the resulting birth-cohort effect, there is no need for any paradoxical telomere lengthening in older men's gonads to interpret the old-father-long-telomered-offspring data. PMID:26858775

  15. 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

  16. 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.

  17. Dynamics of telomere length in different age groups in a Latvian population.

    Science.gov (United States)

    Zole, Egija; Pliss, Liana; Ranka, Renate; Krumina, Astrida; Baumanis, Viesturs

    2013-12-01

    The shortening of telomeres with ageing is a well-documented observation; however, the reported number of nucleotides in telomeres varies between different laboratories and studies. Such variability is likely caused by ethnic differences between the populations studied. Until now, there were no studies that investigated the variability of telomere length in a senescent Latvian population of the most common mitochondrial haplogroups, defined as H (45%), U (25%), Y chromosomal N1c (40%) and R1a1 (40%). Telomere length was determined in 121 individuals in different age groups, including a control group containing individuals of 20-40 years old and groups of individuals between 60-70 years old, 71-80 years old, 81-90 years old, and above 90 years old. Telomere length was determined using the Southern blot telomeric restriction fragment assay (TRF). Decreased telomere length with ageing was confirmed, but a comparison of centenarians and individuals between 60-90 years of age did not demonstrate a significant difference in telomere length. However, significant variability in telomere length was observed in the control group, indicating probable rapid telomere shortening in some individuals that could lead up to development of health status decline appearing with ageing. Telomere length measured in mononuclear blood cells (MNC) was compared with the telomere length measured in whole peripheral white blood cells (WBC) using TRF. Telomere length in MNC was longer than in WBC for the control group with individuals 20 to 40 years old; in contrast, for the group of individuals aged 65 to 85 years old, measured telomere length was shorter in MNC when compared to WBC. PMID:23919820

  18. 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

  19. Higher order nuclear organization in growth arrest of humanmammary epithelial cells: A novel role for telomere-associated proteinTIN2

    Energy Technology Data Exchange (ETDEWEB)

    Kaminker, Patrick; Plachot, Cedric; Kim, Sahn-Ho; Chung, Peter; Crippen, Danielle; Petersen, Ole W.; Bissell, Mina J.; Campisi, Judith; Lelievre, Sophie A.

    2004-12-15

    Nuclear organization, such as the formation of specific nuclear subdomains, is generally thought to be involved in the control of cellular phenotype; however, there are relatively few specific examples of how mammalian nuclei organize during radical changes in phenotype, such as those which occur during differentiation and growth arrest. Using human mammary epithelial cells (HMECs) in which growth arrest is essential for morphological differentiation, we show that the arrest of cell proliferation is accompanied by a reorganization of the telomere-associated protein, TIN2, into one to three large nuclear subdomains. The large TIN2 domains do not contain telomeres and occur concomitant with the continued presence of TIN2 at telomeres. The TIN2 domains were sensitive to DNAse, but not RNAse, occurred frequently, but not exclusively near nucleoli, and overlapped often with dense domains containing heterochromatin protein l{gamma}. Expression of truncated forms of TIN2 simultaneously prevented the formation of TIN2 domains and relaxed the stringent morphogenesis-induced growth arrest in HMECs. Our findings reveal a novel extra-telomeric organization of TIN2 associated with the control of cell proliferation and identify TIN2 as an important regulator of mammary epithelial differentiation.

  20. Traffic noise exposure affects telomere length in nestling house sparrows.

    Science.gov (United States)

    Meillère, Alizée; Brischoux, François; Ribout, Cécile; Angelier, Frédéric

    2015-09-01

    In a consistently urbanizing world, anthropogenic noise has become almost omnipresent, and there are increasing evidence that high noise levels can have major impacts on wildlife. While the effects of anthropogenic noise exposure on adult animals have been widely studied, surprisingly, there has been little consideration of the effects of noise pollution on developing organisms. Yet, environmental conditions experienced in early life can have dramatic lifelong consequences for fitness. Here, we experimentally manipulated the acoustic environment of free-living house sparrows (Passer domesticus) breeding in nest boxes. We focused on the impact of such disturbance on nestlings' telomere length and fledging success, as telomeres (the protective ends of chromosomes) appear to be a promising predictor of longevity. We showed that despite the absence of any obvious immediate consequences (growth and fledging success), nestlings reared under traffic noise exposure exhibited reduced telomere lengths compared with their unexposed neighbours. Although the mechanisms responsible for this effect remain to be determined, our results provide the first experimental evidence that noise alone can affect a wild vertebrate's early-life telomere length. This suggests that noise exposure may entail important costs for developing organisms. PMID:26382074

  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. Leukocyte Telomere Length and Late-Life Depression

    NARCIS (Netherlands)

    Schaakxs, Roxanne; Verhoeven, Josine E.; Oude Voshaar, Richard; Comijs, Hannie C.; Penninx, Brenda W. J. H.

    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

  3. siRNA-mediated methylation of Arabidopsis telomeres

    Czech Academy of Sciences Publication Activity Database

    Vrbský, Jan; Akimcheva, S.; Watson, M.; Turner, T.L.; Daxinger, L.; Vyskot, Boris; Aufsatz, W.; Říha, K.

    2010-01-01

    Roč. 6, č. 6 (2010), s. 1-12. ISSN 1553-7390 R&D Projects: GA MŠk(CZ) LC06004 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : DNA methylation * siRNA * telomere Subject RIV: BO - Biophysics Impact factor: 9.543, year: 2010

  4. Drug addiction is associated with leukocyte telomere length

    Science.gov (United States)

    Yang, Zhaoyang; Ye, Junyi; Li, Candong; Zhou, Daizhan; Shen, Qin; Wu, Ji; Cao, Lan; Wang, Ting; Cui, Daxiang; He, Shigang; Qi, Guoyang; He, Lin; Liu, Yun

    2013-01-01

    Telomeres are protective chromosomal structures that play a key role in preserving genomic stability. Telomere length is known to be associated with ageing and age-related diseases. To study the impairment of telomeres induced by drug abuse, we conducted an association study in the Chinese Han population. Multivariate linear regression analyses were performed to evaluate the correlation of leukocyte telomere length (LTL) with addiction control status adjusted for age and gender. The results showed that drug abusers exhibited significantly shorter LTLs than controls (P = 1.32e−06). The time before relapse also presented an inverse correlation with LTL (P = 0.02). Drug abusers who had used heroin and diazepam displayed a shorter LTL than those taking other drugs (P = 0.018 and P = 0.009, respectively). Drug abusers who had ingested drugs via snuff exhibited longer LTLs than those using other methods (P = 0.02). These observations may offer a partial explanation for the effects of drug addiction on health. PMID:23528991

  5. Most Correlated Arms Identification

    OpenAIRE

    Liu, Che-Yu; Bubeck, Sébastien

    2014-01-01

    We study the problem of finding the most mutually correlated arms among many arms. We show that adaptive arms sampling strategies can have significant advantages over the non-adaptive uniform sampling strategy. Our proposed algorithms rely on a novel correlation estimator. The use of this accurate estimator allows us to get improved results for a wide range of problem instances.

  6. 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.

  7. PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases.

    Science.gov (United States)

    Xiong, Shiqin; Patrushev, Nikolay; Forouzandeh, Farshad; Hilenski, Lula; Alexander, R Wayne

    2015-09-01

    Cellular senescence and organismal aging predispose age-related chronic diseases, such as neurodegenerative, metabolic, and cardiovascular disorders. These diseases emerge coincidently from elevated oxidative/electrophilic stress, inflammation, mitochondrial dysfunction, DNA damage, and telomere dysfunction and shortening. Mechanistic linkages are incompletely understood. Here, we show that ablation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) accelerates vascular aging and atherosclerosis, coinciding with telomere dysfunction and shortening and DNA damage. PGC-1α deletion reduces expression and activity of telomerase reverse transcriptase (TERT) and increases p53 levels. Ectopic expression of PGC-1α coactivates TERT transcription and reverses telomere malfunction and DNA damage. Furthermore, alpha lipoic acid (ALA), a non-dispensable mitochondrial cofactor, upregulates PGC-1α-dependent TERT and the cytoprotective Nrf-2-mediated antioxidant/electrophile-responsive element (ARE/ERE) signaling cascades, and counteracts high-fat-diet-induced, age-dependent arteriopathy. These results illustrate the pivotal importance of PGC-1α in ameliorating senescence, aging, and associated chronic diseases, and may inform novel therapeutic approaches involving electrophilic specificity. PMID:26299964

  8. PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases

    Directory of Open Access Journals (Sweden)

    Shiqin Xiong

    2015-09-01

    Full Text Available Cellular senescence and organismal aging predispose age-related chronic diseases, such as neurodegenerative, metabolic, and cardiovascular disorders. These diseases emerge coincidently from elevated oxidative/electrophilic stress, inflammation, mitochondrial dysfunction, DNA damage, and telomere dysfunction and shortening. Mechanistic linkages are incompletely understood. Here, we show that ablation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α accelerates vascular aging and atherosclerosis, coinciding with telomere dysfunction and shortening and DNA damage. PGC-1α deletion reduces expression and activity of telomerase reverse transcriptase (TERT and increases p53 levels. Ectopic expression of PGC-1α coactivates TERT transcription and reverses telomere malfunction and DNA damage. Furthermore, alpha lipoic acid (ALA, a non-dispensable mitochondrial cofactor, upregulates PGC-1α-dependent TERT and the cytoprotective Nrf-2-mediated antioxidant/electrophile-responsive element (ARE/ERE signaling cascades, and counteracts high-fat-diet-induced, age-dependent arteriopathy. These results illustrate the pivotal importance of PGC-1α in ameliorating senescence, aging, and associated chronic diseases, and may inform novel therapeutic approaches involving electrophilic specificity.

  9. Csm4, in collaboration with Ndj1, mediates telomere-led chromosome dynamics and recombination during yeast meiosis.

    Directory of Open Access Journals (Sweden)

    Jennifer J Wanat

    Full Text Available Chromosome movements are a general feature of mid-prophase of meiosis. In budding yeast, meiotic chromosomes exhibit dynamic movements, led by nuclear envelope (NE-associated telomeres, throughout the zygotene and pachytene stages. Zygotene motion underlies the global tendency for colocalization of NE-associated chromosome ends in a "bouquet." In this study, we identify Csm4 as a new molecular participant in these processes and show that, unlike the two previously identified components, Ndj1 and Mps3, Csm4 is not required for meiosis-specific telomere/NE association. Instead, it acts to couple telomere/NE ensembles to a force generation mechanism. Mutants lacking Csm4 and/or Ndj1 display the following closely related phenotypes: (i elevated crossover (CO frequencies and decreased CO interference without abrogation of normal pathways; (ii delayed progression of recombination, and recombination-coupled chromosome morphogenesis, with resulting delays in the MI division; and (iii nondisjunction of homologs at the MI division for some reason other than absence of (the obligatory CO(s. The recombination effects are discussed in the context of a model where the underlying defect is chromosome movement, the absence of which results in persistence of inappropriate chromosome relationships that, in turn, results in the observed mutant phenotypes.

  10. Genomic Organization of the Drosophila Telomere RetrotransposableElements

    Energy Technology Data Exchange (ETDEWEB)

    George, J.A.; DeBaryshe, P.G.; Traverse, K.L.; Celniker, S. E.; Pardue, M-L.

    2006-10-16

    The emerging sequence of the heterochromatic portion of the Drosophila melanogaster genome, with the most recent update of euchromatic sequence, gives the first genome-wide view of the chromosomal distribution of the telomeric retrotransposons, HeT-A, TART, and Tahre. As expected, these elements are entirely excluded from euchromatin, although sequence fragments of HeT-A and TART 3 untranslated regions are found in nontelomeric heterochromatin on the Y chromosome. The proximal ends of HeT-A/TART arrays appear to be a transition zone because only here do other transposable elements mix in the array. The sharp distinction between the distribution of telomeric elements and that of other transposable elements suggests that chromatin structure is important in telomere element localization. Measurements reported here show (1) D. melanogaster telomeres are very long, in the size range reported for inbred mouse strains (averaging 46 kb per chromosome end in Drosophila stock 2057). As in organisms with telomerase, their length varies depending on genotype. There is also slight under-replication in polytene nuclei. (2) Surprisingly, the relationship between the number of HeT-A and TART elements is not stochastic but is strongly correlated across stocks, supporting the idea that the two elements are interdependent. Although currently assembled portions of the HeT-A/TART arrays are from the most-proximal part of long arrays, {approx}61% of the total HeT-A sequence in these regions consists of intact, potentially active elements with little evidence of sequence decay, making it likely that the content of the telomere arrays turns over more extensively than has been thought.

  11. Childhood Physical and Sexual Abuse History and Leukocyte Telomere Length among Women in Middle Adulthood.

    Directory of Open Access Journals (Sweden)

    Susan M Mason

    Full Text Available Abuse victimization in childhood is associated with a variety of age-related cardiometabolic diseases, but the mechanisms remain unknown. Telomeres, which form the protective caps at the ends of chromosomes, have been proposed as measures of biological age, and a growing body of research suggests that telomere attrition may help to explain relationships between stress and cardiometabolic degradation. We examined the association between childhood abuse victimization and leukocyte telomere length among 1,135 participants in the Nurses' Health Study II (NHSII.The NHSII ascertained physical and sexual child abuse histories in 2001. Telomere length was measured in genomic DNA extracted from peripheral blood leukocytes collected between 1996 and 1999. The ratio of telomere repeat copy number to a single gene copy number (T/S was determined by a modified version of the quantitative real-time PCR telomere assay. Telomere length was log-transformed and corrected for assay variation across batch. We regressed telomere length on childhood abuse exposure variables and covariates using linear regression.We observed a reduction in telomere length associated with moderate physical abuse versus no physical abuse, but there was no evidence of a dose-response relationship for increased severity of physical abuse. No associations were noted for sexual abuse.We found no evidence of an association between severity of childhood physical or sexual abuse and leukocyte telomere length in the NHSII.

  12. Variations in telomere maintenance and the role of telomerase inhibition in gastrointestinal cancer

    Directory of Open Access Journals (Sweden)

    Heeg S

    2015-12-01

    Full Text Available Steffen Heeg Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Medical Center – University of Freiburg, Freiburg, Germany Abstract: Immortalization is an important step toward the malignant transformation of human cells and is critically dependent upon telomere maintenance. There are two known mechanisms to maintain human telomeres. The process of telomere maintenance is either mediated through activation of the enzyme telomerase or through an alternative mechanism of telomere lengthening called ALT. While 85% of all human tumors show reactivation of telomerase, the remaining 15% are able to maintain telomeres via ALT. The therapeutic potential of telomerase inhibitors is currently investigated in a variety of human cancers. Gastrointestinal tumors are highly dependent on telomerase as a mechanism of telomere maintenance, rendering telomeres as well as telomerase potential targets for cancer therapy. This article focuses on the molecular mechanisms of telomere biology and telomerase activation in gastrointestinal cancers and reviews strategies of telomerase inhibition and their potential therapeutic use in these tumor entities. Keywords: telomere based therapy, gastrointestinal cancer, telomere maintenance, telomerase inhibition

  13. Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies.

    Science.gov (United States)

    Jafri, Mohammad A; Ansari, Shakeel A; Alqahtani, Mohammed H; Shay, Jerry W

    2016-01-01

    Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized. PMID:27323951

  14. TERRA-Reinforced Association of LSD1 with MRE11 Promotes Processing of Uncapped Telomeres

    Directory of Open Access Journals (Sweden)

    Antonio Porro

    2014-02-01

    Full Text Available Telomeres protect chromosome ends from being recognized as sites of DNA damage. Upon telomere shortening or telomere uncapping induced by loss of telomeric repeat-binding factor 2 (TRF2, telomeres elicit a DNA-damage response leading to cellular senescence. Here, we show that following TRF2 depletion, the levels of the long noncoding RNA TERRA increase and LSD1, which binds TERRA, is recruited to telomeres. At uncapped telomeres, LSD1 associates with MRE11, one of the nucleases implicated in the processing of 3′ telomeric G overhangs, and we show that LSD1 is required for efficient removal of these structures. The LSD1-MRE11 interaction is reinforced in vivo following TERRA upregulation in TRF2-deficient cells and in vitro by TERRA-mimicking RNA oligonucleotides. Furthermore, LSD1 enhances the nuclease activity of MRE11 in vitro. Our data indicate that recruitment of LSD1 to deprotected telomeres requires MRE11 and is promoted by TERRA. LSD1 stimulates MRE11 catalytic activity and nucleolytic processing of uncapped telomeres.

  15. Telomere length in hepatocellular carcinoma and paired adjacent non-tumor tissues by quantitative PCR.

    Science.gov (United States)

    Zhang, Yujing; Shen, Jing; Ming-Whei; Lee, Yu Po-Huang; Santella, Regina M

    2007-12-01

    Telomere shortening limits the proliferative capacity of human cells, restrains the regenerative capacity of organ systems during chronic diseases and aging and also induces chromosomal instability as well as initiation of cancer. Previous studies demonstrated that telomeres are often significantly shorter in tumor tissue, including hepatocellular carcinoma (HCC), compared to the surrounding tissue, but telomere length in HCC tissues was not correlated with several clinical parameters, such as age, sex, HBV or HCV infections and tumor size. In the present study, the telomere length ratio of 36 paired HCC, and their adjacent non-tumor tissues was measured by quantitative PCR (Q-PCR). The mean telomere lengths (SD) for HCC and adjacent non-tumor tissues were 0.26 (0.10) and 0.47 (0.20) respectively (t = 6.22, P telomere length in tumor and adjacent non-tumor tissues. The number of tumors with telomere length shorter than 0.50 was much higher than that of adjacent non-tumor tissues; more than 90% of the tissues with telomere length > or = 0.50 were adjacent non-tumor tissues. The correlations between telomere length and aflatoxin B1- and polycyclic aromatic hydrocarbon-DNA adducts level, p53 mutations and p16 hypermethylation status were also tested, but no significant associations were found. The relationship between telomere length shortening, chemical carcinogen exposure, and genetic and epigenetic changes in hepatocarcinogenesis needs further investigation. PMID:18058461

  16. The arms race control

    International Nuclear Information System (INIS)

    Written in 1961, this paper presents the content of a book entitled 'The arms race control' where the author outlined the difference between disarmament and arms control, described the economic and moral role of arms race, the importance of force balance for international security. He wandered whether arms control could ensure this balance and whether nuclear balance meant force balance. Force balance then appears to be a precarious and unsteady component of international security. He commented the challenges of disarmament, recalled some arguments for a nuclear disarmament. Then he discussed what would be an arms control with or without disarmament (either nuclear or conventional)

  17. HCCS1-armed, quadruple-regulated oncolytic adenovirus specific for liver cancer as a cancer targeting gene-viro-therapy strategy

    Directory of Open Access Journals (Sweden)

    Xu Hai-Neng

    2011-11-01

    Full Text Available Abstract Background In previously published studies, oncolytic adenovirus-mediated gene therapy has produced good results in targeting cancer cells. However, safety and efficacy, the two most important aspects in cancer therapy, remain serious challenges. The specific expression or deletion of replication related genes in an adenovirus has been frequently utilized to regulate the cancer cell specificity of a virus. Accordingly, in this study, we deleted 24 bp in E1A (bp924-bp947 and the entirety of E1B, including those genes encoding E1B 55kDa and E1B19kDa. We used the survivin promoter (SP to control E1A in order to construct a new adenovirus vector named Ad.SP.E1A(Δ24.ΔE1B (briefly Ad.SPDD. HCCS1 (hepatocellular carcinoma suppressor 1 is a novel tumor suppressor gene that is able to specifically induce apoptosis in cancer cells. The expression cassette AFP-HCCS1-WPRE-SV40 was inserted into Ad.SPDD to form Ad.SPDD-HCCS1, enabling us to improve the safety and efficacy of oncolytic-mediated gene therapy for liver cancer. Results Ad.SPDD showed a decreased viral yield and less toxicity in normal cells but enhanced toxicity in liver cancer cells, compared with the cancer-specific adenovirus ZD55 (E1B55K deletion. Ad.SPDD-HCCS1 exhibited a potent anti-liver-cancer ability and decreased toxicity in vitro. Ad.SPDD-HCCS1 also showed a measurable capacity to inhibit Huh-7 xenograft tumor growth on nude mice. The underlying mechanism of Ad.SPDD-HCCS1-induced liver cancer cell death was found to be via the mitochondrial apoptosis pathway. Conclusions These results demonstrate that Ad.SPDD-HCCS1 was able to elicit reduced toxicity and enhanced efficacy both in vitro and in vivo compared to a previously constructed oncolytic adenovirus. Ad.SPDD-HCCS1 could be a promising candidate for liver cancer therapy.

  18. Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis.

    Science.gov (United States)

    Oh, Bong-Kyeong; Kim, Young-Joo; Park, Chanil; Park, Young Nyun

    2005-01-01

    The telomeric repeat-binding factor 1 (TRF1), TRF2, and the TRF1-interacting nuclear protein 2 (TIN2) are involved in telomere maintenance. We describe the regulation of expression of these genes along with their relationship to telomere length in hepatocarcinogenesis. The transcriptional expression of these genes, TRF1 protein, and telomere length was examined in 9 normal livers, 14 chronic hepatitis, 24 liver cirrhosis, 5 large regenerative nodules, 14 low-grade dysplastic nodules (DNs), 7 high-grade DNs, 10 DNs with hepatocellular carcinoma (HCC) foci, and 31 HCCs. The expression of TRF1, TRF2, TIN2 mRNA, and TRF1 protein was gradually increased according to the progression of hepatocarcinogenesis with a marked increase in high-grade DNs and DNs with HCC foci and a further increase in HCCs. There was a gradual shortening of telomere during hepatocarcinogenesis with a significant reduction in length in DNs. Most nodular lesions (52 of 67) had shorter telomeres than their adjacent chronic hepatitis or liver cirrhosis, and the telomere lengths were inversely correlated with the mRNA level of these genes (P HCC foci. In conclusion, TRF1, TRF2, and TIN2 might be involved in multistep hepatocarcinogenesis by playing crucial roles in telomere shortening. PMID:15632001

  19. Selected Telomere Length Changes and Aberrant Three-dimensional Nuclear Telomere Organization during Fast-Onset Mouse Plasmacytomas

    Directory of Open Access Journals (Sweden)

    Alexandra Kuzyk

    2012-04-01

    Full Text Available Mouse plasmacytoma (PCT can develop within 45 days when induced by a v-abl/myc replication-deficient retrovirus. This fast-onset PCT development is always associated with trisomy of cytoband E2 of mouse chromosome 11 (11E2. Trisomy of 11E2 was identified as the sole aberration in all fast-onset mouse PCTs in [T38HxBALB/c]N congenic mice, with a reciprocal translocation between chromosome X and 11 (rcpT(X;11 (Genes Cancer 2010;1:847–858. Using this mouse model, we have now examined the overall and individual telomere lengths in fast-onset PCTs compared with normal B cells using two-dimensional and three-dimensional quantitative fluorescent in situ hybridization of telomeres. We found fast-onset PCTs to have a significantly different three-dimensional telomere profile, compared with primary B cells of wild-type littermates with and without rcpT(X;11 (P < .0001 and P = .006, respectively. Our data also indicate for primary PCT cells, from the above mouse strain, that the translocation chromosome carrying 11E2 is the only chromosome with telomere lengthening (P = 4 x 10-16. This trend is not seen for T(X;11 in primary B cells of control [T38HxBALB/c]N mice with the rcpT(X;11. This finding supports the concept of individual telomere lengthening of chromosomes that are functionally important for the tumorigenic process.

  20. Ku is required for telomeric C-rich strand maintenance but not for end-to-end chromosome fusions in Arabidopsis

    OpenAIRE

    Riha, Karel; Dorothy E Shippen

    2003-01-01

    Telomere dysfunction arising from mutations in telomerase or in telomere capping proteins leads to end-to-end chromosome fusions. Paradoxically, the Ku70/80 heterodimer, essential for nonhomologous end-joining double-strand break repair, is also found at telomeres, and in mammals it is required to prevent telomere fusion. Previously, we showed that inactivation of Ku70 in Arabidopsis results in telomere lengthening. Here, we have demonstrated that this telomere elongation is telomerase depend...

  1. Telomere shortening: a new prognostic factor for cardiovascular disease post-radiation exposure

    International Nuclear Information System (INIS)

    Telomere length has been proposed as a marker of mitotic cell age and as a general index of human organism aging. Telomere shortening in peripheral blood lymphocytes has been linked to cardiovascular-related morbidity and mortality. The authors investigated the potential correlation of conventional risk factors, radiation dose and telomere shortening with the development of coronary artery disease (CAD) following radiation therapy in a large cohort of Hodgkin lymphoma (HL) patients. Multivariate analysis demonstrated that hypertension and telomere length were the only independent risk factors. This is the first study in a large cohort of patients that demonstrates significant telomere shortening in patients treated by radiation therapy who developed cardiovascular disease. Telomere length appears to be an independent prognostic factor that could help determine patients at high risk of developing CAD after exposure in order to implement early detection and prevention. (authors)

  2. 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.

  3. Age-dependence of relative telomere length profiles during spermatogenesis in man

    DEFF Research Database (Denmark)

    Jørgensen, Pernille Bach; Fedder, Jens; Koelvraa, Steen;

    2013-01-01

    Telomeres, the protective structures at the outmost ends of chromosomes, shorten in all somatic cells with each cell-division and by cumulative oxidative damage. To counteract that these shortened telomeres are passed on to offspring, the telomeres are elongated by the enzyme, telomerase, during...... human spermatogenesis. A few groups have tried to elucidate this process by measuring telomerase activity in the various cell-types during spermatogenesis, but until now, no one has ever measured telomere length (TL) during these different stages in humans. Some groups have measured TL in spermatozoa...... measured by telomere QFISH. Our data revealed no difference in the TL profile during spermatogenesis between younger and older men. All men had a similar profile which strongly resembled the telomerase expression profile found by others. This indicates that the longer telomeres in older men are not caused...

  4. Visualization of Telomere Integrity and Function In Vitro and In Vivo Using Immunofluorescence Techniques.

    Science.gov (United States)

    Cesare, Anthony J; Heaphy, Christopher M; O'Sullivan, Roderick J

    2015-01-01

    In cancer cells, telomere length maintenance occurs largely via the direct synthesis of TTAGGG repeats at chromosome ends by telomerase, or less frequently by the recombination-dependent alternative lengthening of telomeres (ALT) pathway. The latter is characterized by the atypical clustering of telomeres within promyelocytic leukemia (PML) nuclear bodies, which harbor proteins that are linked with DNA repair and recombination activity. For this reason, it is speculated that these associated PML bodies represent the sites of the recombination that maintains telomere length. The protocols described here can be employed for the routine investigation of the structural integrity of telomeres and the association of proteins at telomeres in normal cells, challenged cells, and archived formalin-fixed paraffin-embedded clinical tissue specimens that may have activated the ALT pathway. PMID:26132175

  5. Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX.

    Science.gov (United States)

    Clynes, David; Jelinska, Clare; Xella, Barbara; Ayyub, Helena; Scott, Caroline; Mitson, Matthew; Taylor, Stephen; Higgs, Douglas R; Gibbons, Richard J

    2015-01-01

    Fifteen per cent of cancers maintain telomere length independently of telomerase by the homologous recombination (HR)-associated alternative lengthening of telomeres (ALT) pathway. A unifying feature of these tumours are mutations in ATRX. Here we show that expression of ectopic ATRX triggers a suppression of the pathway and telomere shortening. Importantly ATRX-mediated ALT suppression is dependent on the histone chaperone DAXX. Re-expression of ATRX is associated with a reduction in replication fork stalling, a known trigger for HR and loss of MRN from telomeres. A G-quadruplex stabilizer partially reverses the effect of ATRX, inferring ATRX may normally facilitate replication through these sequences that, if they persist, promote ALT. We propose that defective telomere chromatinization through loss of ATRX promotes the persistence of aberrant DNA secondary structures, which in turn present a barrier to DNA replication, leading to replication fork stalling, collapse, HR and subsequent recombination-mediated telomere synthesis in ALT cancers. PMID:26143912

  6. Tumor size-independence of telomere length indicates an aggressive feature of HCC.

    Science.gov (United States)

    Nakajima, Tomoki; Katagishi, Tatsuo; Moriguchi, Michihisa; Sekoguchi, Satoru; Nishikawa, Taichirou; Takashima, Hidetaka; Watanabe, Tadashi; Kimura, Hiroyuki; Minami, Masahito; Itoh, Yoshito; Kagawa, Keizo; Okanoue, Takeshi

    2004-12-24

    Using quantitative fluorescence in situ hybridization (Q-FISH), the average telomere length of hepatoma cells was assessed by the average telomeric signal intensity of cancer cells relative to that of stromal cells. We demonstrated first the applicability of Q-FISH for tissue sections by comparing Q-FISH and Southern blotting results. Tumors less than 50mm in diameter and with a relative telomeric intensity of less than 0.6 were categorized as group A and the remainder as group B. In group A, the telomere length correlated negatively with tumor size, whereas in group B there was no correlation. Compared with the group A tumors, the group B tumors were of significantly more advanced stage, showed higher telomerase and proliferative activities, and exhibited less differentiated histology. Therefore, we considered that a lack of correlation between telomere length and tumor size, namely, size-independence of telomere length, is associated with unfavorable clinicopathological features of hepatocellular carcinomas. PMID:15555545

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

    Directory of Open Access Journals (Sweden)

    Owen M Wolkowitz

    Full Text Available BACKGROUND: 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. METHODOLOGY: 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. PRINCIPAL FINDINGS: 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. CONCLUSIONS: 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

  8. THE TELOMERES OF REPLICATING MACRONUCLEAR DNA-MOLECULES OF THE HYPOTRICHOUS CILIATE STYLONYCHIA LEMNAE

    OpenAIRE

    Juranek, Stefan; Jonsson, Franziska; Maercker, Christian; Lipps, Hans

    2000-01-01

    While the telomeres of higher eukaryotic cells show heterogenity in their length no such length heterogenity is observed in the macronuclear DNA of hypotrichous ciliates. Since the analysis of the telomere structure of replicating DNA molecules might give an insight in the mechanisms of telomere length regulation Stylonychia cell cultures were synchronized, the replicating DNA was labeled with BrdU and isolated by immuno-precipitation. The 3as well as the 5-end of these replicating DNA was la...

  9. The Power of Exercise: Buffering the Effect of Chronic Stress on Telomere Length

    OpenAIRE

    Puterman, Eli; Lin, Jue; Blackburn, Elizabeth; O'Donovan, Aoife; Adler, Nancy; Epel, Elissa

    2010-01-01

    Background 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, str...

  10. Recombination-mediated lengthening of terminal telomeric repeats requires the Sgs1 DNA helicase

    OpenAIRE

    Cohen, Haim; Sinclair, David A.

    2001-01-01

    The Saccharomyces cerevisiae SGS1 gene encodes a RecQ-like DNA helicase, human homologues of which are implicated in the genetic instability disorders, Bloom syndrome (BS), Rothmund-Thomson syndrome (RTS), and Werner syndrome (WS). Telomerase-negative yeast cells can recover from senescence via two recombinational telomere elongation pathways. The “type I” pathway generates telomeres with large blocks of telomeric and subtelomeric sequences and short terminal repea...

  11. Disease mutant analysis identifies a new function of DAXX in telomerase regulation and telomere maintenance

    OpenAIRE

    Tang, Mengfan; Li, Yujing; Zhang, Yi; Chen, Yuxi; Huang, Wenjun; Wang, Dan; Zaug, Arthur J.; Liu, Dan; Zhao, Yong; Cech, Thomas R.; Ma, Wenbin; Songyang, Zhou

    2015-01-01

    Most human cancers depend on the telomerase to maintain telomeres; however, about 10% of cancers are telomerase negative and utilize the alternative lengthening of telomeres (ALT) mechanism. Mutations in the DAXX gene have been found frequently in both telomerase-positive and ALT cells, and how DAXX mutations contribute to cancers remains unclear. We report here that endogenous DAXX can localize to Cajal bodies, associate with the telomerase and regulate telomerase targeting to telomeres. Fur...

  12. Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX

    OpenAIRE

    Clynes, David; Jelinska, Clare; Xella, Barbara; Ayyub, Helena; Scott, Caroline; Mitson, Matthew; Taylor, Stephen; Higgs, Douglas R.; Gibbons, Richard J.

    2015-01-01

    Fifteen per cent of cancers maintain telomere length independently of telomerase by the homologous recombination (HR)-associated alternative lengthening of telomeres (ALT) pathway. A unifying feature of these tumours are mutations in ATRX. Here we show that expression of ectopic ATRX triggers a suppression of the pathway and telomere shortening. Importantly ATRX-mediated ALT suppression is dependent on the histone chaperone DAXX. Re-expression of ATRX is associated with a reduction in replica...

  13. Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres

    OpenAIRE

    Espejel, Silvia; Franco, Sonia; Rodríguez-Perales, Sandra; Bouffler, Simon D; Cigudosa, Juan C.; Blasco, María A.

    2002-01-01

    Here we analyze the functional interaction between Ku86 and telomerase at the mammalian telomere by studying mice deficient for both proteins. We show that absence of Ku86 prevents the end-to-end chromosomal fusions that result from critical telomere shortening in telomerase-deficient mice. In addition, Ku86 deficiency rescues the male early germ cell apoptosis triggered by short telomeres in these mice. Together, these findings define a role for Ku86 in mediating chromosomal instability and ...

  14. Alternative mechanisms of telomere lengthening: permissive mutations, DNA repair proteins and tumorigenic progression

    OpenAIRE

    Sandy Gocha1, April Renee; Harris, Julia; Groden, Joanna

    2012-01-01

    Telomeres protect chromosome termini to maintain genomic stability and regulate cellular lifespan. Maintenance of telomere length is required for neoplastic cells after the acquisition of mutations that deregulate cell cycle control and increase cellular proliferation, and can occur through expression of the enzyme telomerase or in a telomerase-independent manner termed alternative lengthening of telomeres (ALT). The precise mechanisms that govern the activation of ALT or telomerase in tumor ...

  15. Visualization of Telomere Integrity and Function In Vitro and In Vivo Using Immunofluorescence Techniques

    OpenAIRE

    Cesare, Anthony J.; Heaphy, Christopher M.; O’Sullivan, Roderick J.

    2015-01-01

    In cancer cells, telomere length maintenance occurs largely via the direct synthesis of TTAGGG repeats at chromosome ends by telomerase, or less frequently by the recombination-dependent alternative lengthening of telomeres (ALT) pathway. The latter is characterized by the atypical clustering of telomeres within promyelocytic leukemia (PML) nuclear bodies, which harbor proteins that are linked with DNA repair and recombination activity. For this reason, it is speculated that these associated ...

  16. Replication Proteins Influence the Maintenance of Telomere Length and Telomerase Protein Stability

    OpenAIRE

    Dahlén, Maria; Sunnerhagen, Per; Wang, Teresa S.-F.

    2003-01-01

    We investigated the effects of fission yeast replication genes on telomere length maintenance and identified 20 mutant alleles that confer lengthening or shortening of telomeres. The telomere elongation was telomerase dependent in the replication mutants analyzed. Furthermore, the telomerase catalytic subunit, Trt1, and the principal initiation and lagging-strand synthesis DNA polymerase, Polα, were reciprocally coimmunoprecipitated, indicating these proteins physically coexist as a complex i...

  17. Rapid induction of Alternative Lengthening of Telomeres by depletion of the histone chaperone ASF1

    OpenAIRE

    O'Sullivan, Roderick J; Arnoult, Nausica; Daniel H Lackner; Oganesian, Liana; Haggblom, Candy; Corpet, Armelle; Almouzni, Genevieve; Karlseder, Jan

    2014-01-01

    The mechanism of activation of the Alternative Lengthening of Telomeres (ALT) pathway of mammalian chromosome end maintenance has remained an unresolved issue. We have discovered that co-depletion of the histone chaperones ASF1a and ASF1b in human cells induced all hallmarks of ALT in both primary and cancer cells. These included the formation of ALT associated PML bodies (APBs), extra-chromosomal telomeric DNA species an elevated frequency of telomeric sister chromatid exchanges (t-SCE) even...

  18. Sudden Telomere Lengthening Triggers a Rad53-dependent Checkpoint in Saccharomyces cerevisiae

    OpenAIRE

    Viscardi, Valeria; Baroni, Enrico; Romano, Michele; Lucchini, Giovanna; Longhese, Maria Pia

    2003-01-01

    Telomeres are specialized functional complexes that ensure chromosome stability by protecting chromosome ends from fusions and degradation and avoiding chromosomal termini from being sensed as DNA breaks. Budding yeast Tel1 is required both for telomere metabolism and for a Rad53-dependent checkpoint responding to unprocessed double-strand breaks. We show that overexpression of a GAL1-TEL1 fusion causes transient telomere lengthening and activation of a Rad53-dependent...

  19. Telomere Length in Epidemiology: A Biomarker of Aging, Age-Related Disease, Both, or Neither?

    OpenAIRE

    Sanders, Jason L.; Newman, Anne B.

    2013-01-01

    Telomeres are nucleoprotein caps flanking DNA. They are shortened by cell division and oxidative stress and are lengthened by the enzyme telomerase and DNA exchange during mitosis. Short telomeres induce cellular senescence. As an indicator of oxidative stress and senescence (2 processes thought to be fundamental to aging), telomere length is hypothesized to be a biomarker of aging. This hypothesis has been tested for more than a decade with epidemiologic study methods. In cross-sectional stu...

  20. Social Isolation Shortens Telomeres in African Grey Parrots (Psittacus erithacus erithacus)

    OpenAIRE

    Denise Aydinonat; Penn, Dustin J.; Steve Smith; Yoshan Moodley; Franz Hoelzl; Felix Knauer; Franz Schwarzenberger

    2014-01-01

    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 te...

  1. Parental Responsiveness Moderates the Association Between Early-life Stress and Reduced Telomere Length

    OpenAIRE

    Asok, A.; Bernard, K.; Roth, T.L.; Rosen, J.B.; Dozier, M.

    2013-01-01

    Early-life stress, such as maltreatment, institutionalization, and exposure to violence, is associated with accelerated telomere shortening. Telomere shortening may thus represent a biomarker of early adversity. Previous studies have suggested that responsive parenting may protect children from the negative biological and behavioral consequences of early adversity. This study examined the role of parental responsiveness in buffering children from telomere shortening following experiences of e...

  2. Chlamydomonas reinhardtii telomere repeats form unstable structures involving guanine-guanine base pairs.

    OpenAIRE

    Petracek, M E; Berman, J.

    1992-01-01

    Unusual DNA structures involving four guanines in a planar formation (guanine tetrads) are formed by guanine-rich (G-rich) telomere DNA and other G-rich sequences (reviewed in (1)) and may be important in the structure and function of telomeres. These structures result from intrastrand and/or interstrand Hoogsteen base pairs between the guanines. We used the telomeric repeat of Chlamydomonas reinhardtii, TTTTAGGG, which contains 3 guanines and has a long interguanine A + T tract, to determine...

  3. ATR cooperates with CTC1 and STN1 to maintain telomeres and genome integrity in Arabidopsis

    OpenAIRE

    Boltz, Kara A.; Leehy, Katherine; Song, Xiangyu; Nelson, Andrew D.; Shippen, Dorothy E.

    2012-01-01

    The CTC1/STN1/TEN1 (CST) complex is an essential constituent of plant and vertebrate telomeres. Here we show that CST and ATR (ataxia telangiectasia mutated [ATM] and Rad3-related) act synergistically to maintain telomere length and genome stability in Arabidopsis. Inactivation of ATR, but not ATM, temporarily rescued severe morphological phenotypes associated with ctc1 or stn1. Unexpectedly, telomere shortening accelerated in plants lacking CST and ATR. In first-generation (G1) ctc1 atr muta...

  4. Nature vs nurture: Interplay between the genetic control of telomere length and environmental factors

    OpenAIRE

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

    2013-01-01

    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 kee...

  5. Telomere length trajectory and its determinants in persons with coronary artery disease: longitudinal findings from the heart and soul study.

    Directory of Open Access Journals (Sweden)

    Ramin Farzaneh-Far

    Full Text Available BACKGROUND: Leukocyte telomere length, an emerging marker of biological age, has been shown to predict cardiovascular morbidity and mortality. However, the natural history of telomere length in patients with coronary artery disease has not been studied. We sought to investigate the longitudinal trajectory of telomere length, and to identify the independent predictors of telomere shortening, in persons with coronary artery disease. METHODOLOGY/PRINCIPAL FINDINGS: In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline, and again after five years of follow-up. We used multivariable linear and logistic regression models to identify the independent predictors of leukocyte telomere trajectory. Baseline and follow-up telomere lengths were normally distributed. Mean telomere length decreased by 42 base pairs per year (p<0.001. Three distinct telomere trajectories were observed: shortening in 45%, maintenance in 32%, and lengthening in 23% of participants. The most powerful predictor of telomere shortening was baseline telomere length (OR per SD increase = 7.6; 95% CI 5.5, 10.6. Other independent predictors of telomere shortening were age (OR per 10 years = 1.6; 95% CI 1.3, 2.1, male sex (OR = 2.4; 95% CI 1.3, 4.7, and waist-to-hip ratio (OR per 0.1 increase = 1.4; 95% CI 1.0, 2.0. CONCLUSIONS/SIGNIFICANCE: Leukocyte telomere length may increase as well as decrease in persons with coronary artery disease. Telomere length trajectory is powerfully influenced by baseline telomere length, possibly suggesting negative feedback regulation. Age, male sex, and abdominal obesity independently predict telomere shortening. The mechanisms and reversibility of telomeric aging in cardiovascular disease deserve further study.

  6. 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....

  7. Blood and Dried Blood Spot Telomere Length Measurement by qPCR: Assay Considerations

    OpenAIRE

    Zanet, DeAnna L.; Sara Saberi; Laura Oliveira; Beheroze Sattha; Izabella Gadawski; Côté, Hélène C. F.

    2013-01-01

    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...

  8. The E3 ubiquitin ligase RNF8 stabilizes TPP1 to promote telomere end protection

    OpenAIRE

    Rai, Rekha; Li, Ju-mei; Zheng, Hong; Lok, Gabriel Tsz-Mei; Deng, Yu; Huen, Michael; Chen, Junjie; Jin, Jianping; Chang, Sandy

    2011-01-01

    TPP1, a component of the mammalian shelterin complex, plays essential roles in telomere maintenance. It forms a heterodimer with POT1 to repress ATR-dependent DNA damage signaling at telomeres, and recruits telomerase to chromosome ends. Here we show that the E3 ubiquitin ligase RNF8 localizes to and promotes the accumulation of DNA damage proteins 53BP1 and γ-H2AX to uncapped telomeres. TPP1 is unstable in the absence of RNF8, resulting in telomere shortening and chromosome fusions via the a...

  9. Telomere Protection by TPP1 Is Mediated by POT1a and POT1b ▿

    OpenAIRE

    Kibe, Tatsuya; Osawa, Gail A.; Keegan, Catherine E.; de Lange, Titia

    2009-01-01

    Mammalian telomeres are protected by the shelterin complex, which contains single-stranded telomeric DNA binding proteins (POT1a and POT1b in rodents, POT1 in other mammals). Mouse POT1a prevents the activation of the ATR kinase and contributes to the repression of the nonhomologous end-joining pathway (NHEJ) at newly replicated telomeres. POT1b represses unscheduled resection of the 5′-ended telomeric DNA strand, resulting in long 3′ overhangs in POT1b KO cells. Both POT1 proteins bind TPP1,...

  10. Effects of Telomerase and Telomere Length on Epidermal Stem Cell Behavior

    Science.gov (United States)

    Flores, Ignacio; Cayuela, María L.; Blasco, María A.

    2005-08-01

    A key process in organ homeostasis is the mobilization of stem cells out of their niches. We show through analysis of mouse models that telomere length, as well as the catalytic component of telomerase, Tert, are critical determinants in the mobilization of epidermal stem cells. Telomere shortening inhibited mobilization of stem cells out of their niche, impaired hair growth, and resulted in suppression of stem cell proliferative capacity in vitro. In contrast, Tert overexpression in the absence of changes in telomere length promoted stem cell mobilization, hair growth, and stem cell proliferation in vitro. The effects of telomeres and telomerase on stem cell biology anticipate their role in cancer and aging.

  11. The three-dimensional organization of telomeres in the nucleus of mammalian cells

    Directory of Open Access Journals (Sweden)

    Perrin Mathilde

    2004-06-01

    Full Text Available Abstract Background The observation of multiple genetic markers in situ by optical microscopy and their relevance to the study of three-dimensional (3D chromosomal organization in the nucleus have been greatly developed in the last decade. These methods are important in cancer research because cancer is characterized by multiple alterations that affect the modulation of gene expression and the stability of the genome. It is, therefore, essential to analyze the 3D genome organization of the interphase nucleus in both normal and cancer cells. Results We describe a novel approach to study the distribution of all telomeres inside the nucleus of mammalian cells throughout the cell cycle. It is based on 3D telomere fluorescence in situ hybridization followed by quantitative analysis that determines the telomeres' distribution in the nucleus throughout the cell cycle. This method enables us to determine, for the first time, that telomere organization is cell-cycle dependent, with assembly of telomeres into a telomeric disk in the G2 phase. In tumor cells, the 3D telomere organization is distorted and aggregates are formed. Conclusions The results emphasize a non-random and dynamic 3D nuclear telomeric organization and its importance to genomic stability. Based on our findings, it appears possible to examine telomeric aggregates suggestive of genomic instability in individual interphase nuclei and tissues without the need to examine metaphases. Such new avenues of monitoring genomic instability could potentially impact on cancer biology, genetics, diagnostic innovations and surveillance of treatment response in medicine.

  12. 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.

  13. A novel form of the telomere-associated protein TIN2 localizes to the nuclear matrix

    OpenAIRE

    Kaminker, Patrick G.; Kim, Sahn-Ho; Desprez, Pierre-Yves; Campisi, Judith

    2009-01-01

    Telomeres are specialized heterochromatin at the ends of linear chromosomes. Telomeres are crucial for maintaining genome stability and play important roles in cellular senescence and tumor biology. Six core proteins—TRF1, TRF2, TIN2, POT1, TPP1 and Rap1 (termed the telosome or shelterin complex)—regulate telomere structure and function. One of these proteins, TIN2, regulates telomere length and structure indirectly by interacting with TRF1, TRF2 and TPP1, but no direct function has been attr...

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

    DEFF Research Database (Denmark)

    Palanduz, Sukru; Serakinci, Nedime; Cefle, Kivanc; Aktan, Melih; Tutkan, Gulcin; Ozturk, Sukru; Bozkurt, Gokay; Dincol, Guncag; Pekcelen, Yuksel; Koch, Jørn

    2006-01-01

    Telomeric sequences, located at the very end of the chromosomes, compensate for the chromosomal shortening as it happens after each round of cell division. Telomeric sequences influence the progress of cellular senescence and cancer progression. It has been reported that telomeres are shortened in...... erosion in CLL may reflect the dominance of malignant cells with an abnormally long life span. These cells may have encountered many antigenic stimulants in the past and hence underwent multiple clonal expansions. Our findings imply that shortened telomeres in CLL may be reflecting the "history" of the...

  15. Short telomere length, cancer survival, and cancer risk in 47102 individuals

    DEFF Research Database (Denmark)

    Weischer, Maren; Nordestgaard, Børge G; Cawthon, Richard M; Freiberg, Jacob J; Tybjærg-Hansen, Anne; Bojesen, Stig E

    2013-01-01

    Recent meta-analyses have suggested that short telomere length was associated with increased risk of cancer. We therefore tested the hypotheses that short telomere length was associated with increased risk of cancer and with increased risk of early death after cancer.......Recent meta-analyses have suggested that short telomere length was associated with increased risk of cancer. We therefore tested the hypotheses that short telomere length was associated with increased risk of cancer and with increased risk of early death after cancer....

  16. PARP1 Is a TRF2-associated Poly(ADP-Ribose)Polymerase and Protects Eroded Telomeres

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yie [ORNL; Wu, Jun [ORNL; Schreiber, Valerie [Universite Louis Pasteur, France; Dunlap, John [University of Tennessee, Knoxville (UTK); Dantzer, Francoise [Universite Louis Pasteur, France; Wang, Yisong [University of Tennessee, Knoxville (UTK) & Oak Ridge National Laboratory (ORNL)

    2006-01-01

    Poly(ADP-ribose)polymerase 1 (PARP1) is well characterized for its role in base excision repair (BER), where it is activated by and binds to DNA breaks and catalyzes the poly(ADP-ribosyl)ation of several substrates involved in DNA damage repair. Here we demonstrate that PARP1 associates with telomere repeat binding factor 2 (TRF2) and is capable of poly(ADP-ribosyl)ation of TRF2, which affects binding of TRF2 to telomeric DNA. Immunostaining of interphase cells or metaphase spreads shows that PARP1 is detected sporadically at normal telomeres, but it appears preferentially at eroded telomeres caused by telomerase deficiency or damaged telomeres induced by DNA-damaging reagents. Although PARP1 is dispensable in the capping of normal telomeres, Parp1 deficiency leads to an increase in chromosome end-to-end fusions or chromosome ends without detectable telomeric DNA in primary murine cells after induction of DNA damage. Our results suggest that upon DNA damage, PARP1 is recruited to damaged telomeres, where it can help protect telomeres against chromosome end-to-end fusions and genomic instability.

  17. PARP1 is a TRF2-associated poly(ADP-ribose) polymerase and protects eroded telomeres

    Energy Technology Data Exchange (ETDEWEB)

    Gomez, Marla V [ORNL; Wu, Jun [ORNL; Wang, Yisong [ORNL; Liu, Yie [ORNL

    2006-01-01

    Poly(ADP-ribose)polymerase 1 (PARP1) is well characterized for its role in base excision repair (BER), where it is activated by and binds to DNA breaks and catalyzes the poly(ADP-ribosyl)ation of several substrates involved in DNA damage repair. Here we demonstrate that PARP1 associates with telomere repeat binding factor 2 (TRF2) and is capable of poly(ADP-ribosyl)ation of TRF2, which affects binding of TRF2 to telomeric DNA. Immunostaining of interphase cells or metaphase spreads shows that PARP1 is detected sporadically at normal telomeres, but it appears preferentially at eroded telomeres caused by telomerase deficiency or damaged telomeres induced by DNA-damaging reagents. Although PARP1 is dispensable in the capping of normal telomeres, Parp1 deficiency leads to an increase in chromosome end-to-end fusions or chromosome ends without detectable telomeric DNA in primary murine cells after induction of DNA damage. Our results suggest that upon DNA damage, PARP1 is recruited to damaged telomeres, where it can help protect telomeres against chromosome end-to-end fusions and genomic instability.

  18. Positive association of long telomeres with the invasive capacity of hepatocellular carcinoma cells.

    Science.gov (United States)

    Ko, Eunkyong; Jung, Guhung

    2014-05-01

    Invasion, the representative feature of malignant tumors, leads to an increase in mortality. The malignant liver tumor - hepatocellular carcinoma (HCC) - has an enhanced invasive capacity that results in increased patient mortality. Moreover, this enhanced invasive capacity is due to the up-regulation of invasion promoters such as zinc finger protein SNAI1 (Snail) and matrix metalloproteinases (MMPs), and the down-regulation of invasion suppressor molecules such as E-cadherin. Telomerase reverse transcriptase (TERT), which encodes the catalytic subunit of telomerase, is highly expressed in a variety of invasive cancers, including HCC. Telomerase activation induces telomere elongation, thereby leading to cell immortalization during malignant tumor progression. However, the relationship between telomere length and invasion is yet to be experimentally corroborated. In this paper, we revealed that invasive HCC cells passing through the Matrigel display significantly longer telomeres than non-invasive HCC cells. Moreover, we established a method that can distinguish and sort cells containing long telomeres and short telomeres. Using this system, we observed that the HCC cells containing long telomeres had a high-level expression of invasion-promoting genes and a low-level expression of invasion-suppressing E-cadherin. Furthermore, HCC cells containing long telomeres exhibited a higher invasive capacity than HCC cells containing short telomeres. Taken together, our findings suggest that long telomeres are positively associated with the invasive capacity of HCC cells and may be a potent target for malignant liver cancer treatment. PMID:24732358

  19. TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions.

    Science.gov (United States)

    Rai, Rekha; Chen, Yong; Lei, Ming; Chang, Sandy

    2016-01-01

    Repressor/activator protein 1 (RAP1) is a highly conserved telomere-interacting protein. Yeast Rap1 protects telomeres from non-homologous end joining (NHEJ), plays important roles in telomere length control and is involved in transcriptional gene regulation. However, a role for mammalian RAP1 in telomere end protection remains controversial. Here we present evidence that mammalian RAP1 is essential to protect telomere from homology directed repair (HDR) of telomeres. RAP1 cooperates with the basic domain of TRF2 (TRF2(B)) to repress PARP1 and SLX4 localization to telomeres. Without RAP1 and TRF2(B), PARP1 and SLX4 HR factors promote rapid telomere resection, resulting in catastrophic telomere loss and the generation of telomere-free chromosome fusions in both mouse and human cells. The RAP1 Myb domain is required to repress both telomere loss and formation of telomere-free fusions. Our results highlight the importance of the RAP1-TRF2 heterodimer in protecting telomeres from inappropriate processing by the HDR pathway. PMID:26941064

  20. 人类早期胚胎发育端粒维持初步研究%Telomere Maintenance in Human Early Embryogenesis Study

    Institute of Scientific and Technical Information of China (English)

    曾思聪; 周菂; 卢光琇

    2011-01-01

    目的:探讨人类胚胎在早期发育过程中端粒维持的机制.方法:利用端粒特异性探针对临床IVF过程中2~8细胞时期停止发育不适合移植的胚胎和来自于囊胚期的人类胚胎干细胞进行荧光原位杂交检测端粒重组.结果:人类早期胚胎发育中存在端粒交换的结构APB小体,而来自于囊胚期的胚胎干细胞不再具有这种结构,胚胎干细胞端粒交换发生频率较低(0.15%).结论:结合其他实验报道,提示人类胚胎早期发育过程中出现两种端粒维持机制的并存.%Objective: The mechanism of telomere maintenance in human early embryogenesis. Methods: Telomere probes were used to detect the telomere recombination in clinical unwanted 2 ~ 8 cells embryos and in vitro cultured stem cells by FISH ( Fluorescence In Situ Hybridization). Results: Telomere recombination specific structure APB bodies were detected in nuclei of early embryos but not in embryonic stem cells which generated from blastocyst inner cells, low frequency of sister chromatid exchange(0.15 % ) was detected in embryonic stem cells. Conclusion :Consider to when taken previous report into consideration, It is shown that early development has experienced two difference telomere maintenance mechanisms.

  1. Detecting Illegal Arms Trade

    OpenAIRE

    DellaVigna, Stefano; Ferrara, Eliana La

    2010-01-01

    Illegal arms are responsible for thousands of deaths in civil wars every year. Yet, their trade is very hard to detect. We propose a method to statistically detect illegal arms trade based on the investor knowledge embedded in financial markets. We focus on eight countries under UN arms embargo in the period 1990-2005, and analyze eighteen events during the embargo that suddenly increase or decrease conflict intensity. If the weapon-making companies are not trading or are trading legally, an ...

  2. Incorporating the Hayflick Limit into a model of Telomere Dynamics

    CERN Document Server

    Cyrenne, Benoit M

    2013-01-01

    A model of telomere dynamics is proposed and examined. Our model, which extends a previously introduced two-compartment 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. In addition, qualitatively different results are obtained for the evolution of the total cell population. Last, in comparison to available leukocyte baboon data, this new model is shown to provide a better fit to biological data.

  3. A Global Obstacle-avoidance Map for Anthropomorphic Arms

    Directory of Open Access Journals (Sweden)

    Cheng Fang

    2014-07-01

    Full Text Available More and more humanoid robots are used in human society, and they face a wide variety of complicated manipulation tasks, which are mainly to be achieved by their anthropomorphic arms. Obstacle avoidance for the anthropomorphic arm must be a fundamental consideration to guarantee the successful implementation of these tasks. Different from traditional methods searching for feasible or optimal collision-free solutions for the anthropomorphic arm, a global obstacle- avoidance map for the whole arm is proposed to indicate the complete set of feasible solutions. In this map, the motion of the arm can be appropriately planned to intuitively control the configuration of the arm in motion. First, the cubic spline function is adopted to interpolate some well-chosen path points to generate a smooth collision-free path for the wrist of the anthropomorphic arm. Second, based on the path function of the wrist, the time and the self-rotation angle of the arm about the “shoulder-wrist” axis are used to parameterize all possible configurations of the arm so that a global two- dimensional map considering the obstacle avoidance can be established. Subsequently, a collision-free self-rotation angle profile of the arm can be well planned. Finally, the joint trajectories of a specific anthropomorphic arm, which correspond to the planned path of the wrist and self-rotation angle profile of the arm, can be solved on the basis of the general kinematic analysis of the anthropomorphic arm, and the specific structure. Several simulations are conducted to verify that the proposed collision-free motion planning method for anthropomorphic arms has some advantages and can be regarded as a convenient and intuitive tool to control the configuration of the anthropomorphic arm in motion, without collision with obstacles in its surroundings.

  4. Telomeres and Early-Life Stress: An Overview

    OpenAIRE

    Price, Lawrence H.; Kao, Hung-Teh; Burgers, Darcy E.; Carpenter, Linda L.; Tyrka, Audrey R.

    2012-01-01

    The long-term sequelae of adverse early-life experiences have long been a focus in psychiatry, with a historic neurobiological emphasis on physiological systems that are demonstrably stress-responsive, such as the hypothalamic-pituitary-adrenal (HPA) axis and neuroimmune function. However, there has been increasing recognition in the general medical literature that such sequelae might encompass more pervasive alterations in health status and physiology. Recent findings in telomere biology hav...

  5. Telomere elongation in immortal human cells without detectable telomerase activity.

    OpenAIRE

    Bryan, T M; Englezou, A; J Gupta; Bacchetti, S; Reddel, R. R.

    1995-01-01

    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 line...

  6. The diversity and evolution of telomeres in algae

    Czech Academy of Sciences Publication Activity Database

    Fulnečková, J.; Ševčíková, T.; Fajkus, J.; Lukešová, Alena; Eliáš, M.; Sýkorová, Eva

    2015-01-01

    Roč. 50, Supp 1 (2015), s. 149-150. ISSN 0967-0262. [European Phycological Congress /6./. 23.08.2015-28.08.2015, London] R&D Projects: GA ČR GA13-06595S Grant ostatní: GA MŠk(CZ) EE2.3.20.0189 Institutional support: RVO:60077344 ; RVO:68081707 Keywords : telomeres * algae Subject RIV: EE - Microbiology, Virology

  7. Chromatin structure in relation to telomere length maintenance in plants

    Czech Academy of Sciences Publication Activity Database

    Fajkus, Jiří; Mozgová, I.; Procházková Schrumpfová, P.; Majerová, E.; Fojtová, M.

    Zürich, 2009. s. 1. [European Workshop on Plant Chromatin. 03.09.2009-04.09.2009, Zürich] R&D Projects: GA ČR(CZ) GD204/08/H054; GA ČR(CZ) GA204/08/1530; GA MŠk(CZ) LC06004 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : telomere * HMGB1 protein * DNA methylation Subject RIV: BO - Biophysics

  8. Compromised telomere maintenance in hypomethylated Arabidopsis thaliana plants

    Czech Academy of Sciences Publication Activity Database

    Ogrocká, A.; Polanská, P.; Majerová, E.; Janeba, Zlatko; Fajkus, Jiří; Fojtová, M.

    2014-01-01

    Roč. 42, č. 5 (2014), s. 2919-2931. ISSN 0305-1048 Grant ostatní: GA ČR(CZ) GAP501/11/0596; GA MŠk(CZ) ED1.1.00/02.0068 Institutional support: RVO:61388963 ; RVO:68081707 Keywords : DNA methylation * cytosine methylation * mammalian telomeres Subject RIV: CE - Biochemistry; BO - Biophysics (BFU-R) Impact factor: 9.112, year: 2014

  9. Telomere-independent cellular senescence in human fetal cardiomyocytes

    OpenAIRE

    Ball, Andrew J.; Levine, F

    2005-01-01

    Fetal cardiomyocytes have been proposed as a potential source of cell-based therapy for heart failure. This study examined cellular senescence in cultured human fetal ventricular cardiomyocytes (HFCs). HFCs were isolated and identified by immunocytochemistry and RT-PCR. Cells were found to senesce after 20-25 population doublings, as determined by growth arrest, morphological changes and senescence-associated beta-galactosidase activity. Using the telomeric repeat amplification protocol assay...

  10. 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. PMID:9451957

  11. Genetic Inactivation of ATRX Leads to a Decrease in the Amount of Telomeric Cohesin and Level of Telomere Transcription in Human Glioma Cells.

    Science.gov (United States)

    Eid, Rita; Demattei, Marie-Véronique; Episkopou, Harikleia; Augé-Gouillou, Corinne; Decottignies, Anabelle; Grandin, Nathalie; Charbonneau, Michel

    2015-08-01

    Mutations in ATRX (alpha thalassemia/mental retardation syndrome X-linked), a chromatin-remodeling protein, are associated with the telomerase-independent ALT (alternative lengthening of telomeres) pathway of telomere maintenance in several types of cancer, including human gliomas. In telomerase-positive glioma cells, we found by immunofluorescence that ATRX localized not far from the chromosome ends but not exactly at the telomere termini. Chromatin immunoprecipitation (ChIP) experiments confirmed a subtelomeric localization for ATRX, yet short hairpin RNA (shRNA)-mediated genetic inactivation of ATRX failed to trigger the ALT pathway. Cohesin has been recently shown to be part of telomeric chromatin. Here, using ChIP, we showed that genetic inactivation of ATRX provoked diminution in the amount of cohesin in subtelomeric regions of telomerase-positive glioma cells. Inactivation of ATRX also led to diminution in the amount of TERRAs, noncoding RNAs resulting from transcription of telomeric DNA, as well as to a decrease in RNA polymerase II (RNAP II) levels at the telomeres. Our data suggest that ATRX might establish functional interactions with cohesin on telomeric chromatin in order to control TERRA levels and that one or the other or both of these events might be relevant to the triggering of the ALT pathway in cancer cells that exhibit genetic inactivation of ATRX. PMID:26055325

  12. The telomeric sync model of speciation: species-wide telomere erosion triggers cycles of transposon-mediated genomic rearrangements, which underlie the saltatory appearance of nonadaptive characters

    Science.gov (United States)

    Stindl, Reinhard

    2014-03-01

    Charles Darwin knew that the fossil record is not overwhelmingly supportive of genetic and phenotypic gradualism; therefore, he developed the core of his theory on the basis of breeding experiments. Here, I present evidence for the existence of a cell biological mechanism that strongly points to the almost forgotten European concept of saltatory evolution of nonadaptive characters, which is in perfect agreement with the gaps in the fossil record. The standard model of chromosomal evolution has always been handicapped by a paradox, namely, how speciation can occur by spontaneous chromosomal rearrangements that are known to decrease the fertility of heterozygotes in a population. However, the hallmark of almost all closely related species is a differing chromosome complement and therefore chromosomal rearrangements seem to be crucial for speciation. Telomeres, the caps of eukaryotic chromosomes, erode in somatic tissues during life, but have been thought to remain stable in the germline of a species. Recently, a large human study spanning three healthy generations clearly found a cumulative telomere effect, which is indicative of transgenerational telomere erosion in the human species. The telomeric sync model of speciation presented here is based on telomere erosion between generations, which leads to identical fusions of chromosomes and triggers a transposon-mediated genomic repatterning in the germline of many individuals of a species. The phenotypic outcome of the telomere-triggered transposon activity is the saltatory appearance of nonadaptive characters simultaneously in many individuals. Transgenerational telomere erosion is therefore the material basis of aging at the species level.

  13. 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.

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

    International Nuclear Information System (INIS)

    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 (AtTRB21–64) using nuclear magnetic resonance (NMR) spectroscopy. In addition, the inter-molecular interaction between AtTRB21–64 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

  15. Stable expression of promyelocytic leukaemia (PML) protein in telomerase positive MCF7 cells results in alternative lengthening of telomeres phenotype

    OpenAIRE

    Yong Jacklyn W Y; Yeo Xiujun; Khan Md; Lee Martin B; Prakash Hande M

    2012-01-01

    Abstract Background Cancer cells can employ telomerase or the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. Cancer cells that use the ALT pathway exhibit distinct phenotypes such as heterogeneous telomeres and specialised Promyelocytic leukaemia (PML) nuclear foci called APBs. In our study, we used wild-type PML and a PML mutant, in which the coiled-coil domain is deleted (PML C/C-), to investigate how these proteins can affect telomere maintenance pathways in c...

  16. Direct Single-Stranded DNA Binding by Teb1 Mediates the Recruitment of Tetrahymena thermophila Telomerase to Telomeres

    OpenAIRE

    Upton, Heather E.; Hong, Kyungah; Collins, Kathleen

    2014-01-01

    The eukaryotic reverse transcriptase telomerase copies its internal RNA template to synthesize telomeric DNA repeats at chromosome ends in balance with sequence loss during cell proliferation. Previous work has established several factors involved in telomerase recruitment to telomeres in yeast and mammalian cells; however, it remains unclear what determines the association of telomerase with telomeres in other organisms. Here we investigate the cell cycle dependence of telomere binding by ea...

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

    OpenAIRE

    Marco Parolini; Andrea Romano; Lela Khoriauli; Nergadze, Solomon G.; Manuela Caprioli; Diego Rubolini; Marco Santagostino; Nicola Saino; Elena Giulotto

    2015-01-01

    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 r...

  18. Increased attrition of leukocyte telomere length in young adults is associated with poorer cognitive function in midlife

    OpenAIRE

    Cohen-Manheim, Irit; Doniger, Glen Michael; Sinnreich, Ronit; Simon, Ely Samuel; Pinchas, Ronit; Aviv, Abraham; Kark, Jeremy David

    2015-01-01

    Evidence for an association of leukocyte telomere length (LTL) with cognitive function, predominantly in older adults, is inconsistent. No report has examined the association of LTL dynamics (age-specific LTL and its attrition rate) with cognitive function. We aimed to examine the association of LTL dynamics over 13 years in young adulthood with cognitive function in midlife. 497 individuals who had LTL measured at ages 28–32 and 41–46 years were assessed at ages 48–52 for global cognitive fu...

  19. ARM Mentor Selection Process

    Energy Technology Data Exchange (ETDEWEB)

    Sisterson, D. L. [Argonne National Lab. (ANL), Argonne, IL (United States)

    2015-10-01

    The Atmospheric Radiation Measurement (ARM) Program was created in 1989 with funding from the U.S. Department of Energy (DOE) to develop several highly instrumented ground stations to study cloud formation processes and their influence on radiative transfer. In 2003, the ARM Program became a national scientific user facility, known as the ARM Climate Research Facility. This scientific infrastructure provides for fixed sites, mobile facilities, an aerial facility, and a data archive available for use by scientists worldwide through the ARM Climate Research Facility—a scientific user facility. The ARM Climate Research Facility currently operates more than 300 instrument systems that provide ground-based observations of the atmospheric column. To keep ARM at the forefront of climate observations, the ARM infrastructure depends heavily on instrument scientists and engineers, also known as lead mentors. Lead mentors must have an excellent understanding of in situ and remote-sensing instrumentation theory and operation and have comprehensive knowledge of critical scale-dependent atmospheric processes. They must also possess the technical and analytical skills to develop new data retrievals that provide innovative approaches for creating research-quality data sets. The ARM Climate Research Facility is seeking the best overall qualified candidate who can fulfill lead mentor requirements in a timely manner.

  20. Managing new arms races

    International Nuclear Information System (INIS)

    The management of new arms races in the region of Asia-Pacific includes considerations of weapons trade and transfer in the region, with an emphasis on nuclear weapons proliferation. It deals with the problem of controlling the arms trade and the efforts to control conventional weapons and underlines the possible role and influence of Conference on Cooperation and Security in Europe (CSCE)

  1. Acute Exercise Leads to Regulation of Telomere-Associated Genes and MicroRNA Expression in Immune Cells

    OpenAIRE

    Chilton, Warrick L.; Francine Z Marques; Jenny West; George Kannourakis; Berzins, Stuart P.; Brendan J O'Brien; Charchar, Fadi J.

    2014-01-01

    Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune syste...

  2. Prenatal detection of short arm deletion and isochromosome 18 formation investigated by molecular techniques.

    OpenAIRE

    Qumsiyeh, M B; Tomasi, A; Taslimi, M

    1995-01-01

    A patient was referred for amniocentesis because of advanced maternal age and polyhydramnios. The fetal karyotype was a mosaic 46,XX,del(18)(p11.1)/46,XX,-18,+i(18q)de novo. The deletion appeared to encompass the whole short arm as evidenced by G banding and in situ hybridisation. However, telomere sequences were found on both ends of the deleted chromosome as well as the isochromosome. The normal 18 and the isochromosome showed more alphoid sequences than the del(18). Subsequent passages of ...

  3. Zebrafish as a model system to study the physiological function of telomeric protein TPP1.

    Directory of Open Access Journals (Sweden)

    Yiying Xie

    Full Text Available Telomeres are specialized chromatin structures at the end of chromosomes. Telomere dysfunction can lead to chromosomal abnormalities, DNA damage responses, and even cancer. In mammalian cells, a six-protein complex (telosome/shelterin is assembled on the telomeres through the interactions between various domain structures of the six telomere proteins (POT1, TPP1, TIN2, TRF1, TRF2 and RAP1, and functions in telomere maintenance and protection. Within the telosome, TPP1 interacts directly with POT1 and TIN2 and help to mediate telosome assembly. Mechanisms of telomere regulation have been extensively studied in a variety of model organisms. For example, the physiological roles of telomere-targeted proteins have been assessed in mice through homozygous inactivation. In these cases, early embryonic lethality has prevented further studies of these proteins in embryogenesis and development. As a model system, zebrafish offers unique advantages such as genetic similarities with human, rapid developmental cycles, and ease of manipulation of its embryos. In this report, we detailed the identification of zebrafish homologues of TPP1, POT1, and TIN2, and showed that the domain structures and interactions of these telosome components appeared intact in zebrafish. Importantly, knocking down TPP1 led to multiple abnormalities in zebrafish embryogenesis, including neural death, heart malformation, and caudal defect. And these embryos displayed extensive apoptosis. These results underline the importance of TPP1 in zebrafish embryogenesis, and highlight the feasibility and advantages of investigating the signaling pathways and physiological function of telomere proteins in zebrafish.

  4. Telomere length and mental well-being in eldery men from the Netherlands and Greece

    NARCIS (Netherlands)

    Rius-Ottenheim, N.; Houben, J.M.J.; Kromhout, D.; Kafatos, A.; Mast, van der R.C.; Zitman, F.G.; Geleijnse, J.M.; Hageman, G.J.; Giltay, E.J.

    2012-01-01

    Telomeres, repetitive DNA sequences that promote chromosomal stability, have been related to different measures of mental well-being and self-rated health, but mainly in women during adulthood. We aimed to investigate whether accelerated telomere shortening is associated with poor mental well-being

  5. The DNA damage response at eroded telomeres and tethering to the nuclear pore complex

    DEFF Research Database (Denmark)

    Khadaroo, Basheer; Teixeira, M Teresa; Luciano, Pierre;

    2009-01-01

    The ends of linear eukaryotic chromosomes are protected by telomeres, which serve to ensure proper chromosome replication and to prevent spurious recombination at chromosome ends. In this study, we show by single cell analysis that in the absence of telomerase, a single short telomere is sufficient...

  6. Collapse of Telomere Homeostasis in Hematopoietic Cells Caused by Heterozygous Mutations in Telomerase Genes

    NARCIS (Netherlands)

    Aubert, Geraldine; Baerlocher, Gabriela M.; Vulto, Irma; Poon, Steven S.; Lansdorp, Peter M.

    2012-01-01

    Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain telomere length with proliferation in vitro and with age in vivo. We performed a detailed study of the telomere length by flow FISH analysis in leukocytes from 835

  7. Genetic variation in TERT and TERC and human leukocyte telomere length and longevity

    DEFF Research Database (Denmark)

    Soerensen, Mette; Thinggaard, Mikael; Nygaard, Marianne;

    2012-01-01

    Telomerase is of key importance for telomere maintenance, and variants of the genes encoding its major subunits, telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), are candidates for interindividual variation in telomere length. Recently, the two SNPs rs3772190 and rs...

  8. Molecular and Cellular Evidence for the Alternative Lengthening of Telomeres (ALT) Mechanism in Chicken

    OpenAIRE

    O'Hare, T.H.; Delany, M. E.

    2011-01-01

    Telomere maintenance is an important genetic mechanism controlling cellular proliferation. Normally, telomeres are maintained by telomerase which is downregulated upon cellular differentiation in most somatic cell lineages. Telomerase activity is upregulated in immortalized cells and cancers to support an infinite lifespan and uncontrolled cell growth; however, some immortalized and transformed cells lack telomerase activity. Telomerase-negative tumors and immortalized cells utilize an altern...

  9. 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.

  10. Rif1 and Exo1 regulate the genomic instability following telomere losses.

    Science.gov (United States)

    Xue, Yuan; Marvin, Marcus E; Ivanova, Iglika G; Lydall, David; Louis, Edward J; Maringele, Laura

    2016-06-01

    Telomere attrition is linked to cancer, diabetes, cardiovascular disease and aging. This is because telomere losses trigger further genomic modifications, culminating with loss of cell function and malignant transformation. However, factors regulating the transition from cells with short telomeres, to cells with profoundly altered genomes, are little understood. Here, we use budding yeast engineered to lack telomerase and other forms of telomere maintenance, to screen for such factors. We show that initially, different DNA damage checkpoint proteins act together with Exo1 and Mre11 nucleases, to inhibit proliferation of cells undergoing telomere attrition. However, this situation changes when survivors lacking telomeres emerge. Intriguingly, checkpoint pathways become tolerant to loss of telomeres in survivors, yet still alert to new DNA damage. We show that Rif1 is responsible for the checkpoint tolerance and proliferation of these survivors, and that is also important for proliferation of cells with a broken chromosome. In contrast, Exo1 drives extensive genomic modifications in survivors. Thus, the conserved proteins Rif1 and Exo1 are critical for survival and evolution of cells with lost telomeres. PMID:27004475

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

    DEFF Research Database (Denmark)

    Olsen, Morten Tange

    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...

  12. Stressful life events and leukocyte telomere attrition in adulthood : a prospective population-based cohort study

    NARCIS (Netherlands)

    van Ockenburg, S. L.; Bos, E. H.; de Jonge, P.; van der Harst, P.; Gans, R. O. B.; Rosmalen, J. G. M.

    2015-01-01

    Background. Telomere attrition might be one of the mechanisms through which psychosocial stress leads to somatic disease. To date it is unknown if exposure to adverse life events in adulthood is associated with telomere shortening prospectively. In the current study we investigated whether life even

  13. 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

    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...

  14. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma.

    Science.gov (United States)

    Farazi, Paraskevi A; Glickman, Jonathan; Jiang, Shan; Yu, Alice; Rudolph, Karl Lenhard; DePinho, Ronald A

    2003-08-15

    Telomere maintenance and telomerase reactivation are near universal features of human hepatocellular carcinoma (HCC), yet the shorter telomeres and highly abnormal cytogenetic profiles of HCC suggest that telomere erosion and dysfunction may be operative during the formative stages of tumorigenesis. Previous studies have established that the cancer-enhancing or suppressing impact of telomere dysfunction is highly dependent on several parameters including cell type, tumor stage, and p53 status. Here, to understand better the pathogenetic role of telomere dysfunction in the initiation and progression in human HCC, we have used three mechanistically distinct liver cancer-prone model systems (urokinase plasminogen activator transgenic mice, carbon tetrachloride exposure, and diethylnistrosamine treatment) in the context of successive generations of telomerase-deficient mice null for the telomerase RNA component, mTERC. Across all of the HCC model systems, telomere dysfunction suppressed both the incidence and growth of HCC lesions, a trend that mirrored the level of intratumoral proliferative arrest and apoptosis. On the histological level, telomere dysfunction was associated with a significant increase in the number of early stage neoplastic lesions and a reciprocal decline in the occurrence of high-grade malignancies. These genetic data in the mouse indicate that telomere dysfunction exerts an opposing role in the initiation versus progression of HCC and provide a framework for understanding the intimate link among chronic liver disease, chromosomal instability, and increased HCC in humans. PMID:12941829

  15. 端粒、端粒酶与肿瘤%Telomere, Telomerase and Tumor

    Institute of Scientific and Technical Information of China (English)

    张岭; 李龙芸

    1999-01-01

    Telomere is the end structure of chromosome and it will be shortened during replication. Telomerase is a reverse transcripatse consisting of both RNA and protein components and synthesizes telomeric DNA by copying the template sequence of its own RNA components to maintain telomere length for function.Telomerase activity in germline cells,immortal and neoplastic cells was detected,but not in mostly normal cells.The telomere-telomerase hypothesis was brung out to explain this phenomenon.According to this hypothesis,re-actived telomerase will maintain telomere's length for protecting chromosome to make the cell immortal.The aging procedure will be explained by this hypothesis too.This hypothesis provides a new concepts of cancer and cancer's treatment.

  16. Live Cell Imaging Reveals the Dynamics of Telomerase Recruitment to Telomeres.

    Science.gov (United States)

    Schmidt, Jens C; Zaug, Arthur J; Cech, Thomas R

    2016-08-25

    Telomerase maintains genome integrity by adding repetitive DNA sequences to the chromosome ends in actively dividing cells, including 90% of all cancer cells. Recruitment of human telomerase to telomeres occurs during S-phase of the cell cycle, but the molecular mechanism of the process is only partially understood. Here, we use CRISPR genome editing and single-molecule imaging to track telomerase trafficking in nuclei of living human cells. We demonstrate that telomerase uses three-dimensional diffusion to search for telomeres, probing each telomere thousands of times each S-phase but only rarely forming a stable association. Both the transient and stable association events depend on the direct interaction of the telomerase protein TERT with the telomeric protein TPP1. Our results reveal that telomerase recruitment to telomeres is driven by dynamic interactions between the rapidly diffusing telomerase and the chromosome end. PMID:27523609

  17. On the origin of the eukaryotic chromosome: the role of noncanonical DNA structures in telomere evolution.

    Science.gov (United States)

    Garavís, Miguel; González, Carlos; Villasante, Alfredo

    2013-01-01

    The transition of an ancestral circular genome to multiple linear chromosomes was crucial for eukaryogenesis because it allowed rapid adaptive evolution through aneuploidy. Here, we propose that the ends of nascent linear chromosomes should have had a dual function in chromosome end protection (capping) and chromosome segregation to give rise to the "proto-telomeres." Later on, proper centromeres evolved at subtelomeric regions. We also propose that both noncanonical structures based on guanine-guanine interactions and the end-protection proteins recruited by the emergent telomeric heterochromatin have been required for telomere maintenance through evolution. We further suggest that the origin of Drosophila telomeres may be reminiscent of how the first telomeres arose. PMID:23699225

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    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......18 rs6548238, and the CRP promoter polymorphism rs3091244 in instrumental variable analyses, we estimated the associations between genetically increased BMI and telomere length and between genetically increased C-reactive protein and telomere length. RESULTS: In multivariable-adjusted observational...... analyses, telomere length decreased with seven base pairs (95% confidence interval, -9--5) per unit increase in BMI, and further adjustment for C-reactive protein attenuated this association to -5 base pairs (-8--3). In accordance, instrumental variable analysis showed a non-significant telomere length...

  19. Proliferation and telomere length in acutely mobilized blood mononuclear cells in HIV infected patients

    DEFF Research Database (Denmark)

    Søndergaard, S R; Essen, M V; Schjerling, P;

    2002-01-01

    infusion for 1 h. Blood was sampled before, during and 1 h after adrenalin infusion. Proliferation and mean telomere restriction fragment length (telomeres) of blood mononuclear cells (BMNC) and purified CD8+ and CD4+ cells were investigated at all time points. In patients, the proliferation to pokeweed...... mitogens (PWM) was lower and decreased more during adrenalin infusion. After adrenalin infusion the proliferation to PWM was restored only in the controls. In all subjects telomeres in CD4+ cells declined during adrenalin infusion. Additionally, the patients had shortened telomeres in their CD8+ cells, and...... particularly HAART treated patients had shortened telomeres in all cell-subtypes. The finding that patients mobilized cells with an impaired proliferation to PWM during and after adrenalin infusion has possible clinical relevance for HIV infected patients during pathological stressful conditions, such as...

  20. Naval trends in ASEAN: is there a new arms race?

    OpenAIRE

    Jones, Frank Curtis

    1995-01-01

    Global military spending is decreasing. However this trend does not apply to some regions of the world, specifically Southeast Asia. This thesis describes the ongoing naval arms buildup in this region and examines why it is occurring when the rest of the world is decreasing military spending. Next, this thesis asks if this arms build-up is dangerous. Unlike many other arms races around the world, the Southeast Asian build-up is not particularly dangerous because of the parallel development of...