Srs2 mediates PCNA-SUMO-dependent inhibition of DNA repair synthesis

Burkovics, Peter; Šebesta, Marek; Sisakova, Alexandra; Plault, Nicolas; Szukacsov, Valéria; Robert, Thomas; Pintér, Lajos; Marini, Victoria; Kolesar, Peter; Haracska, Lajos; Gangloff, Serge; Krejčí, Lumír

doi:10.1038/emboj.2013.9

Cited by 71 publications

(81 citation statements)

References 85 publications

(158 reference statements)

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“…At the C‐terminus, Srs2 contains a variety of regulatory motifs, which are modulated through post‐translational modifications and/or required for the interactions of Srs2 with other proteins, including PCNA, and these are important for its role at replication forks (Papouli et al , 2005; Pfander et al , 2005; Burgess et al , 2009) and regulation of the D‐loop extension (Burkovics et al , 2013). However, most of the C‐terminus was not required for the role of Srs2 in DSB repair via de novo telomere addition, BIR and SSA (Fig 8A–D).…”

Section: Resultsmentioning

confidence: 99%

Unloading of homologous recombination factors is required for restoring double‐stranded DNA at damage repair loci

et al. 2017

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Cells use homology‐dependent DNA repair to mend chromosome breaks and restore broken replication forks, thereby ensuring genome stability and cell survival. DNA break repair via homology‐based mechanisms involves nuclease‐dependent DNA end resection, which generates long tracts of single‐stranded DNA required for checkpoint activation and loading of homologous recombination proteins Rad52/51/55/57. While recruitment of the homologous recombination machinery is well characterized, it is not known how its presence at repair loci is coordinated with downstream re‐synthesis of resected DNA. We show that Rad51 inhibits recruitment of proliferating cell nuclear antigen (PCNA), the platform for assembly of the DNA replication machinery, and that unloading of Rad51 by Srs2 helicase is required for efficient PCNA loading and restoration of resected DNA. As a result, srs2Δ mutants are deficient in DNA repair correlating with extensive DNA processing, but this defect in srs2Δ mutants can be suppressed by inactivation of the resection nuclease Exo1. We propose a model in which during re‐synthesis of resected DNA, the replication machinery must catch up with the preceding processing nucleases, in order to close the single‐stranded gap and terminate further resection.

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Section: Resultsmentioning

confidence: 99%

Unloading of homologous recombination factors is required for restoring double‐stranded DNA at damage repair loci

et al. 2017

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“…Srs2 is a translocase that prevents HR by dismantling Rad51 filaments (Krejci et al 2003;Veaute et al 2003) and regulates the extent of DNA repair synthesis in a SUMO-PCNA-dependent manner (Burkovics et al 2013). Here we uncovered that, in response to damage during replication, SUMOmediated interactions and proteasome-dependent turnover intersect to promote local down-regulation of Srs2 and facilitate recombination-mediated DDT (Fig.…”

Section: Discussionmentioning

confidence: 99%

Local regulation of the Srs2 helicase by the SUMO-like domain protein Esc2 promotes recombination at sites of stalled replication

et al. 2015

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Accurate completion of replication relies on the ability of cells to activate error-free recombination-mediated DNA damage bypass at sites of perturbed replication. However, as anti-recombinase activities are also recruited to replication forks, how recombination-mediated damage bypass is enabled at replication stress sites remained puzzling. Here we uncovered that the conserved SUMO-like domain-containing Saccharomyces cerevisiae protein Esc2 facilitates recombination-mediated DNA damage tolerance by allowing optimal recruitment of the Rad51 recombinase specifically at sites of perturbed replication. Mechanistically, Esc2 binds stalled replication forks and counteracts the anti-recombinase Srs2 helicase via a two-faceted mechanism involving chromatin recruitment and turnover of Srs2. Importantly, point mutations in the SUMO-like domains of Esc2 that reduce its interaction with Srs2 cause suboptimal levels of Rad51 recruitment at damaged replication forks. In conclusion, our results reveal how recombination-mediated DNA damage tolerance is locally enabled at sites of replication stress and globally prevented at undamaged replicating chromosomes.

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“…Knowing that Mus81-Mms4 and Srs2 promote crossover and non-crossover pathways, respectively, the functional crosstalk between Mus81-Mms4 and Srs2 may be regulated to balance the repair pathway choice. In a separate study, binding of Srs2 to SUMO-PCNA has been found to attenuate repair synthesis by occluding Polδ and Polη from binding to PCNA (Burkovics et al 2013). Again, this activity does not require the helicase activity of Srs2 (Burkovics et al 2013).…”

Section: Non-motor Roles For Srs2mentioning

confidence: 99%

Multifunctional Roles of Saccharomyces cerevisiae Srs2 protein in Replication, Recombination and Repair

Niu

Klein

2016

FEMS Yeast Research

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One sentence summary: Srs2 is a multifunctional protein that acts during cell replication to insure faithful and accurate copying of genetic information. Editor: Uffe Mortensen ABSTRACTThe Saccharomyces cerevisiae Srs2 DNA helicase has important roles in DNA replication, recombination and repair. In replication, Srs2 aids in repair of gaps by repair synthesis by preventing gaps from being used to initiate recombination. This is considered to be an anti-recombination role. In recombination, Srs2 plays both prorecombination and anti-recombination roles to promote the synthesis-dependent strand annealing recombination pathway and to inhibit gaps from initiating homologous recombination. In repair, the Srs2 helicase actively promotes gap repair through an interaction with the Exo1 nuclease to enlarge a gap for repair and to prevent Rad51 protein from accumulating on single-stranded DNA. Finally, Srs2 helicase can unwind hairpin-forming repeat sequences to promote replication and prevent repeat instability. The Srs2 activities can be controlled by phosphorylation, SUMO modification and interaction with key partners at DNA damage or lesions sites, which include PCNA and Rad51. These interactions can also limit DNA polymerase function during recombinational repair independent of the Srs2 translocase or helicase activity, further highlighting the importance of the Srs2 protein in regulating recombination. Here we review the myriad roles of Srs2 that have been documented in genome maintenance and distinguish between the translocase, helicase and additional functions of the Srs2 protein.

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Srs2 mediates PCNA-SUMO-dependent inhibition of DNA repair synthesis

Cited by 71 publications

References 85 publications

Unloading of homologous recombination factors is required for restoring double‐stranded DNA at damage repair loci

Unloading of homologous recombination factors is required for restoring double‐stranded DNA at damage repair loci

Local regulation of the Srs2 helicase by the SUMO-like domain protein Esc2 promotes recombination at sites of stalled replication

Multifunctional Roles of Saccharomyces cerevisiae Srs2 protein in Replication, Recombination and Repair

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