A telomeric repeat sequence adjacent to a DNA double-stranded break produces an anticheckpoint

Michelson, Rhett J.; Rosenstein, Saul; Weinert, Ted

doi:10.1101/gad.1293805

Cited by 68 publications

(85 citation statements)

References 54 publications

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“…DNA double-strand breaks are typically resected, initially being degraded from 59 to 39 to create single-stranded 39 overhangs at the break (White and Haber 1990). However, it has been shown that when short tracts of telomere repeat sequences are placed adjacent to the DNA break site, the broken DNA end is protected from degradation (Diede and Gottschling 1999;Michelson et al 2005;Hirano and Sugimoto 2007). The presence of this telomere ''seed'' sequence also greatly stimulates the addition of new telomere repeats to the DSB (Diede and Gottschling 1999).…”

Section: Resultsmentioning

confidence: 99%

TEN1Is Essential forCDC13-Mediated Telomere Capping

Petreaca

Gasparyan

et al. 2009

Genetics

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Telomere binding proteins protect chromosome ends from degradation and mask chromosome termini from checkpoint surveillance. In Saccharomyces cerevisiae, Cdc13 binds single-stranded G-rich telomere repeats, maintaining telomere integrity and length. Two additional proteins, Ten1 and Stn1, interact with Cdc13 but their contributions to telomere integrity are not well defined. Ten1 is known to prevent accumulation of aberrant single-stranded telomere DNA; whether this results from defective end protection or defective telomere replication is unclear. Here we report our analysis of a new group of ten1 temperature-sensitive (ts) mutants. At permissive temperatures, ten1-ts strains display greatly elongated telomeres. After shift to nonpermissive conditions, however, ten1-ts mutants accumulate extensive telomeric single-stranded DNA. Cdk1 activity is required to generate these single-stranded regions, and deleting the EXO1 nuclease partially suppresses ten1-ts growth defects. This is similar to cdc13-1 mutants, suggesting ten1-ts strains are defective for end protection. Moreover, like Cdc13, our analysis reveals Ten1 promotes de novo telomere addition. Interestingly, in ten1-ts strains at high temperatures, telomeric singlestranded DNA and Rad52-YFP repair foci are strongly induced despite Cdc13 remaining associated with telomeres, revealing Cdc13 telomere binding is not sufficient for end protection. Finally, unlike cdc13-1 mutants, ten1-ts strains display strong synthetic interactions with mutations in the POLa complex. These results emphasize that Cdc13 relies on Ten1 to execute its essential function, but leave open the possibility that Ten1 has a Cdc13-independent role in DNA replication.

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Section: Resultsmentioning

confidence: 99%

TEN1Is Essential forCDC13-Mediated Telomere Capping

Petreaca

Gasparyan

et al. 2009

Genetics

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“…In any case, loss of the distal DNA fragment could shut off checkpoint signaling. Recently, Michelson et al (2005) showed that telomeric TG repeat sequence inhibits checkpoint signaling from damage sites, and they proposed a model in which the TG sequence could inhibit checkpoint signaling nearby. In their report, the TG sequence was inserted only into the centromereproximal side of the HO cleavage site that is 20 kb away from the chromosome end.…”

Section: Discussionmentioning

confidence: 99%

“…However, the ATM and ATR family proteins are also required for proper maintenance of telomeres (Greenwell et al, 1995;Metcalfe et al, 1996;Ritchie et al, 1999). Recent evidence suggests that addition of telomeric TG repeats adjacent to DSBs inhibits the activation of checkpoint response in budding yeast (Michelson et al, 2005). However, it is not clear how telomeres control ATR/Mec1 and ATM/Tel1 to inhibit checkpoint responses.…”

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confidence: 94%

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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“…Work from the Weinert group, published in this issue of Genes & Development (Michelson et al 2005), provides new insights into this process, by reporting that telomere repeats are able to quench local DNA damage responses, thereby conferring what the authors dub an "anticheckpoint." Their experimental approach exploited a previously developed system to induce de novo telomere formation at a newly created DNA end (Diede and Gottschling 1999): An inducible site-specific endonuclease, called HO, is used to generate a DSB immediately downstream of an internal tract of yeast telomere repeats (Fig.…”

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confidence: 99%

“…Michelson et al (2005) discovered that although the nontelomeric product of the cleavage reaction (i.e., the end of the distal portion of the chromosome) ( Fig. 1) was still capable of invoking an initial DNA damage response, the extent of this response was affected by the proximity of the DSB to the new telomere.…”

mentioning

confidence: 99%