Articles de revues : « Rif2, Tel1, telomere, yeast »

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Craven, Rolf J., et Thomas D. Petes. « Dependence of the Regulation of Telomere Length on the Type of Subtelomeric Repeat in the Yeast Saccharomyces cerevisiae ». Genetics 152, n^o 4 (1 août 1999) : 1531–41. http://dx.doi.org/10.1093/genetics/152.4.1531.

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Abstract In the yeast Saccharomyces cerevisiae, chromosomes terminate with ∼400 bp of a simple repeat poly(TG1-3). Based on the arrangement of subtelomeric X and Y′ repeats, two types of yeast telomeres exist, those with both X and Y′ (Y′ telomeres) and those with only X (X telomeres). Mutations that result in abnormally short or abnormally long poly(TG1-3) tracts have been previously identified. In this study, we investigated telomere length in strains with two classes of mutations, one that resulted in short poly(TG1-3) tracts (tel1) and one that resulted in elongated tracts (pif1, rap1-17, rif1, or rif2). In the tel1 pif1 strain, Y′ telomeres had about the same length as those in tel1 strains and X telomeres had lengths intermediate between those in tel1 and pif1 strains. Strains with either the tel1 rap1-17 or tel1 rif2 genotypes had short tracts for all chromosome ends examined, demonstrating that the telomere elongation characteristic of rap1-17 and rif2 strains is Tel1p-dependent. In strains of the tel1 rif1 or tel1 rif1 rif2 genotypes, telomeres with Y′ repeats had short terminal tracts, whereas most of the X telomeres had long terminal tracts. These results demonstrate that the regulation of telomere length is different for X and Y′ telomeres.

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Viscardi, Valeria, Enrico Baroni, Michele Romano, Giovanna Lucchini et Maria Pia Longhese. « Sudden Telomere Lengthening Triggers a Rad53-dependent Checkpoint inSaccharomyces cerevisiae ». Molecular Biology of the Cell 14, n^o 8 (août 2003) : 3126–43. http://dx.doi.org/10.1091/mbc.e02-11-0719.

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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 G2/M checkpoint in cells whose telomeres are short due to the lack of either Tel1 or Yku70. Sudden telomere elongation and checkpoint-mediated cell cycle arrest are also triggered in wild-type cells by overproducing a protein fusion between the telomeric binding protein Cdc13 and the telomerase-associated protein Est1. Checkpoint activation by GAL1-TEL1 requires ongoing telomere elongation. In fact, it is turned off concomitantly with telomeres reaching a new stable length and is partially suppressed by deletion of the telomerase EST2 gene. Moreover, both telomere length rebalancing and checkpoint inactivation under galactose-induced conditions are accelerated by high levels of either the Sae2 protein, involved in double-strand breaks processing, or the negative telomere length regulator Rif2. These data suggest that sudden telomere lengthening elicits a checkpoint response that inhibits the G2/M transition.

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Fukunaga, Kenzo, Yukinori Hirano et Katsunori Sugimoto. « Subtelomere-binding protein Tbf1 and telomere-binding protein Rap1 collaborate to inhibit localization of the Mre11 complex to DNA ends in budding yeast ». Molecular Biology of the Cell 23, n^o 2 (15 janvier 2012) : 347–59. http://dx.doi.org/10.1091/mbc.e11-06-0568.

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Chromosome ends, known as telomeres, have to be distinguished from DNA double-strand breaks that activate DNA damage checkpoints. In budding yeast, the Mre11-Rad50-Xrs2 (MRX) complex associates with DNA ends and promotes checkpoint activation. Rap1 binds to double-stranded telomeric regions and recruits Rif1 and Rif2 to telomeres. Rap1 collaborates with Rif1 and Rif2 and inhibits MRX localization to DNA ends. This Rap1-Rif1-Rif2 function becomes attenuated at shortened telomeres. Here we show that Rap1 acts together with the subtelomere-binding protein Tbf1 and inhibits MRX localization to DNA ends. The placement of a subtelomeric sequence or TTAGGG repeats together with a short telomeric TG repeat sequence inhibits MRX accumulation at nearby DNA ends in a Tbf1-dependent manner. Moreover, tethering of both Tbf1 and Rap1 proteins decreases MRX and Tel1 accumulation at nearby DNA ends. This Tbf1- and Rap1-dependent pathway operates independently of Rif1 or Rif2 function. Depletion of Tbf1 protein stimulates checkpoint activation in cells containing short telomeres but not in cells containing normal-length telomeres. These data support a model in which Tbf1 and Rap1 collaborate to maintain genomic stability of short telomeres.

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Sholes, Samantha L., Kayarash Karimian, Ariel Gershman, Thomas J. Kelly, Winston Timp et Carol W. Greider. « Chromosome-specific telomere lengths and the minimal functional telomere revealed by nanopore sequencing ». Genome Research 32, n^o 4 (26 octobre 2021) : 616–28. http://dx.doi.org/10.1101/gr.275868.121.

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We developed a method to tag telomeres and measure telomere length by nanopore sequencing in the yeast S. cerevisiae. Nanopore allows long-read sequencing through the telomere, through the subtelomere, and into unique chromosomal sequence, enabling assignment of telomere length to a specific chromosome end. We observed chromosome end–specific telomere lengths that were stable over 120 cell divisions. These stable chromosome-specific telomere lengths may be explained by slow clonal variation or may represent a new biological mechanism that maintains equilibrium unique to each chromosome end. We examined the role of RIF1 and TEL1 in telomere length regulation and found that TEL1 is epistatic to RIF1 at most telomeres, consistent with the literature. However, at telomeres that lack subtelomeric Y′ sequences, tel1Δ rif1Δ double mutants had a very small, but significant, increase in telomere length compared with the tel1Δ single mutant, suggesting an influence of Y′ elements on telomere length regulation. We sequenced telomeres in a telomerase-null mutant (est2Δ) and found the minimal telomere length to be ∼75 bp. In these est2Δ mutants, there were apparent telomere recombination events at individual telomeres before the generation of survivors, and these events were significantly reduced in est2Δ rad52Δ double mutants. The rate of telomere shortening in the absence of telomerase was similar across all chromosome ends at ∼5 bp per generation. This new method gives quantitative, high-resolution telomere length measurement at each individual chromosome end and suggests possible new biological mechanisms regulating telomere length.

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Ji, Hong, Margaret H. Platts, Latif M. Dharamsi et Katherine L. Friedman. « Regulation of Telomere Length by an N-Terminal Region of the Yeast Telomerase Reverse Transcriptase ». Molecular and Cellular Biology 25, n^o 20 (15 octobre 2005) : 9103–14. http://dx.doi.org/10.1128/mcb.25.20.9103-9114.2005.

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ABSTRACT Telomerase is a reverse transcriptase that maintains chromosome integrity through synthesis of repetitive telomeric sequences on the ends of eukaryotic chromosomes. In the yeast Saccharomyces cerevisiae, telomere length homeostasis is achieved through negative regulation of telomerase access to the chromosome terminus by telomere-bound Rap1 protein and its binding partners, Rif1p and Rif2p, and positive regulation by factors such as Ku70/80, Tel1p, and Cdc13p. Here we report the identification of mutations within an N-terminal region (region I) of the yeast telomerase catalytic subunit (Est2p) that cause telomere lengthening without altering measurable catalytic properties of the enzyme in vitro. These telomerase mutations affect telomere length through a Ku-independent mechanism and do not alter chromosome end structure. While Tel1p is required for expression of the telomere-lengthening phenotype, Rif1p and Rif2p are not, suggesting that telomere overextension is independent of Rap1p. Taken together, these data suggest that specific amino acids within region I of the catalytic subunit of yeast telomerase play a previously unanticipated role in the response to Tel1p regulation at the telomere.

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Zhang, Ling-Li, Zhenfang Wu et Jin-Qiu Zhou. « Tel1 and Rif2 oppositely regulate telomere protection at uncapped telomeres in Saccharomyces cerevisiae ». Journal of Genetics and Genomics 45, n^o 9 (septembre 2018) : 467–76. http://dx.doi.org/10.1016/j.jgg.2018.09.001.

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Nakamura, Toru M., Bettina A. Moser et Paul Russell. « Telomere Binding of Checkpoint Sensor and DNA Repair Proteins Contributes to Maintenance of Functional Fission Yeast Telomeres ». Genetics 161, n^o 4 (1 août 2002) : 1437–52. http://dx.doi.org/10.1093/genetics/161.4.1437.

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Abstract Telomeres, the ends of linear chromosomes, are DNA double-strand ends that do not trigger a cell cycle arrest and yet require checkpoint and DNA repair proteins for maintenance. Genetic and biochemical studies in the fission yeast Schizosaccharomyces pombe were undertaken to understand how checkpoint and DNA repair proteins contribute to telomere maintenance. On the basis of telomere lengths of mutant combinations of various checkpoint-related proteins (Rad1, Rad3, Rad9, Rad17, Rad26, Hus1, Crb2, Chk1, Cds1), Tel1, a telomere-binding protein (Taz1), and DNA repair proteins (Ku70, Rad32), we conclude that Rad3/Rad26 and Tel1/Rad32 represent two pathways required to maintain telomeres and prevent chromosome circularization. Rad1/Rad9/Hus1/Rad17 and Ku70 are two additional epistasis groups, which act in the Rad3/Rad26 pathway. However, Rad3/Rad26 must have additional target(s), as cells lacking Tel1/Rad32, Rad1/Rad9/Hus1/Rad17, and Ku70 groups did not circularize chromosomes. Cells lacking Rad3/Rad26 and Tel1/Rad32 senesced faster than a telomerase trt1Δ mutant, suggesting that these pathways may contribute to telomere protection. Deletion of taz1 did not suppress chromosome circularization in cells lacking Rad3/Rad26 and Tel1/Rad32, also suggesting that two pathways protect telomeres. Chromatin immunoprecipitation analyses found that Rad3, Rad1, Rad9, Hus1, Rad17, Rad32, and Ku70 associate with telomeres. Thus, checkpoint sensor and DNA repair proteins contribute to telomere maintenance and protection through their association with telomeres.

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Ogi, Hiroo, Greicy H. Goto, Avik Ghosh, Sevil Zencir, Everett Henry et Katsunori Sugimoto. « Requirement of the FATC domain of protein kinase Tel1 for localization to DNA ends and target protein recognition ». Molecular Biology of the Cell 26, n^o 19 (octobre 2015) : 3480–88. http://dx.doi.org/10.1091/mbc.e15-05-0259.

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Two large phosphatidylinositol 3-kinase–related protein kinases (PIKKs), ATM and ATR, play a central role in the DNA damage response pathway. PIKKs contain a highly conserved extreme C-terminus called the FRAP-ATM-TRRAP-C-terminal (FATC) domain. In budding yeast, ATM and ATR correspond to Tel1 and Mec1, respectively. In this study, we characterized functions of the FATC domain of Tel1 by introducing substitution or truncation mutations. One substitution mutation, termed tel1-21, and a truncation mutation, called tel1-ΔC, did not significantly affect the expression level. The tel1-21 mutation impaired the cellular response to DNA damage and conferred moderate telomere maintenance defect. In contrast, the tel1-ΔC mutation behaved like a null mutation, conferring defects in both DNA damage response and telomere maintenance. Tel1-21 protein localized to DNA ends as effectively as wild-type Tel1 protein, whereas Tel1-ΔC protein failed. Introduction of a hyperactive TEL1-hy mutation suppressed the tel1-21 mutation but not the tel1-ΔC mutation. In vitro analyses revealed that both Tel1-21 and Tel1-ΔC proteins undergo efficient autophosphorylation but exhibit decreased kinase activities toward the exogenous substrate protein, Rad53. Our results show that the FATC domain of Tel1 mediates localization to DNA ends and contributes to phosphorylation of target proteins.

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Craven, Rolf J., Patricia W. Greenwell, Margaret Dominska et Thomas D. Petes. « Regulation of Genome Stability by TEL1 and MEC1, Yeast Homologs of the Mammalian ATM and ATR Genes ». Genetics 161, n^o 2 (1 juin 2002) : 493–507. http://dx.doi.org/10.1093/genetics/161.2.493.

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Abstract In eukaryotes, a family of related protein kinases (the ATM family) is involved in regulating cellular responses to DNA damage and telomere length. In the yeast Saccharomyces cerevisiae, two members of this family, TEL1 and MEC1, have functionally redundant roles in both DNA damage repair and telomere length regulation. Strains with mutations in both genes are very sensitive to DNA damaging agents, have very short telomeres, and undergo cellular senescence. We find that strains with the double mutant genotype also have ∼80-fold increased rates of mitotic recombination and chromosome loss. In addition, the tel1 mec1 strains have high rates of telomeric fusions, resulting in translocations, dicentrics, and circular chromosomes. Similar chromosome rearrangements have been detected in mammalian cells with mutations in ATM (related to TEL1) and ATR (related to MEC1) and in mammalian cells that approach cell crisis.

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Ritchie, Kim B., Julia C. Mallory et Thomas D. Petes. « Interactions of TLC1 (Which Encodes the RNA Subunit of Telomerase), TEL1, and MEC1 in Regulating Telomere Length in the Yeast Saccharomyces cerevisiae ». Molecular and Cellular Biology 19, n^o 9 (1 septembre 1999) : 6065–75. http://dx.doi.org/10.1128/mcb.19.9.6065.

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ABSTRACT In the yeast Saccharomyces cerevisiae, chromosomes terminate with a repetitive sequence [poly(TG1–3)] 350 to 500 bp in length. Strains with a mutation of TEL1, a homolog of the human gene (ATM) mutated in patients with ataxia telangiectasia, have short but stable telomeric repeats. Mutations of TLC1 (encoding the RNA subunit of telomerase) result in strains that have continually shortening telomeres and a gradual loss of cell viability; survivors of senescence arise as a consequence of a Rad52p-dependent recombination events that amplify telomeric and subtelomeric repeats. We show that a mutation inMEC1 (a gene related in sequence to TEL1 andATM) reduces telomere length and that tel1 mec1double mutant strains have a senescent phenotype similar to that found in tlc1 strains. As observed in tlc1 strains, survivors of senescence in the tel1 mec1 strains occur by a Rad52p-dependent amplification of telomeric and subtelomeric repeats. In addition, we find that strains with both tel1 andtlc1 mutations have a delayed loss of cell viability compared to strains with the single tlc1 mutation. This result argues that the role of Tel1p in telomere maintenance is not solely a direct activation of telomerase.

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Hirano, Yukinori, et Katsunori Sugimoto. « Cdc13 Telomere Capping Decreases Mec1 Association but Does Not Affect Tel1 Association with DNA Ends ». Molecular Biology of the Cell 18, n^o 6 (juin 2007) : 2026–36. http://dx.doi.org/10.1091/mbc.e06-12-1074.

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Chromosome ends, known as telomeres, have to be distinguished from DNA breaks that activate DNA damage checkpoint. Two large protein kinases, ataxia-teleangiectasia mutated (ATM) and ATM-Rad3-related (ATR), control not only checkpoint activation but also telomere length. In budding yeast, Mec1 and Tel1 correspond to ATR and ATM, respectively. Here, we show that Cdc13-dependent telomere capping attenuates Mec1 association with DNA ends. The telomeric TG repeat sequence inhibits DNA degradation and decreases Mec1 accumulation at the DNA end. The TG-mediated degradation block requires binding of multiple Cdc13 proteins. The Mre11–Rad50-Xrs2 complex and Exo1 contribute to DNA degradation at DNA ends. Although the TG sequence impedes Exo1 association with DNA ends, it allows Mre11 association. Moreover, the TG sequence does not affect Tel1 association with the DNA end. Our results suggest that the Cdc13 telomere cap coordinates Mec1 and Tel1 accumulation rather than simply covering the DNA ends at telomeres.

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Ritchie, Kim B., et Thomas D. Petes. « The Mre11p/Rad50p/Xrs2p Complex and the Tel1p Function in a Single Pathway for Telomere Maintenance in Yeast ». Genetics 155, n^o 1 (1 mai 2000) : 475–79. http://dx.doi.org/10.1093/genetics/155.1.475.

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Abstract The Mre11p/Rad50p/Xrs2p complex is involved in the repair of double-strand DNA breaks, nonhomologous end joining, and telomere length regulation. TEL1 is primarily involved in telomere length regulation. By an epistasis analysis, we conclude that Tel1p and the Mre11p/Rad50p/Xrs2p complex function in a single pathway of telomere length regulation.

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Fritz, Eberhard, Anna A. Friedl, Ralf M. Zwacka, Friederike Eckardt-Schupp et M. Stephen Meyn. « The YeastTEL1Gene Partially Substitutes for HumanATMin Suppressing Hyperrecombination, Radiation-Induced Apoptosis and Telomere Shortening in A-T Cells ». Molecular Biology of the Cell 11, n^o 8 (août 2000) : 2605–16. http://dx.doi.org/10.1091/mbc.11.8.2605.

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Homozygous mutations in the human ATM gene lead to a pleiotropic clinical phenotype of ataxia-telangiectasia (A-T) patients and correlating cellular deficiencies in cells derived from A-T donors. Saccharomyces cerevisiae tel1 mutants lacking Tel1p, which is the closest sequence homologue to the ATM protein, share some of the cellular defects with A-T. Through genetic complementation of A-T cells with the yeast TEL1 gene, we provide evidence that Tel1p can partially compensate for ATM in suppressing hyperrecombination, radiation-induced apoptosis, and telomere shortening. Complementation appears to be independent of p53 activation. The data provided suggest that TEL1 is a functional homologue of human ATM in yeast, and they help to elucidate different cellular and biochemical pathways in human cells regulated by the ATM protein.

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Subramanian, Lakxmi, Bettina A. Moser et Toru M. Nakamura. « Recombination-Based Telomere Maintenance Is Dependent on Tel1-MRN and Rap1 and Inhibited by Telomerase, Taz1, and Ku in Fission Yeast ». Molecular and Cellular Biology 28, n^o 5 (26 décembre 2007) : 1443–55. http://dx.doi.org/10.1128/mcb.01614-07.

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ABSTRACT Fission yeast cells survive loss of the telomerase catalytic subunit Trt1 (TERT) through recombination-based telomere maintenance or through chromosome circularization. Although trt1Δ survivors with linear chromosomes can be obtained, they often spontaneously circularize their chromosomes. Therefore, it was difficult to establish genetic requirements for telomerase-independent telomere maintenance. In contrast, when the telomere-binding protein Taz1 is also deleted, taz1Δ trt1Δ cells are able to stably maintain telomeres. Thus, taz1Δ trt1Δ cells can serve as a valuable tool in understanding the regulation of telomerase-independent telomere maintenance. In this study, we show that the checkpoint kinase Tel1 (ATM) and the DNA repair complex Rad32-Rad50-Nbs1 (MRN) are required for telomere maintenance in taz1Δ trt1Δ cells. Surprisingly, Rap1 is also essential for telomere maintenance in taz1Δ trt1Δ cells, even though recruitment of Rap1 to telomeres depends on Taz1. Expression of catalytically inactive Trt1 can efficiently inhibit recombination-based telomere maintenance, but the inhibition requires both Est1 and Ku70. While Est1 is essential for recruitment of Trt1 to telomeres, Ku70 is dispensable. Thus, we conclude that Taz1, TERT-Est1, and Ku70-Ku80 prevent telomere recombination, whereas MRN-Tel1 and Rap1 promote recombination-based telomere maintenance. Evolutionarily conserved proteins in higher eukaryotic cells might similarly contribute to telomere recombination.

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Poschke, Heiko, Martina Dees, Michael Chang, Sandeep Amberkar, Lars Kaderali, Rodney Rothstein et Brian Luke. « Rif2 Promotes a Telomere Fold-Back Structure through Rpd3L Recruitment in Budding Yeast ». PLoS Genetics 8, n^o 9 (20 septembre 2012) : e1002960. http://dx.doi.org/10.1371/journal.pgen.1002960.

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Galli, Michela, Chiara Frigerio, Maria Pia Longhese et Michela Clerici. « The regulation of the DNA damage response at telomeres : focus on kinases ». Biochemical Society Transactions 49, n^o 2 (26 mars 2021) : 933–43. http://dx.doi.org/10.1042/bst20200856.

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The natural ends of linear chromosomes resemble those of accidental double-strand breaks (DSBs). DSBs induce a multifaceted cellular response that promotes the repair of lesions and slows down cell cycle progression. This response is not elicited at chromosome ends, which are organized in nucleoprotein structures called telomeres. Besides counteracting DSB response through specialized telomere-binding proteins, telomeres also prevent chromosome shortening. Despite of the different fate of telomeres and DSBs, many proteins involved in the DSB response also localize at telomeres and participate in telomere homeostasis. In particular, the DSB master regulators Tel1/ATM and Mec1/ATR contribute to telomere length maintenance and arrest cell cycle progression when chromosome ends shorten, thus promoting a tumor-suppressive process known as replicative senescence. During senescence, the actions of both these apical kinases and telomere-binding proteins allow checkpoint activation while bulk DNA repair activities at telomeres are still inhibited. Checkpoint-mediated cell cycle arrest also prevents further telomere erosion and deprotection that would favor chromosome rearrangements, which are known to increase cancer-associated genome instability. This review summarizes recent insights into functions and regulation of Tel1/ATM and Mec1/ATR at telomeres both in the presence and in the absence of telomerase, focusing mainly on discoveries in budding yeast.

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Runge, K. W., et V. A. Zakian. « TEL2, an essential gene required for telomere length regulation and telomere position effect in Saccharomyces cerevisiae. » Molecular and Cellular Biology 16, n^o 6 (juin 1996) : 3094–105. http://dx.doi.org/10.1128/mcb.16.6.3094.

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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 caused telomere lengthening in wild-type cells. The transcription of genes placed near yeast telomeres is reversibly repressed, a phenomenon called the telomere position effect. The tel2-1 mutation reduced the position effect but did not affect transcriptional repression at the silent mating type cassettes, HMRa and HML alpha. The TEL2 gene was cloned, sequenced, and disrupted. Cells lacking TEL2 function died, with some cells arresting as large cells with three or four small protrusions or "blebs."

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Li, Bibo, et Titia de Lange. « Rap1 Affects the Length and Heterogeneity of Human Telomeres ». Molecular Biology of the Cell 14, n^o 12 (décembre 2003) : 5060–68. http://dx.doi.org/10.1091/mbc.e03-06-0403.

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Telomere length is controlled in part by cis-acting negative regulators that limit telomere extension by telomerase. In budding yeast, the major telomere length regulator scRap1 binds to telomeric DNA and acts to inhibit telomere elongation in cis. Because the human Rap1 ortholog hRap1 does not bind to telomeric DNA directly but is recruited to telomeres by TRF2, we examined its role in telomere length control. The data are consistent with hRap1 being a negative regulator of telomere length, indicating functional conservation. Deletion mapping confirmed that hRap1 is tethered to telomeres through interaction of its C terminus with TRF2. The telomere length phenotypes of hRap1 deletion mutants implicated both the BRCT and Myb domain as protein interaction domains involved in telomere length regulation. By contrast, scRap1 binds to telomeres with its Myb domains and uses its C terminus to recruit the telomere length regulators Rif1 and Rif2. Together, our data show that although the role of Rap1 at telomeres has been largely conserved, the domains of Rap1 have undergone extensive functional changes during eukaryotic evolution. Surprisingly, hRap1 alleles lacking the BRCT domain diminished the heterogeneity of human telomeres, indicating that hRap1 also plays a role in the regulation of telomere length distribution.

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Tsai, Yun-Luen, Shun-Fu Tseng, Shih-Husan Chang, Chuan-Chuan Lin et Shu-Chun Teng. « Involvement of Replicative Polymerases, Tel1p, Mec1p, Cdc13p, and the Ku Complex in Telomere-Telomere Recombination ». Molecular and Cellular Biology 22, n^o 16 (15 août 2002) : 5679–87. http://dx.doi.org/10.1128/mcb.22.16.5679-5687.2002.

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ABSTRACT Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the action of the reverse transcriptase telomerase. In both tumor and yeast cells that lack telomerase, telomeres are maintained by an alternative recombination mechanism. Genetic studies have led to the identification of DNA polymerases, cell cycle checkpoint proteins, and telomere binding proteins involved in the telomerase pathway. However, how these proteins affect telomere-telomere recombination has not been identified to date. Using an assay to trace the in vivo recombinational products throughout the course of survivor development, we show here that three major replicative polymerases, α, δ, and ε, play roles in telomere-telomere recombination and that each causes different effects and phenotypes when they as well as the telomerase are defective. Polymerase δ appears to be the main activity for telomere extension, since neither type I nor type II survivors arising via telomere-telomere recombination were seen in its absence. The frequency of type I versus type II is altered in the polymerase α and ε mutants relative to the wild type. Each prefers to develop a particular type of survivor. Moreover, type II recombination is mediated by the cell cycle checkpoint proteins Tel1 and Mec1, and telomere-telomere recombination is regulated by telomere binding protein Cdc13 and the Ku complex. Together, our results suggest that coordination between DNA replication machinery, DNA damage signaling, DNA recombination machinery, and the telomere protein-DNA complex allows telomere recombination to repair telomeric ends in the absence of telomerase.

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McNees, Carolyn J., Agueda M. Tejera, Paula Martínez, Matilde Murga, Francisca Mulero, Oscar Fernandez-Capetillo et Maria A. Blasco. « ATR suppresses telomere fragility and recombination but is dispensable for elongation of short telomeres by telomerase ». Journal of Cell Biology 188, n^o 5 (8 mars 2010) : 639–52. http://dx.doi.org/10.1083/jcb.200908136.

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Telomere shortening caused by incomplete DNA replication is balanced by telomerase-mediated telomere extension, with evidence indicating that the shortest telomeres are preferred substrates in primary cells. Critically short telomeres are detected by the cellular DNA damage response (DDR) system. In budding yeast, the important DDR kinase Tel1 (homologue of ATM [ataxia telangiectasia mutated]) is vital for telomerase recruitment to short telomeres, but mammalian ATM is dispensable for this function. We asked whether closely related ATR (ATM and Rad3 related) kinase, which is important for preventing replicative stress and chromosomal breakage at common fragile sites, might instead fulfill this role. The newly created ATR-deficient Seckel mouse strain was used to examine the function of ATR in telomerase recruitment and telomere function. Telomeres were recently found to resemble fragile sites, and we show in this study that ATR has an important role in the suppression of telomere fragility and recombination. We also find that wild-type ATR levels are important to protect short telomeres from chromosomal fusions but do not appear essential for telomerase recruitment to short telomeres in primary mouse embryonic fibroblasts from the ATR-deficient Seckel mouse model. These results reveal a previously unnoticed role for mammalian ATR in telomere protection and stability.

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Hailemariam, Sarem, Paolo De Bona, Roberto Galletto, Marcel Hohl, John H. Petrini et Peter M. Burgers. « The telomere-binding protein Rif2 and ATP-bound Rad50 have opposing roles in the activation of yeast Tel1ATM kinase ». Journal of Biological Chemistry 294, n^o 49 (22 octobre 2019) : 18846–52. http://dx.doi.org/10.1074/jbc.ra119.011077.

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Pennaneach, Vincent, et Richard D. Kolodner. « Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast ». Nature Genetics 36, n^o 6 (9 mai 2004) : 612–17. http://dx.doi.org/10.1038/ng1359.

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Pobiega, Sabrina, Olivier Alibert et Stéphane Marcand. « A new assay capturing chromosome fusions shows a protection trade-off at telomeres and NHEJ vulnerability to low-density ionizing radiation ». Nucleic Acids Research 49, n^o 12 (14 juin 2021) : 6817–31. http://dx.doi.org/10.1093/nar/gkab502.

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Abstract Chromosome fusions threaten genome integrity and promote cancer by engaging catastrophic mutational processes, namely chromosome breakage–fusion–bridge cycles and chromothripsis. Chromosome fusions are frequent in cells incurring telomere dysfunctions or those exposed to DNA breakage. Their occurrence and therefore their contribution to genome instability in unchallenged cells is unknown. To address this issue, we constructed a genetic assay able to capture and quantify rare chromosome fusions in budding yeast. This chromosome fusion capture (CFC) assay relies on the controlled inactivation of one centromere to rescue unstable dicentric chromosome fusions. It is sensitive enough to quantify the basal rate of end-to-end chromosome fusions occurring in wild-type cells. These fusions depend on canonical nonhomologous end joining (NHEJ). Our results show that chromosome end protection results from a trade-off at telomeres between positive effectors (Rif2, Sir4, telomerase) and a negative effector partially antagonizing them (Rif1). The CFC assay also captures NHEJ-dependent chromosome fusions induced by ionizing radiation. It provides evidence for chromosomal rearrangements stemming from a single photon–matter interaction.

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Khayat, Freddy, Elda Cannavo, Majedh Alshmery, William R. Foster, Charly Chahwan, Martino Maddalena, Christopher Smith et al. « Inhibition of MRN activity by a telomere protein motif ». Nature Communications 12, n^o 1 (22 juin 2021). http://dx.doi.org/10.1038/s41467-021-24047-2.

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AbstractThe MRN complex (MRX in Saccharomyces cerevisiae, made of Mre11, Rad50 and Nbs1/Xrs2) initiates double-stranded DNA break repair and activates the Tel1/ATM kinase in the DNA damage response. Telomeres counter both outcomes at chromosome ends, partly by keeping MRN-ATM in check. We show that MRX is disabled by telomeric protein Rif2 through an N-terminal motif (MIN, MRN/X-inhibitory motif). MIN executes suppression of Tel1, DNA end-resection and non-homologous end joining by binding the Rad50 N-terminal region. Our data suggest that MIN promotes a transition within MRX that is not conductive for endonuclease activity, DNA-end tethering or Tel1 kinase activation, highlighting an Achilles’ heel in MRN, which we propose is also exploited by the RIF2 paralog ORC4 (Origin Recognition Complex 4) in Kluyveromyces lactis and the Schizosaccharomyces pombe telomeric factor Taz1, which is evolutionarily unrelated to Orc4/Rif2. This raises the possibility that analogous mechanisms might be deployed in other eukaryotes as well.

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Rosas Bringas, Fernando Rodrigo, Sonia Stinus, Pien de Zoeten, Marita Cohn et Michael Chang. « Rif2 protects Rap1-depleted telomeres from MRX-mediated degradation in Saccharomyces cerevisiae ». eLife 11 (19 janvier 2022). http://dx.doi.org/10.7554/elife.74090.

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Rap1 is the main protein that binds double-stranded telomeric DNA in Saccharomyces cerevisiae. Examination of the telomere functions of Rap1 is complicated by the fact that it also acts as a transcriptional regulator of hundreds of genes and is encoded by an essential gene. In this study, we disrupt Rap1 telomere association by expressing a mutant telomerase RNA subunit (tlc1-tm) that introduces mutant telomeric repeats. tlc1-tm cells grow similar to wild-type cells, although depletion of Rap1 at telomeres causes defects in telomere length regulation and telomere capping. Rif2 is a protein normally recruited to telomeres by Rap1, but we show that Rif2 can still associate with Rap1-depleted tlc1-tm telomeres, and that this association is required to inhibit telomere degradation by the MRX complex. Rif2 and the Ku complex work in parallel to prevent tlc1-tm telomere degradation; tlc1-tm cells lacking Rif2 and the Ku complex are inviable. The partially redundant mechanisms may explain the rapid evolution of telomere components in budding yeast species.

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Hass, Evan P., et David C. Zappulla. « The Ku subunit of telomerase binds Sir4 to recruit telomerase to lengthen telomeres in S. cerevisiae ». eLife 4 (28 juillet 2015). http://dx.doi.org/10.7554/elife.07750.

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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.

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Holland, Cory L., Brian A. Sanderson, James K. Titus, Monica F. Weis, Angelica M. Riojas, Eric Malczewskyj, Brian M. Wasko et L. Kevin Lewis. « Suppression of telomere capping defects of Saccharomyces cerevisiae yku70 and yku80 mutants by telomerase ». G3 Genes|Genomes|Genetics 11, n^o 12 (13 octobre 2021). http://dx.doi.org/10.1093/g3journal/jkab359.

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Abstract The Ku complex performs multiple functions inside eukaryotic cells, including protection of chromosomal DNA ends from degradation and fusion events, recruitment of telomerase, and repair of double-strand breaks (DSBs). Inactivation of Ku complex genes YKU70 or YKU80 in cells of the yeast Saccharomyces cerevisiae gives rise to mutants that exhibit shortened telomeres and temperature-sensitive growth. In this study, we have investigated the mechanism by which overexpression of telomerase suppresses the temperature sensitivity of yku mutants. Viability of yku cells was restored by overexpression of the Est2 reverse transcriptase and TLC1 RNA template subunits of telomerase, but not the Est1 or Est3 proteins. Overexpression of other telomerase- and telomere-associated proteins (Cdc13, Stn1, Ten1, Rif1, Rif2, Sir3, and Sir4) did not suppress the growth defects of yku70 cells. Mechanistic features of suppression were assessed using several TLC1 RNA deletion derivatives and Est2 enzyme mutants. Supraphysiological levels of three catalytically inactive reverse transcriptase mutants (Est2-D530A, Est2-D670A, and Est2-D671A) suppressed the loss of viability as efficiently as the wild-type Est2 protein, without inducing cell senescence. Roles of proteins regulating telomere length were also determined. The results support a model in which chromosomes in yku mutants are stabilized via a replication-independent mechanism involving structural reinforcement of protective telomere cap structures.

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