The Mgs1/WRNIP1 ATPase is required to prevent a recombination salvage pathway at damaged replication forks

Jiménez-Martín, Alberto; Saugar, Irene; Joseph, Chinnu Rose; Mayer, Alexandra; Lehmann, Carl P.; Szakál, Barnabás; Branzei, Dana; Tercero, José Antonio

doi:10.1126/sciadv.aaz3327

Cited by 13 publications

(14 citation statements)

References 40 publications

(123 reference statements)

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“…These findings, in turn, raise the question of how template switch-mediated recombination is specifically facilitated but, in spite of Srs2 antirecombinase being counteracted, other modes of recombination that could be potentially dangerous for genome stability are inhibited at damaged forks. We addressed this question and found that Mgs1, an evolutionarily conserved AAA + ATPase (WRNIP1 in mammalian cells, RarA/MgsA in bacteria) (Hishida et al, 2001 ), contributes to preventing unwanted recombination at damaged and stalled replication forks (Jiménez-Martín et al 2020 ).…”

Section: Mgs1-dependent Inhibition Of a Salvage Pathway Of Recombinatmentioning

confidence: 99%

“…We found that elimination of Mgs1 or its ATPase activity suppresses the high sensitivity of Rad5-deficient cells to MMS or hydroxyurea (HU). A likely explanation for this suppression is the observation that in cells lacking Rad5, the absence of Mgs1 facilitates an alternative pathway of DNA damage bypass that allows overcoming of MMS-induced DNA lesions and the completion of chromosome replication (Jiménez-Martín et al 2020 ) (Fig. 1 ).…”

Section: Mgs1-dependent Inhibition Of a Salvage Pathway Of Recombinatmentioning

confidence: 99%

“…As with template switching at damaged stalled forks (Urulangodi et al 2015 ), Esc2 and Elg1 are necessary for the recombination salvage pathway that the absence of Mgs1 allows in cells lacking Rad5 (Jiménez-Martín et al 2020 ). These common requirements strongly suggest that both pathways are mediated by a similar mechanism that is operated by Esc2 and Elg1 (Fig.…”

Section: Mgs1-dependent Inhibition Of a Salvage Pathway Of Recombinatmentioning

confidence: 99%

“…This would lead to the unloading of the Srs2 antirecombinase bound to SUMO-PCNA and concomitant or subsequent proteasome-dependent degradation mediated by Slx5/Slx8. Local Srs2 degradation would facilitate the binding of Rad51 to damaged forks, followed by a recombination-driven bypass pathway that is dependent on Rad52/Rad59 and Pol δ (Jiménez-Martín et al 2020 ). All this described recombination-driven replication process is prevented in the presence of Mgs1, explaining why in MGS1 + rad5 Δ cells, where there is neither template switching nor an alternative mode of recombination-mediated DNA damage bypass, replication forks block in the face of DNA lesions (Ortiz-Bazán et al 2014 ) (Fig.…”

Section: Mgs1-dependent Inhibition Of a Salvage Pathway Of Recombinatmentioning

confidence: 99%

“…Yet, in the case of template switch recombination, Srs2 is locally counteracted at sites of perturbed replication to allow this error-free mode of DNA damage bypass (Urulangodi et al, 2015 ). Recently, our work has shown that the evolutionarily conserved Mgs1/WRNIP1 ATPase is important to prevent a salvage pathway of recombination at damaged and stalled DNA replication forks (Jiménez-Martín et al 2020 ), uncovering a new role for this protein in the intricate network of mechanisms that contribute to maintaining genome stability.…”

Section: Introductionmentioning

confidence: 99%

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Prevention of unwanted recombination at damaged replication forks

et al. 2020

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Homologous recombination is essential for the maintenance of genome integrity but must be strictly controlled to avoid dangerous outcomes that produce the opposite effect, genomic instability. During unperturbed chromosome replication, recombination is globally inhibited at ongoing DNA replication forks, which helps to prevent deleterious genomic rearrangements. This inhibition is carried out by Srs2, a helicase that binds to SUMOylated PCNA and has an anti-recombinogenic function at replication forks. However, at damaged stalled forks, Srs2 is counteracted and DNA lesion bypass can be achieved by recombination-mediated template switching. In budding yeast, template switching is dependent on Rad5. In the absence of this protein, replication forks stall in the presence of DNA lesions and cells die. Recently, we showed that in cells lacking Rad5 that are exposed to DNA damage or replicative stress, elimination of the conserved Mgs1/WRNIP1 ATPase allows an alternative mode of DNA damage bypass that is driven by recombination and facilitates completion of chromosome replication and cell viability. We have proposed that Mgs1 is important to prevent a potentially harmful salvage pathway of recombination at damaged stalled forks. In this review, we summarize our current understanding of how unwanted recombination is prevented at damaged stalled replication forks.

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Section: Mgs1-dependent Inhibition Of a Salvage Pathway Of Recombinatmentioning

confidence: 99%

Section: Mgs1-dependent Inhibition Of a Salvage Pathway Of Recombinatmentioning

confidence: 99%

Section: Mgs1-dependent Inhibition Of a Salvage Pathway Of Recombinatmentioning

confidence: 99%

Section: Mgs1-dependent Inhibition Of a Salvage Pathway Of Recombinatmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prevention of unwanted recombination at damaged replication forks

et al. 2020

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Mgs1 function at G-quadruplex structures during DNA replication

Paeschke

Burkovics

2020

Curr Genet

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The coordinated action of DNA polymerases and DNA helicases is essential at genomic sites that are hard to replicate. Among these are sites that harbour G-quadruplex DNA structures (G4). G4s are stable alternative DNA structures, which have been implicated to be involved in important cellular processes like the regulation of gene expression or telomere maintenance. G4 structures were shown to hinder replication fork progression and cause genomic deletions, mutations and recombination events. Many helicases unwind G4 structures and preserve genome stability, but a detailed understanding of G4 replication and the re-start of stalled replication forks around formed G4 structures is not clear, yet. In our recent study, we identified that Mgs1 preferentially binds to G4 DNA structures in vitro and is associated with putative G4-forming chromosomal regions in vivo. Mgs1 binding to G4 motifs in vivo is partially dependent on the helicase Pif1. Pif1 is the major G4-unwinding helicase in S. cerevisiae. In the absence of Mgs1, we determined elevated gross chromosomal rearrangement (GCR) rates in yeast, similar to Pif1 deletion. Here, we highlight the recent findings and set these into context with a new mechanistic model. We propose that Mgs1's functions support DNA replication at G4-forming regions.

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