Srs2 and Sgs1–Top3 Suppress Crossovers during Double-Strand Break Repair in Yeast

Ira, Grzegorz; Malkova, Anna; Liberi, Giordano; Foiani, Marco; Haber, James E.

doi:10.1016/s0092-8674(03)00886-9

Cited by 547 publications

(752 citation statements)

References 69 publications

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“…Srs2 could discourage D-loop formation acting at a presynaptic stage (Krejci et al, 2003;Veaute et al, 2003) or a postsynaptic stage by disrupting the D-loop to relocate the formerly arrested, now elongated, strand back onto its original template. This is similar to its function in promoting SDSA in double-strand break repair ( Figure 5E; Ira et al, 2003;Dupaigne et al, 2008). Alternatively, if the displaced strand of the D-loop structure hybridizes with the complementary strand, a single HJ is formed ( Figure 5C).…”

Section: Mph1 Is Likely To Have a Role In Recombinational Dna Repair mentioning

confidence: 66%

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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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Section: Mph1 Is Likely To Have a Role In Recombinational Dna Repair mentioning

confidence: 66%

“…From genetic studies we know that SRS2 can be placed at a stage where it counteracts recombination (Chanet et al, 1996;Rong et al, 1991) and SGS1 downstream, at its resolution (Fabre et al, 2002;Ira et al, 2003).…”

Section: Mph1 Probably Acts At a Stage After Initiation Of Recombinationmentioning

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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“…Of note, kinesin-14 was only minimally involved in gene conversion indicating that the observed major impact on BIR systems is not related to unforeseen changes in general DNA donor-based repair processes (Fig. 6h,i) 51 . Together, our findings indicate that kinesin-14 and Nup84 are part of a BIR pathway that can act beyond subtelomeric DSBs.…”

Section: Resultsmentioning

confidence: 94%

“…expression of the HO endonuclease 51 . This strain lacks donor sequences (HML and HMR) for homologous recombination.…”

Section: Methodsmentioning

confidence: 99%

Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process

et al. 2015

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DNA double-strand breaks (DSBs) are often targeted to nuclear pore complexes (NPCs) for repair. How targeting is achieved and the DNA repair pathways involved in this process remain unclear. Here, we show that the kinesin-14 motor protein complex (Cik1-Kar3) cooperates with chromatin remodellers to mediate interactions between subtelomeric DSBs and the Nup84 nuclear pore complex to ensure cell survival via break-induced replication (BIR), an error-prone DNA repair process. Insertion of a DNA zip code near the subtelomeric DSB site artificially targets it to NPCs hyperactivating this repair mechanism. Kinesin-14 and Nup84 mediate BIR-dependent repair at non-telomeric DSBs whereas perinuclear telomere tethers are only required for telomeric BIR. Furthermore, kinesin-14 plays a critical role in telomerase-independent telomere maintenance. Thus, we uncover roles for kinesin and NPCs in DNA repair by BIR and reveal that perinuclear telomere anchors license subtelomeric DSBs for this error-prone DNA repair mechanism.

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“…Indeed, elevated levels of sister chromatid exchanges, which arise due to crossing over during or soon after S phase, are currently the most reliable diagnostic feature of Bloom's syndrome (German, 1993). Sgs1 and Top3 have also been demonstrated to function in the same HR repair pathway to prevent crossing over during double-strand break repair in S. cerevisiae (Ira et al, 2003). Therefore, current thinking suggests that RecQ helicases act in concert with type IA topoisomerases in an evolutionarily conserved pathway to process recombination intermediates that arise during DNA replication without the crossing over of genetic material.…”

Section: Introductionmentioning

confidence: 99%

Top3 Processes Recombination Intermediates and Modulates Checkpoint Activity after DNA Damage

Mankouri

Hickson

2006

MBoC

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Mutation of TOP3 in Saccharomyces cerevisiae causes poor growth, hyperrecombination, and a failure to fully activate DNA damage checkpoints in S phase. Here, we report that overexpression of a dominant-negative allele of TOP3, TOP3 Y356F , which lacks the catalytic (decatenation) activity of Top3, causes impaired S-phase progression and the persistence of abnormal DNA structures (X-shaped DNA molecules) after exposure to methylmethanesulfonate. The impaired S-phase progression is due to a persistent checkpoint-mediated cell cycle delay and can be overridden by addition of caffeine. Hence, the catalytic activity of Top3 is not required for DNA damage checkpoint activation, but it is required for normal S-phase progression after DNA damage. We also present evidence that the checkpoint-mediated cell cycle delay and persistence of X-shaped DNA molecules resulting from overexpression of TOP3 Y356F are downstream of Rad51 function. We propose that Top3 functions in S phase to both process homologous recombination intermediates and modulate checkpoint activity. INTRODUCTIONTopoisomerases are highly conserved proteins that catalyze topological rearrangements in the structure of DNA and are required for many aspects of DNA metabolism. Of the three topoisomerases in yeast, the function(s) of the sole type IA topoisomerase, Top3, remains most poorly understood. However, it is likely that Top3 fulfills important roles in vivo, because deletion of TOP3 in Saccharomyces cerevisiae causes hyperrecombination, sensitivity to genotoxic agents, meiotic defects, and poor growth due to accumulation of cells with a late S/G 2 content of DNA (Wallis et al., 1989;Gangloff et al., 1994Gangloff et al., , 1999Chakraverty et al., 2001). Similarly, deletion of top3 ϩ in Schizosaccharomyces pombe causes lethality due to chromosome missegregation and accumulation of DNA double-strand breaks (Goodwin et al., 1999;Maftahi et al., 1999;Oh et al., 2002;Win et al., 2004). Whereas lower eukaryotes generally contain only one type IA topoisomerase, human cells, like most vertebrates, possess at least two Top3 homologues, hTOPIII␣ and hTOPIII␤ (Hanai et al., 1996;Ng et al., 1999). In mice, mutation of TOP3␣ causes embryonic lethality (Li and Wang, 1998), whereas mutation of TOP3␤ causes a shortened life span (Kwan et al., 2003). Interestingly, in S. cerevisiae and S. pombe, deletion of SGS1 or rqh1 ϩ can largely suppress the phenotypes caused by deletion of TOP3 or top3 ϩ , respectively (Gangloff et al., 1994;Goodwin et al., 1999;Maftahi et al., 1999;Chakraverty et al., 2001). Because both SGS1 and rqh1 ϩ belong to the same family of proteins, the RecQ DNA helicases, this intriguing genetic interaction has led to the suggestion that type IA topoisomerases may be functionally associated with RecQ helicases. Indeed, both Sgs1 and Rqh1 physically interact with Top3 in their respective organisms (Gangloff et al., 1994;Bennett et al., 2000;Fricke et al., 2001;Onodera et al., 2002;Laursen et al., 2003;Ahmad and Stewart, 2005;Ui et al., 2005), and a close as...

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Srs2 and Sgs1–Top3 Suppress Crossovers during Double-Strand Break Repair in Yeast

Cited by 547 publications

References 69 publications

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

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

Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process

Top3 Processes Recombination Intermediates and Modulates Checkpoint Activity after DNA Damage

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