Repair of Chromosome Ends after Telomere Loss in<i>Saccharomyces</i>

Mangahas, Jeff L.; Alexander, Mary Kate; Sandell, Lisa L.; Zakian, Virginia A.

doi:10.1091/mbc.12.12.4078

Cited by 72 publications

(87 citation statements)

References 46 publications

(69 reference statements)

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“…Chromosome VII has no other TG tract Ͼ20 base pairs (Mangahas et al, 2001), consistent with our finding that the 22-base pair TG sequence assists DSB repair by telomere addition, whereas the 11-base pair TG sequence does not. Notably, the haploid genome contains only 14 TG repeats, the length of which is Ͼ20 base pairs (Mangahas et al, 2001). We detected weak Cdc13 association with TG(Ϫ) ends at the ADH4 locus on chromosome VII ( Figure 4B).…”

Section: Checkpoint Inhibition By Telomere Capsupporting

confidence: 90%

“…On chromosome VII, telomere addition frequently occurs at only a single location, which corresponds to a 35-base pair TG stretch that is 50 kb from the left telomere end (35 kb away from the ADH4 locus). Chromosome VII has no other TG tract Ͼ20 base pairs (Mangahas et al, 2001), consistent with our finding that the 22-base pair TG sequence assists DSB repair by telomere addition, whereas the 11-base pair TG sequence does not. Notably, the haploid genome contains only 14 TG repeats, the length of which is Ͼ20 base pairs (Mangahas et al, 2001).…”

supporting

confidence: 90%

“…Alternatively, Ten1 might localize to DNA ends that are covered with multiple Cdc13 proteins. Previous findings indicate that telomere addition takes place at a very limited number of chromosome sites in budding yeast (Mangahas et al, 2001). On chromosome VII, telomere addition frequently occurs at only a single location, which corresponds to a 35-base pair TG stretch that is 50 kb from the left telomere end (35 kb away from the ADH4 locus).…”

Section: Discussionmentioning

confidence: 97%

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Cdc13 Telomere Capping Decreases Mec1 Association but Does Not Affect Tel1 Association with DNA Ends

Hirano

Sugimoto

2007

MBoC

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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. INTRODUCTIONDNA double-strand breaks (DSBs) are induced by exogenous DNA-damaging agents and carcinogens or by endogenous by-products, including reactive oxygen species (Friedberg et al., 2006). The repair of DSBs is crucial for maintaining genome stability. All organisms respond to DSBs by promptly launching the DNA damage response. This response involves the recruitment of DNA repair factors and the activation of signal transduction pathways, often termed DNA damage checkpoint pathways (Zhou and Elledge, 2000). Activation of the checkpoint pathway induces cell cycle arrest and expression of genes required for DNA repair.The checkpoint signals are initiated through two large protein kinases, ataxia-teleangiectasia mutated (ATM) and ATM-Rad3-related (ATR) (Zhou and Elledge, 2000;Abraham, 2001). ATM and ATR are highly conserved among eukaryotes. ATR is closely related to Mec1 in the budding yeast Saccharomyces cerevisiae and Rad3 in the fission yeast Schizosaccharomyces pombe. ATM homologues are termed Tel1 in both budding and fission yeasts. Current evidence indicates that the Mre11-Rad50 -Nbs1 (Xrs2 in budding yeast) complex is the primary sensor that recruits ATR/ Mec1 and ATM/Tel1 to DSBs (Nakada et al., 2003a(Nakada et al., , 2004Falck et al., 2005;You et al., 2005). In budding yeast, there is compelling evidence that the Mre11-Rad50 -Xrs2 (MRX) complex collaborates with exonuclease 1 (Exo1) in the generation of single-stranded DNA (ssDNA) at DSB ends (Krogh and Symington, 2004). ATM/Tel1 interacts with the C terminus of Nbs1/Xrs2 to localize to DNA ends (Nakada et al., 2003a;Falck et al., 2005;You et al., 2005). Meanwhile, the ssDNA that is generated at the DSB is covered with replication protein A (RPA) (Wold, 1997;Krogh and Symington, 2004). RPA-covered DNA recruits ATR/Mec1 to a region near the DSB end (Zou and Elledge, 2003;Nakada et al., 2005). ATM and ATR activate the downstream kinases CHK1 and CHK2 with assistance of checkpoint mediators, including 53BP1, BRCA1, and MDC1 (Zhou and Elledge, 2000;Bakke...

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Section: Checkpoint Inhibition By Telomere Capsupporting

confidence: 90%

supporting

confidence: 90%

Section: Discussionmentioning

confidence: 97%

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Cdc13 Telomere Capping Decreases Mec1 Association but Does Not Affect Tel1 Association with DNA Ends

Hirano

Sugimoto

2007

MBoC

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“…The PIF1 helicase subfamily appears to perform many cellular functions, ranging from nuclear DNA replication, 15 telomere length regulation, [12][13][14]26,29,30 mitochondrial genome integrity, [7][8][9][10][11]20 DNA repair, [8][9][10] Okazaki fragment processing, 16 assisting the replication fork progress through nonnucleosomal protein-DNA complexes.…”

Section: Disclosure Of Potential Conflicts Of Interestmentioning

confidence: 99%

Determination of the biochemical properties of full-length human PIF1 ATPase

Wang

et al. 2013

Prion

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“…In the presence of doublestranded DNA breaks, chromosome ends are rarely healed by the de novo addition of telomeres (54). In the absence of nuclear ScPif1, gross chromosomal rearrangements are in-creased, and healing of broken ends via telomere addition is more frequent (42,47,48,61). Nuclear ScPif1 is also essential for mitigating the deregulated activity of the RecQ helicase Sgs1 observed in top3⌬ cells (71).…”

mentioning

confidence: 99%

Murine Pif1 Interacts with Telomerase and Is Dispensable for Telomere Function In Vivo

Snow

Mateyak

Paderova

et al. 2007

Molecular and Cellular Biology

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Pif1 is a 5 -to-3 DNA helicase critical to DNA replication and telomere length maintenance in the budding yeast Saccharomyces cerevisiae. ScPif1 is a negative regulator of telomeric repeat synthesis by telomerase, and recombinant ScPif1 promotes the dissociation of the telomerase RNA template from telomeric DNA in vitro. In order to dissect the role of mPif1 in mammals, we cloned and disrupted the mPif1 gene. In wild-type animals, mPif1 expression was detected only in embryonic and hematopoietic lineages. mPif1 ؊/؊ mice were viable at expected frequencies, displayed no visible abnormalities, and showed no reproducible alteration in telomere length in two different null backgrounds, even after several generations. Spectral karyotyping of mPif1 ؊/؊ fibroblasts and splenocytes revealed no significant change in chromosomal rearrangements. Furthermore, induction of apoptosis or DNA damage revealed no differences in cell viability compared to what was found for wild-type fibroblasts and splenocytes. Despite a novel association of mPif1 with telomerase, mPif1 did not affect the elongation activity of telomerase in vitro. Thus, in contrast to what occurs with ScPif1, murine telomere homeostasis or genetic stability does not depend on mPif1, perhaps due to fundamental differences in the regulation of telomerase and/or telomere length between mice and yeast or due to genetic redundancy with other DNA helicases.Homeostatic telomere length is achieved by a balance between the extension of the 3Ј telomeric repeats by telomerase or by homologous recombination between telomeric tracts and telomere erosion due to incomplete DNA replication or nucleolytic degradation (30). Telomerase acts to lengthen telomeres via the reverse transcription of an RNA template (encoded by TERC in mammals or TLC1 in Saccharomyces cerevisiae) by a telomerase reverse transcriptase (TERT or Est2, respectively) (30). In the absence of telomerase, telomeric repeats can also be maintained via homologous recombination (12). Excessive telomere lengthening is usually curtailed by cis-inhibitory telomere binding factors, such as Rif1 and Rap1 in S. cerevisiae and TRF1 in humans, or by the action of nucleases (30). In particular instances, telomeric tracts undergo saltatory attrition via the excision of telomeric DNA circles, thus preventing unregulated telomere lengthening (12,40,73).This equilibrium is not simply a push and pull between factors that strictly promote or oppose telomere extension. In S. cerevisiae, the trimeric protein complex composed of Cdc13, Stn1, and Ten1 plays a critical role in the protection of chromosome ends from nucleolytic degradation, and the complex serves both positive and negative roles in the access of telomerase to the telomere during late S phase (24,27,66). The Ku70/Ku80 heterodimer, while essential for nonhomologous end joining, also plays a key role both in the recruitment of telomerase to the telomere and in the protection of ends from degradation (9,25,65,74). Several DNA helicases and nucleases are also known to play ...

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Repair of Chromosome Ends after Telomere Loss inSaccharomyces

Cited by 72 publications

References 46 publications

Cdc13 Telomere Capping Decreases Mec1 Association but Does Not Affect Tel1 Association with DNA Ends

Cdc13 Telomere Capping Decreases Mec1 Association but Does Not Affect Tel1 Association with DNA Ends

Determination of the biochemical properties of full-length human PIF1 ATPase

Murine Pif1 Interacts with Telomerase and Is Dispensable for Telomere Function In Vivo

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