The FANCM Ortholog Fml1 Promotes Recombination at Stalled Replication Forks and Limits Crossing Over during DNA Double-Strand Break Repair

Sun, Weibo; Nandi, Saikat; Osman, Fekret; Ahn, Jong Sook; Jakovleska, Jovana; Lorenz, Alexander; Whitby, Matthew C.

doi:10.1016/j.molcel.2008.08.024

Cited by 144 publications

(272 citation statements)

References 33 publications

(60 reference statements)

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“…41,42 In S. pombe, Fml1 is shown to play a role in promoting HR at stalled replication forks. 43 Importantly, our present studies identified NER and HR as the major DNA repair mechanisms involved in acetaldehyde response. To understand the relationship between the FA proteins and downstream DNA repair processes such as NER and HR, we performed epistasis analyses.…”

Section: Ner Acts Downstream Of Fml1mentioning

confidence: 55%

“…7 Studies in S. pombe also described a role of Fml1 in HR. 43,44 However, fml1D rad52D showed much higher acetaldehyde sensitivity than either single mutant. This result suggests that, although HR may still function downstream of Fml1 FANCM as previously suggested in mammalian cells and S. pombe, 7,43,44 HR is also initiated in a manner independent of the FA pathway (Fig 9).…”

Section: Discussionmentioning

confidence: 91%

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Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast

et al. 2016

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Acetaldehyde, a primary metabolite of alcohol, forms DNA adducts and disrupts the DNA replication process, causing genomic instability, a hallmark of cancer. Indeed, chronic alcohol consumption accounts for approximately 3.6% of all cancers worldwide. However, how the adducts are prevented and repaired after acetaldehyde exposure is not well understood. In this report, we used the fission yeast Schizosaccharomyces pombe as a model organism to comprehensively understand the genetic controls of DNA damage avoidance in response to acetaldehyde. We demonstrate that Atd1 functions as a major acetaldehyde detoxification enzyme that prevents accumulation of Rad52-DNA repair foci, while Atd2 and Atd3 have minor roles in acetaldehyde detoxification. We found that acetaldehyde causes DNA damage at the replication fork and activates the cell cycle checkpoint to coordinate cell cycle arrest with DNA repair. Our investigation suggests that acetaldehyde-mediated DNA adducts include interstrand-crosslinks and DNA-protein crosslinks. We also demonstrate that acetaldehyde activates multiple DNA repair pathways. Nucleotide excision repair and homologous recombination, which are both epistatically linked to the Fanconi anemia pathway, have major roles in acetaldehyde tolerance, while base excision repair and translesion synthesis also contribute to the prevention of acetaldehyde-dependent genomic instability. We also show the involvement of Wss1-related metalloproteases, Wss1 and Wss2, in acetaldehyde tolerance. These results indicate that acetaldehyde causes cellular stresses that require cells to coordinate multiple cellular processes in order to prevent genomic instability. Considering that acetaldehyde is a human carcinogen, our genetic studies serve as a guiding investigation into the mechanisms of acetaldehyde-dependent genomic instability and carcinogenesis.

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Section: Ner Acts Downstream Of Fml1mentioning

confidence: 55%

Section: Discussionmentioning

confidence: 91%

Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast

et al. 2016

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“…The first model proposes that the Smc5/6 complex binds Mph1 and regulates its action as a pro-recombinogenic factor. Mph1 orthologs can catalyze replication fork regression/migration (22)(23)(24). It is thus possible that the Smc5/6 complex modulates Mph1 to prevent fork regression or channels the regressed forks to direct restart instead of recombination.…”

Section: Discussionmentioning

confidence: 99%

“…An activity shared by Mph1 and its orthologs is the dissociation of DNA D-loop structures, a function important in limiting crossovers during mitotic recombination (21)(22)(23). In addition, Fml1, FANCM, and Hef can catalyze the regression or unwinding of replication forks, which can potentially lead to recombination (22)(23)(24).…”

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confidence: 99%

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Interplay between the Smc5/6 complex and the Mph1 helicase in recombinational repair

Chen

Choi²,

Szakál³

et al. 2009

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

134

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The evolutionarily conserved Smc5/6 complex is implicated in recombinational repair, but its function in this process has been elusive. Here we report that the budding yeast Smc5/6 complex directly binds to the DNA helicase Mph1. Mph1 and its helicase activity define a replication-associated recombination subpathway. We show that this pathway is toxic when the Smc5/6 complex is defective, because mph1⌬ and its helicase mutations suppress multiple defects in mutants of the Smc5/6 complex, including their sensitivity to replication-blocking agents, growth defects, and inefficient chromatid separation, whereas MPH1 overexpression exacerbates some of these defects. We further demonstrate that Mph1 and its helicase activity are largely responsible for the accumulation of potentially deleterious recombination intermediates in mutants of the Smc5/6 complex. We also present evidence that mph1⌬ does not alleviate sensitivity to DNA damage or the accumulation of recombination intermediates in cells lacking Sgs1, which is thought to function together with the Smc5/6 complex. Thus, our results reveal a function of the Smc5/6 complex in the Mph1-dependent recombinational subpathway that is distinct from Sgs1. We suggest that the Smc5/6 complex can counteract/ modulate a pro-recombinogenic function of Mph1 or facilitate the resolution of recombination structures generated by Mph1.

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Strategies for DNA interstrand crosslink repair: Insights from worms, flies, frogs, and slime molds

McVey

2010

Environ and Mol Mutagen

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DNA interstrand crosslinks (ICLs) are complex lesions that covalently link both strands of the DNA double helix and impede essential cellular processes such as DNA replication and transcription. Recent studies suggest that multiple repair pathways are involved in their removal. Elegant genetic analysis has demonstrated that at least three distinct sets of pathways cooperate in the repair and/or bypass of ICLs in budding yeast. Although the mechanisms of ICL repair in mammals appear similar to those in yeast, important differences have been documented. In addition, mammalian crosslink repair requires other repair factors, such as the Fanconi anemia proteins, whose functions are poorly understood. Because many of these proteins are conserved in simpler metazoans, nonmammalian models have become attractive systems for studying the function(s) of key crosslink repair factors. This review discusses the contributions that various model organisms have made to the field of ICL repair. Specifically, it highlights how studies performed with C. elegans, Drosophila, Xenopus, and the social amoeba Dictyostelium serve to complement those from bacteria, yeast, and mammals. Together, these investigations have revealed that although the underlying themes of ICL repair are largely conserved, the complement of DNA repair proteins utilized and the ways in which each of the proteins is used can vary substantially between different organisms.

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The FANCM Ortholog Fml1 Promotes Recombination at Stalled Replication Forks and Limits Crossing Over during DNA Double-Strand Break Repair

Cited by 144 publications

References 33 publications

Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast

Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast

Interplay between the Smc5/6 complex and the Mph1 helicase in recombinational repair

Strategies for DNA interstrand crosslink repair: Insights from worms, flies, frogs, and slime molds

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