The RAD6 Pathway: Control of DNA Damage Bypass and Mutagenesis by Ubiquitin and SUMO

Ulrich, Helle D.

doi:10.1002/cbic.200500139

Cited by 87 publications

(93 citation statements)

References 89 publications

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“…Although the mechanism of fork bypass by the MMS2 error-free branch of PRR is poorly defined, selection of which PRR branch is utilized during a fork stalling event is thought to occur via ubiquitin states of PCNA [48][49][50]. Briefly, upon S-phase DNA damage Rad6p-Rad18p mono-ubiquitinates PCNA on K164 promoting translesion synthesis or mutagenic fork bypass.…”

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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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: 99%

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

et al. 2007

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“…These mechanisms cannot operate during replication, where the two parental strands are separated (Friedberg, 2003). Tolerance of replication blocking lesions requires alternative mechanisms, such as translesion DNA synthesis (TLS), a generally deemed error-prone bypass process and fork regression or homologous recombination (HR), allowing error-free bypass of replication-blocking lesions (Ulrich, 2005;Li and Heyer, 2008). Recently, also repriming on the leading strand has been discussed as a potential errorfree mechanism (Lopes et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies demonstrate that the proliferating cell nuclear antigene (PCNA), an essential processivity clamp for DNA polymerases, is 12 E. R. Panico et al the switchboard between DNA damage-tolerance mechanisms allowing DNA synthesis resumption (for review, see Ulrich, 2005). In response to stalled replication forks, PCNA is monoubiquitinated on Lys164 by the Rad6-Rad18 complex, thus activating TLS (Hoege et al, 2002;Stelter and Ulrich, 2003;Watanabe et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Genetic evidence for a role of Saccharomyces cerevisiae Mph1 in recombinational DNA repair under replicative stress

Panico

Ede

Schildmann

et al. 2009

Yeast

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In yeast as in human, DNA helicases play critical roles in assisting replication fork progression. The Saccharomyces cerevisiae MPH1 gene, homologue of human FANCM, has been involved in homologous recombination and DNA repair. We describe a synthetic growth defect of an mph1 deletion if combined with an srs2 deletion that can result -depending on the genetic background -in synthetic lethality. The lethality is suppressed by mutations in homologous recombination (rad51, rad52, rad55, rad57 ) and in the DNA damage checkpoint (rad9, rad24, rad17 ). Importantly, rad54 and mph1, epistatic for damage sensitivity, are subadditive for spontaneous mutator phenotype. Therefore, Mph1 could be placed at the Rad51-mediated strand invasion process, with a function distinct from Rad54. Moreover, siz1 mutation is viable with mph1 and additive for DNA damage sensitivity. mph1 srs2 double mutants, isolated in a background where they are viable, are synergistically sensitive to DNA damage. Moderate overexpression of SGS1 partially suppresses this sensitivity. Finally, we observe an epistatic relationship in terms of sensitivity to camptothecin of mms4 or mus81 to mph1. Overall, our results support a role of Mph1 in assisting replication progression. We propose two models for the resumption of DNA synthesis under replicative stress where Mph1 is placed at the sister chromatid interaction step.

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“…The prototypic example is the Rad6 pathway of postreplication repair in yeast, which regulates the employment of mutagenic translesion synthesis and͞or recombinogenic activity during the bypass of unrepaired DNA lesions encountered by a replication fork (10). The enzymes of the Rad6 pathway mediate ubiquitination of proliferating cell nuclear antigen (PCNA), a sliding clamp and processivity factor for DNA polymerases and other DNA repair enzymes (11).…”

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confidence: 99%

Involvement of Rad18 in somatic hypermutation

Brinckmann¹,

Ertongur²,

Jungnickel³

2006

Proc. Natl. Acad. Sci. U.S.A.

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Somatic hypermutation of Ig genes is initiated by transcriptioncoupled cytidine deamination in Ig loci. Error-prone processing of the resultant DNA lesions is thought to cause extensive mutagenesis, but it is presently an enigma how and why error-prone rather than error-free repair pathways are recruited. During DNA replication, recruitment of error-prone translesion polymerases may be mediated by Rad6͞Rad18-mediated ubiquitination of proliferating cell nuclear antigen, a major switchboard controlling the fidelity of DNA lesion bypass in eukaryotes. By inactivation of Rad18 in the DT40 B cell line, we show that the Rad6 pathway is involved in somatic hypermutation in these cells. Our findings imply that targeted recruitment of mutagenic polymerases by the Rad6 pathway contributes to the complex process of somatic hypermutation and provide a framework for more detailed mechanistic studies of the mutagenesis phase of secondary Ig diversification.proliferating cell nuclear antigen ͉ ubiquitination ͉ Rad6 pathway G iven the many challenges that damage cellular DNA daily, the faithful maintenance of genetic information requires the interplay of multiple DNA repair pathways. In most cases, these mechanisms ensure restoration of the original DNA sequence, preventing mutations or aberrations that may lead to impairment of cellular function. In some instances, though, a certain imprecision may be tolerated or even favored by the cell to allow for survival in critical situations. DNA repair mechanisms that are inherently imprecise are the basis of the spontaneous mutability of all genomes and may be recruited and adapted for situations where high genetic variability is mandatory for survival.The adaptive immune system of vertebrates has been shaped in coevolution with pathogenic organisms of high genetic diversity and variability. The high diversity of the primary immune repertoire established during V(D)J recombination in B and T cells generates sufficient potential for recognition of any pathogen, but the affinity of binding is often not sufficient for effective neutralization. Therefore, a second wave of diversification during acute infections ensures that the binding affinity of the antibodies produced by B lymphocytes is fine-tuned to the task at hand. The underlying mechanism in humans is somatic hypermutation, which modifies the antigen binding region by targeted mutagenesis in the variable region of the Ig genes (1). An alternative diversification mechanism prevalent in chicken and some mammals, Ig gene conversion alters the same region by targeted homologous recombination with upstream Ig pseudogenes (2).Somatic hypermutation and Ig gene conversion are related processes (3) originating from the same initial DNA lesion. The transcription-coupled deamination of cytosines by activationinduced cytidine deaminase (AID) leads to uracil that may be processed to abasic sites or strand breaks by the excision repair pathway, i.e., uracil-N-glycosylase (4, 5). The resultant DNA lesions may be repaired by mutagenesis or reco...

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The RAD6 Pathway: Control of DNA Damage Bypass and Mutagenesis by Ubiquitin and SUMO

Cited by 87 publications

References 89 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

Genetic evidence for a role of Saccharomyces cerevisiae Mph1 in recombinational DNA repair under replicative stress

Involvement of Rad18 in somatic hypermutation

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