Mus81 and Yen1 Promote Reciprocal Exchange during Mitotic Recombination to Maintain Genome Integrity in Budding Yeast

Ho, Chu Kwen; Mazón, Gerard; Lam, Alicia F.; Symington, Lorraine S.

doi:10.1016/j.molcel.2010.11.016

Cited by 153 publications

(267 citation statements)

References 66 publications

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“…VDE-initiated COs at HIS4 are similar to those initiated by Spo11, in that most depend on MutLg. In contrast, VDE-initiated COs at the 'cold' locus, URA3, more closely resemble mitotic COs, which are independent of MutLg, but are substantially dependent on SSNs (Ho et al, 2010;Ira et al, 2003;Muñoz-Galván et al, 2012). Locus-dependent differences in MutLg-dependence are reduced in pch2D mutants, as are differences in Hop1 occupancy at later times in meiosis I prophase.…”

Section: Discussion Local Chromosome Context Influences Meiotic Co Fomentioning

confidence: 99%

“…These residual crossovers may reflect the activity of a yet-unidentified JM resolvase; they may also reflect the production of half-crossovers by breakinduced replication (Ho et al, 2010;Kogoma, 1996;Llorente et al, 2008) or by other mechanisms that do not involve dHJ-JM formation and resolution (Ivanov and Haber, 1995;Mazó n et al, 2012;Muñoz-Galván et al, 2012). Alternatively, long-tract NCO gene conversion events that include flanking heterologous sequences might be responsible for the products, scored in our molecular assays as COs, that are independent of both MutLg and SSNs.…”

Section: The Interplay Of Resolvase Activities Is Chromosome Context-mentioning

confidence: 99%

“…MutLg does not appear to make significant contributions to mitotic COs (Ira et al, 2003). A minority of events form ZMM-independent JMs that are resolved as both COs and NCOs by the structure-selective nucleases (SSNs) Mus81-Mms4, Yen1, and Slx1-Slx4, which are responsible for most JM resolution during mitosis (Argueso et al, 2004;Santos et al, 2003;De Muyt et al, 2012;Ho et al, 2010;Muñoz-Galván et al, 2012;Zakharyevich et al, 2012; reviewed by Wyatt and West, 2014). A similar picture, with MutLg forming most meiotic COs and SSNs playing a minor role, is observed in several other eukaryotes (Berchowitz et al, 2007;Holloway et al, 2008;Plug et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Local chromosome context is a major determinant of crossover pathway biochemistry during budding yeast meiosis

Medhi¹,

Goldman

Lichten³

2016

Preprint

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The budding yeast genome contains regions where meiotic recombination initiates more frequently than in others. This pattern parallels enrichment for the meiotic chromosome axis proteins Hop1 and Red1. These proteins are important for Spo11-catalyzed double strand break formation; their contribution to crossover recombination remains undefined. Using the sequencespecific VMA1-derived endonuclease (VDE) to initiate recombination in meiosis, we show that chromosome structure influences the choice of proteins that resolve recombination intermediates to form crossovers. At a Hop1-enriched locus, most VDE-initiated crossovers, like most Spo11-initiated crossovers, required the meiosis-specific MutLg resolvase. In contrast, at a locus with lower Hop1 occupancy, most VDE-initiated crossovers were MutLg-independent. In pch2 mutants, the two loci displayed similar Hop1 occupancy levels, and VDE-induced crossovers were similarly MutLg-dependent. We suggest that meiotic and mitotic recombination pathways coexist within meiotic cells, and that features of meiotic chromosome structure determine whether one or the other predominates in different regions.

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Section: Discussion Local Chromosome Context Influences Meiotic Co Fomentioning

confidence: 99%

Section: The Interplay Of Resolvase Activities Is Chromosome Context-mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Local chromosome context is a major determinant of crossover pathway biochemistry during budding yeast meiosis

Medhi¹,

Goldman

Lichten³

2016

Preprint

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“…Any errors generated during BIR leading-strand synthesis would become fixed by second-strand synthesis with no opportunity for mismatch correction because of the absence of a heteroduplex intermediate. BIR is a rare outcome for repair of a two-ended DSB (11,28,29), presumably because of the possibility of increased mutagenesis over tens of kilobases, in addition to the potential for extensive LOH or nonreciprocal translocation. Mechanisms to ensure repair of two-ended DSBs by gene conversion could be defective in aging or cancer cells, contributing to genome instability (30).…”

Section: Discussionmentioning

confidence: 99%

“…If the second end of the break is captured by the D-loop, a double Holliday junction can be generated after DNA repair synthesis and ligation. Double Holliday junctions can either be dissolved by the Sgs1 helicase and Top3 topoisomerase to form noncrossover products or resolved by endonucleases to generate crossovers or noncrossovers (2,11,12). To complete two-ended repair, two short tracts of leading strand DNA synthesis are required, whereas BIR requires extensive leading and lagging strand DNA synthesis (13, 14).…”

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confidence: 99%

Break-induced replication occurs by conservative DNA synthesis

Donnianni

Symington

2013

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

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Break-induced replication (BIR) refers to recombination-dependent DNA synthesis initiated from one end of a DNA double-strand break and can extend for more than 100 kb. BIR initiates by Rad51-catalyzed strand invasion, but the mechanism for DNA synthesis is not known. Here, we used BrdU incorporation to track DNA synthesis during BIR and found that the newly synthesized strands segregate with the broken chromosome, indicative of a conservative mode of DNA synthesis. Furthermore, we show the frequency of BIR is reduced and product formation is progressively delayed when the donor is placed at an increasing distance from the telomere, consistent with replication by a migrating D-loop from the site of initiation to the telomere.H omologous recombination (HR) is an important mechanism to repair DNA double-strand breaks (DSBs) that occur spontaneously during cell growth or following exposure to DNA damaging agents (1). HR relies on the presence of a homologous duplex to template repair of the broken chromosome and is generally considered to be an error-free mechanism. However, HR can lead to a local loss of heterozygosity (LOH) if the recombining sequences are not identical, and to extensive LOH if repair is associated with a crossover between chromosome homologs. Furthermore, if a repeated sequence at an ectopic site is used as the sequence donor and recombination is associated with crossing over, translocations can occur (2, 3). When both ends of the DSB share homology with the donor duplex sequence, HR proceeds by a two-ended mechanism, such as DSB repair or synthesis-dependent strand-annealing (SDSA) (4-6). However, if coordination of the two ends is not maintained or only one end of the break is available, such as at a critically short telomere, repair can occur by break-induced replication (BIR) (7). In this case, following strand invasion replication occurs to the end of the chromosome to generate a stable repaired product (8,9). This process can cause very long gene conversion tracts and significant LOH, and nonreciprocal translocation if invasion occurs at a dispersed repeated sequence (10).The repair of DSBs by HR requires the 5′-3′ nucleolytic degradation of the DNA ends to form invasive 3′ single-stranded DNA (ssDNA) tails (1). The 3′ ssDNA tail created by end resection is bound by Rad51 to form a nucleoprotein filament that searches for homology and promotes pairing between the ssDNA bound by Rad51 and complementary sequence in the donor duplex forming a D-loop intermediate. The invading 3′ end is then used to prime DNA synthesis templated by the donor sequence. If the invading 3′-tail is displaced by helicases and anneals with the other end of break, repair by SDSA results in noncrossover products. If the second end of the break is captured by the D-loop, a double Holliday junction can be generated after DNA repair synthesis and ligation. Double Holliday junctions can either be dissolved by the Sgs1 helicase and Top3 topoisomerase to form noncrossover products or resolved by endonucleases to generate cr...

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Analysis of Crossover Breakpoints Yields New Insights into the Nature of the Gene Conversion Events Associated with LargeNF1Deletions Mediated by Nonallelic Homologous Recombination

et al. 2013

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Large NF1 deletions are mediated by nonallelic homologous recombination (NAHR). An in-depth analysis of gene conversion operating in the breakpoint-flanking regions of large NF1 deletions was performed to investigate whether the rate of discontinuous gene conversion during NAHR with crossover is increased, as has been previously noted in NAHR-mediated rearrangements. All 20 germline type-1 NF1 deletions analyzed were mediated by NAHR associated with continuous gene conversion within the breakpoint-flanking regions. Continuous gene conversion was also observed in 31/32 type-2 NF1 deletions investigated. In contrast to the meiotic type-1 NF1 deletions, type-2 NF1 deletions are predominantly of post-zygotic origin. Our findings therefore imply that the mitotic as well as the meiotic NAHR intermediates of large NF1 deletions are processed by long-patch mismatch repair (MMR), thereby ensuring gene conversion tract continuity instead of the discontinuous gene conversion that is characteristic of short-patch repair. However, the single type-2 NF1 deletion not exhibiting continuous gene conversion was processed without MMR, yielding two different deletion-bearing chromosomes, which were distinguishable in terms of their breakpoint positions. Our findings indicate that MMR failure during NAHR, followed by post-meiotic/mitotic segregation, has the potential to give rise to somatic mosaicism in human genomic rearrangements by generating breakpoint heterogeneity.

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Mus81 and Yen1 Promote Reciprocal Exchange during Mitotic Recombination to Maintain Genome Integrity in Budding Yeast

Cited by 153 publications

References 66 publications

Local chromosome context is a major determinant of crossover pathway biochemistry during budding yeast meiosis

Local chromosome context is a major determinant of crossover pathway biochemistry during budding yeast meiosis

Break-induced replication occurs by conservative DNA synthesis

Analysis of Crossover Breakpoints Yields New Insights into the Nature of the Gene Conversion Events Associated with LargeNF1Deletions Mediated by Nonallelic Homologous Recombination

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