Saccharomyces cerevisiae MGS1 is essential in strains deficient in the RAD6-dependent DNA damage tolerance pathway

Hishida, Takashi

doi:10.1093/emboj/21.8.2019

Cited by 78 publications

(111 citation statements)

References 53 publications

(83 reference statements)

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“…The authors suggested an alternative model in which PCNA monoubiquitination may disrupt its interactions with a protein(s) that inhibits binding to the TLS polymerases. To date no such candidate protein has been identified, although we notice a recent report [130] that Mgs1, a protein with homology to E. coli RuvB and eukaryotic clamp loader protein RFC, as well as DNA-dependent ATPase activity and DNA-annealing activities [131,132], associates with PCNA and appears to repress the RAD6 pathway in the absence of exogenous damage. Other concerns with the above paradigm include the stability of monoubiquitinated PCNA, particularly in mammalian cells, that extends past the expected time required to bypass the damage [122], which would allow persistent TLS with unnecessarily increased mutation rates.…”

Section: Regulated Access Of Y-family Polymerases To the Damage Sitementioning

confidence: 93%

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

Andersen¹,

Xiao³

2007

Cell Res

185

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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Section: Regulated Access Of Y-family Polymerases To the Damage Sitementioning

confidence: 93%

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

Andersen¹,

Xiao³

2007

Cell Res

185

187

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“…Lysine 123 of Rad6 Is Essential for Lys-4 Methylation of Histone H3-Rad6 is a ubiquitin-conjugating enzyme (E2) (17) involved in DNA repair (17,18), DNA damage-induced mutagenesis (19,20), meiosis (21), transposition of retrotransposons (22), and gene silencing (23). Rad6 catalyzes ubiquitination of Lys-123 of histone H2B (24).…”

Section: Development Of a Biochemical Screen In 96-well Plates To Idementioning

confidence: 99%

“…Rad6 in diverse cellular processes (17)(18)(19)(20)(21)(22). However, our genome-wide survey of S. cerevisiae revealed that none of the mutants missing these (non-essential) Rad6-interacting proteins, including those that act with Rad6 in DNA damage repair (Rad18 and Rex4) and the N-end rule-dependent protein degradation pathway (Ubr1 and Ubr2), are involved in methylation of histone H3 Lys-4 (Fig.…”

Section: Involvement Of Other Rad6-interacting Proteins In Lys-4 Methmentioning

confidence: 99%

Methylation of Histone H3 by COMPASS Requires Ubiquitination of Histone H2B by Rad6

Dover¹,

Schneider²,

Tawiah-Boateng³

et al. 2002

Journal of Biological Chemistry

497

413

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. To learn about the mechanism of histone methylation, we surveyed the genome of the yeast Saccharomyces cerevisiae for genes necessary for this process. By analyzing ϳ4800 mutant strains, each deleted for a different non-essential gene, we discovered that the ubiquitin-conjugating enzyme Rad6 is required for methylation of lysine 4 of histone H3. Ubiquitination of histone H2B on lysine 123 is the signal for the methylation of histone H3, which leads to silencing of genes located near telomeres.

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“…MGS1 encodes for a DNA-dependent ATPase with ssDNA annealing activities that has been suggested to compete with the PRR pathway for resolution of fork stalling lesions [6,37,38]. RAD30 has been implicated in an error-free form of translesion synthesis [39,40] that some have placed in the PRR pathway [41].…”

Section: Epistasis Analysis Defines a Role For Exo1 In The Mms2 Errormentioning

confidence: 99%

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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Saccharomyces cerevisiae MGS1 is essential in strains deficient in the RAD6-dependent DNA damage tolerance pathway

Cited by 78 publications

References 53 publications

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

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

Methylation of Histone H3 by COMPASS Requires Ubiquitination of Histone H2B by Rad6

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

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