Requirement of the Mre11 Complex and Exonuclease 1 for Activation of the Mec1 Signaling Pathway

Nakada, Daisuke; Hirano, Yukinori; Sugimoto, Katsunori

doi:10.1128/mcb.24.22.10016-10025.2004

Cited by 105 publications

(126 citation statements)

References 67 publications

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“…In addition to the role of EXO1 in PRR proposed here, EXO1 has been implicated to function in cell cycle checkpoint, fork maintenance and fork repair pathways [20][21][22]51,52]. EXO1 has been shown to play subtle roles in end-processing for mitotic recombination and function redundantly with at least one other unidentified nuclease.…”

Section: Discussionmentioning

confidence: 77%

“…This "other" redundant nuclease may be regulated by the Mre11p-Rad50p-Xrs2p (MRX) complex for recombination [51]. However, more recently the MRX complex and Exo1p have been implicated in the activation of DSBand UV-induced Mec1p-dependent checkpoints [52]. The MRX complex and Exo1p were shown to collaborate in producing long ssDNA tails at DSB ends and promote Mec1p association with the DSBs.…”

Section: Discussionmentioning

confidence: 99%

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A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair

et al. 2007

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Replication forks stall at DNA lesions or as a result of an unfavorable replicative environment. These fork stalling events have been associated with recombination and gross chromosomal rearrangements. Recombination and fork bypass pathways are the mechanisms accountable for restart of stalled forks. An important lesion bypass mechanism is the highly conserved postreplication repair (PRR) pathway that is composed of error-prone translesion and error-free bypass branches. EXO1 codes for a Rad2p family member nuclease that has been implicated in a multitude of eukaryotic DNA metabolic pathways that include DNA repair, recombination, replication, and telomere integrity. In this report, we show EXO1 functions in the MMS2 error-free branch of the PRR pathway independent of the role of EXO1 in DNA mismatch repair (MMR). Consistent with the idea that EXO1 functions independently in two separate pathways, we defined a domain of Exo1p required for PRR distinct from those required for interaction with MMR proteins. We then generated a point mutant exo1 allele that was defective for the function of Exo1p in MMR due to disrupted interaction with Mlh1p, but still functional for PRR. Lastly, by using a compound exo1 mutant that was defective for interaction with Mlh1p and deficient for nuclease activity, we provide further evidence that Exo1p plays both structural and catalytic roles during MMR.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair

et al. 2007

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“…Hirano and K. Sugimoto Molecular Biology of the Cell 2032 association or Tel1 association with the adjacent DNA end. Exo1 possesses a 5Ј-to-3Ј exonuclease activity and acts redundantly with the MRX complex in DNA degradation of DSB ends (Moreau et al, 2001;Nakada et al, 2004). We further examined whether Exo1 localizes to the TG 81 end by ChIP assay ( Figure 6C).…”

Section: Cdc13-mediated Telomere Capping Does Not Inhibit Tel1mentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

“…Likewise, Fen1/Rad27 has been shown to play a role in telomere maintenance (Parenteau and Wellinger, 2002). The Cdc13 telomere cap could repress functions of other nucleases, such as Fen1/Rad27, by either blocking localization or inhibiting activities.The MRX complex controls both the Mec1 and Tel1 checkpoint pathways (Usui et al, 2001;Nakada et al, 2004). However, the Cdc13 cap can modulate MRX complex functions to regulate Mec1 and Tel1 differently at telomeres.…”

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confidence: 99%

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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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The management of DNA double‐strand breaks in mitotic G₂, and in mammalian meiosis viewed from a mitotic G₂ perspective

Burgoyne¹,

Mahadevaiah²,

Turner³

2007

BioEssays

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DNA double-strand breaks (DSBs) are extremely hazardous lesions for all DNA-bearing organisms and the mechanisms of DSB repair are highly conserved. In the eukaryotic mitotic cell cycle, DSBs are often present following DNA replication while, in meiosis, hundreds of DSBs are generated as a prelude to the reshuffling of the maternally and paternally derived genomes. In both cases, the DSBs are repaired by a process called homologous recombinational repair (HRR), which utilises an intact DNA molecule as the repair template. Mitotic and meiotic HRR are managed by 'checkpoints' that inhibit cell division until DSB repair is complete. Here we attempt to summarise the substantial recent progress in understanding the checkpoint management of HRR in mitosis (focussing mainly on mammals) and then go on to use this information as a framework for understanding the presumed checkpoint management of HRR in mammalian meiosis.

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Requirement of the Mre11 Complex and Exonuclease 1 for Activation of the Mec1 Signaling Pathway

Cited by 105 publications

References 67 publications

A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair

A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair

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

The management of DNA double‐strand breaks in mitotic G₂, and in mammalian meiosis viewed from a mitotic G₂ perspective

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Requirement of the Mre11 Complex and Exonuclease 1 for Activation of the Mec1 Signaling Pathway

Cited by 105 publications

References 67 publications

A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair

A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair

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

The management of DNA double‐strand breaks in mitotic G2, and in mammalian meiosis viewed from a mitotic G2 perspective

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The management of DNA double‐strand breaks in mitotic G₂, and in mammalian meiosis viewed from a mitotic G₂ perspective