The RING finger ATPase Rad5p of Saccharomyces cerevisiae contributes to DNA double-strand break repair in a ubiquitin-independent manner

Chen, Shuhua; Davies, Adelina A.; Sagan, Daniel; Ulrich, Helle D.

doi:10.1093/nar/gki902

Cited by 71 publications

(83 citation statements)

References 45 publications

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“…al. recently isolated a separation of function mutant of RAD5 for PRR and MRE11-XRS2-RAD50-dependent double strand break repair [57]. Given the data supporting multiple PRRindependent functions of RAD5, we believe the synthetic lethality between exo1Δ and rad5Δ uncovers a redundancy for an essential PRR-independent function or possibly a straindependent phenomenon.…”

Section: Discussionmentioning

confidence: 88%

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: 88%

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

et al. 2007

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“…The notable exception was RAD5, the loss of which increased the sensitivity to MNNG quite dramatically. This might be explained by the involvement of Rad5 in DSB repair in addition to its function in the error-free MMS2/UBC13-dependent pathway activated by polyubiquitylation of PCNA (Chen et al 2005). Mutations in genes encoding the Sgs1 helicase and its associated factors Top3 and Rmi1 also increased MNNG cytotoxicity quite substantially.…”

Section: Resultsmentioning

confidence: 99%

Interplay of DNA Repair Pathways Controls Methylation Damage Toxicity in Saccharomyces cerevisiae

Ćejka

Jiricny

2008

Genetics

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“…In addition, RAD5 has been reported to promote instability of simple repetitive sequences [57] and to inhibit non-homologous end-joining of DSBs [59]. Indeed, Rad5 is involved in double-strand break repair independent of its ubiquitination activity [60].…”

Section: Ddt In Saccharomyces Cerevisiaementioning

confidence: 99%

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Andersen¹,

Xiao³

2007

Cell Res

184

187

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npg In addition to well-defined DNA repair pathways, all living organisms have evolved mechanisms to avoid cell death caused by replication fork collapse at a site where replication is blocked due to disruptive covalent modifications of DNA. The term DNA damage tolerance (DDT) has been employed loosely to include a collection of mechanisms by which cells survive replication-blocking lesions with or without associated genomic instability. Recent genetic analyses indicate that DDT in eukaryotes, from yeast to human, consists of two parallel pathways with one being error-free and another highly mutagenic. Interestingly, in budding yeast, these two pathways are mediated by sequential modifications of the proliferating cell nuclear antigen (PCNA) by two ubiquitination complexes Rad6-Rad18 and Mms2-Ubc13-Rad5. Damage-induced monoubiquitination of PCNA by Rad6-Rad18 promotes translesion synthesis (TLS) with increased mutagenesis, while subsequent polyubiquitination of PCNA at the same K164 residue by Mms2-Ubc13-Rad5 promotes error-free lesion bypass. Data obtained from recent studies suggest that the above mechanisms are conserved in higher eukaryotes. In particular, mammals contain multiple specialized TLS polymerases. Defects in one of the TLS polymerases have been linked to genomic instability and cancer. DNA damage toleranceIn the presence of spontaneous or carcinogen-induced DNA damage, living cells have to maintain and complete DNA synthesis or risk replication fork collapse. Since the process of DNA licensing is to ensure the genome is duplicated once and only once during each cell cycle, stalled or collapsed replication forks may not be able to restart, which often results in double-strand breaks (DSBs) and causes compromised genome integrity or cell death. In addition to highly conserved DNA repair pathways, all living organisms have evolved schemes to ensure continuation of DNA synthesis in the presence of damage. These schemes were originally termed DNA postreplication repair (PRR) due to observations of transient shortened nascent DNA structures following S phase in response to DNA damage. In bacteria and unicellular yeast, these shortened DNA segments can be measured by an alkaline sedimentation assay [1] or directly observed in electron micrographs [2]. In wild-type cells, these truncated DNA segments were restored to full length following a short recovery time. One typical experiment [1] involved the restoration of the nascent strand following UV exposure in nucleotide excision repair (NER)-deficient cells and was originally assumed to represent a mechanism of DNA repair. However, further investigation revealed that, although the nascent fragments were re-annealed, the original UV-induced pyrimidine dimers, which were responsible for the generation of single-strand gaps, often persisted in the genome [3,4]. It was argued that the replication-blocking lesion was not necessarily corrected, but rather transiently bypassed and carried over to the next generation. Perhaps it is more beneficial for the organi...

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The RING finger ATPase Rad5p of Saccharomyces cerevisiae contributes to DNA double-strand break repair in a ubiquitin-independent manner

Cited by 71 publications

References 45 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

Interplay of DNA Repair Pathways Controls Methylation Damage Toxicity in Saccharomyces cerevisiae

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

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