Break-induced replication promotes formation of lethal joint molecules dissolved by Srs2

Elango, Rajula; Sheng, Ziwei; Jackson, Jessica; DeCata, Jenna; Ibrahim, Younis; Pham, Nhung; Liang, Diana H.; Sakofsky, Cynthia J.; Vindigni, Alessandro; Lobachev, Kirill S.; Ira, Grzegorz; Malkova, Anna

doi:10.1038/s41467-017-01987-2

Cited by 61 publications

(75 citation statements)

References 66 publications

(87 reference statements)

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“…Dmc1 Prevents Heteroduplex Joint Disruption by Srs2. Srs2 has the ability to disrupt heteroduplex DNA intermediates, and this activity plays a central role in the ability of Srs2 to contribute to genome integrity (13,15,18,19,27). Similarly, we have shown that Srs2 can disrupt short heteroduplex DNA joints made with Rad51-ssDNA and 70-bp dsDNA fragments harboring a 15-nt tract of homology complementary to the presynaptic ssDNA (44).…”

Section: Resultsmentioning

confidence: 77%

“…1A) (2, [10][11][12][13][14][15][16]. Consequently, srs2Δ mutants have a mitotic hyperrecombination phenotype characterized by frequent crossovers and gross chromosomal rearrangements (15,16,(18)(19)(20). Srs2 antirecombinase activity is counterbalanced by the Rad51 paralog complex Rad55/57, the Shu complex (composed of the Rad51 paralogs Psy3 and Csm2 and the SWIM-domain proteins Shu1 and Shu2), and Rad52, all of which enhance assembly or stability of early HR intermediates ( Fig.…”

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confidence: 99%

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Meiosis-specific recombinase Dmc1 is a potent inhibitor of the Srs2 antirecombinase

Crickard

Kaniecki

Kwon

et al. 2018

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

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Cross-over recombination products are a hallmark of meiosis because they are necessary for accurate chromosome segregation and they also allow for increased genetic diversity during sexual reproduction. However, cross-overs can also cause gross chromosomal rearrangements and are therefore normally down-regulated during mitotic growth. The mechanisms that enhance cross-over product formation upon entry into meiosis remain poorly understood. In Saccharomyces cerevisiae, the Superfamily 1 (Sf1) helicase Srs2, which is an ATP hydrolysis-dependent motor protein that actively dismantles recombination intermediates, promotes synthesisdependent strand annealing, the result of which is a reduction in cross-over recombination products. Here, we show that the meiosisspecific recombinase Dmc1 is a potent inhibitor of Srs2. Biochemical and single-molecule assays demonstrate that Dmc1 acts by inhibiting Srs2 ATP hydrolysis activity, which prevents the motor protein from undergoing ATP hydrolysis-dependent translocation on Dmc1bound recombination intermediates. We propose a model in which Dmc1 helps contribute to cross-over formation during meiosis by antagonizing the antirecombinase activity of Srs2.

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Section: Resultsmentioning

confidence: 77%

mentioning

confidence: 99%

Meiosis-specific recombinase Dmc1 is a potent inhibitor of the Srs2 antirecombinase

Crickard

Kaniecki

Kwon

et al. 2018

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

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“…In consequence, elimination of Srs2 leads to an increase of crossover products (Ira, Malkova et al, 2003, Mitchel, Lehner et al, 2013, Robert, Dervins et al, 2006. Thus besides Mph1, Srs2 may also suppresses BIR, however we have not tested Srs2 here because it is itself very important for BIR (Elango, Sheng et al, 2017). Lack of the enzymes regulating BIR frequency is partially (e.g.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms preventing Break-Induced Replication during repair of two-ended DNA double-strand breaks

Ira

Pham

Yan

et al. 2020

Preprint

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DNA synthesis during homologous recombination (HR) is highly mutagenic and proneto template switches. Two-ended DNA double strand breaks (DSBs) are usually repaired by gene conversion with a short patch of DNA synthesis, thus limiting the mutation load to the vicinity of the DSB. Single-ended DSBs are repaired by Break-Induced Replication (BIR) that involve extensive and mutagenic DNA synthesis spanning even hundreds of kilobases. It remains unknown how mutagenic BIR is suppressed at two-ended DSBs. Here we demonstrate that BIR is suppressed at two-ended DSBs by several proteins coordinating the usage of both DSB ends: ssDNA annealing protein Rad52 and Rad59, D-loop unwinding helicase Mph1, and DSB ends tethering Mre11-Rad50-Xrs2 complex. Finally, BIR is also suppressed when a normally heterochromatic repair template is silenced by Sir2. These findings suggest several mechanisms restricting mutagenic BIR during repair of two-ended DSBs.

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“…In wild-type cells, Srs2 seems to remove Rad51 assembly from the intermediates for the second end capture. Importantly, genetic analysis of mitotic recombination in the srs2 mutant suggest the role of Srs2 to facilitate the annealing of the newly synthesized strand to second resected ends by removing Rad51 from the second end (Elango et al 2017; Ira et al 2003; Liu et al 2017; Mitchel et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Srs2 helicase prevents the formation of toxic DNA damage during late prophase I of yeast meiosis

Sasanuma

Sakurai²,

Furihata³

et al. 2019

Preprint

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Proper repair of double-strand breaks (DSBs) is key to ensure proper chromosome segregation. In this study, we found that the deletion of the SRS2 gene, which encodes a DNA helicase necessary for the control of homologous recombination, induces aberrant chromosome segregation during budding yeast meiosis. This abnormal chromosome segregation in srs2 cells accompanies the formation of a novel DNA damage induced during late meiotic prophase-I. The damage may contain long stretches of single-stranded DNAs (ssDNAs), which lead to aggregate formation of a ssDNA binding protein, RPA, and a RecA homolog, Rad51, as well as other recombination proteins inside of the nuclei. The Rad51 aggregate formation in the srs2 mutant depends on the initiation of meiotic recombination and occurs in the absence of chromosome segregation. Importantly, as an early recombination intermediate, we detected a thin bridge of Rad51 between two Rad51 foci or among the foci in the srs2 mutant, which is rarely seen in wild type. These might be cytological manifestation of the connection of two DSB ends and multi-invasion. The DNA damage with Rad51 aggregates in the srs2 mutant is passed through anaphase-I and -II, suggesting the absence of DNA damage-induced cell-cycle arrest after the pachytene stage. We propose that Srs2 helicase resolves early protein-DNA recombination intermediates to suppress the formation of aberrant lethal DNA damage during late prophase-I.

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Break-induced replication promotes formation of lethal joint molecules dissolved by Srs2

Cited by 61 publications

References 66 publications

Meiosis-specific recombinase Dmc1 is a potent inhibitor of the Srs2 antirecombinase

Meiosis-specific recombinase Dmc1 is a potent inhibitor of the Srs2 antirecombinase

Mechanisms preventing Break-Induced Replication during repair of two-ended DNA double-strand breaks

Srs2 helicase prevents the formation of toxic DNA damage during late prophase I of yeast meiosis

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