Mus81 and converging forks limit the mutagenicity of replication fork breakage

Mayle, Ryan; Campbell, Ian; Beck, Christine R.; Yu, Yang; Wilson, Marenda A.; Shaw, Chad A.; Bjergbæk, Lotte; Lupski, James R.; Ira, Grzegorz

doi:10.1126/science.aaa8391

Cited by 162 publications

(212 citation statements)

References 31 publications

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“…The converging replication fork from ARS 315 (or perhaps ARS 313) must travel a relatively long distance and the low polymerase a conditions will slow the movement of this fork. Thus after replication fork collapse at FS2, there is likely to be a lag until a converging replication fork reaches the location of the break to form a second end, thus promoting BIR (Mayle et al 2015). Alternatively, the replication fork from ARS 310 may not collapse but instead proceed, leaving a singlestrand gap on the lagging strand at the hairpin.…”

Section: Discussionmentioning

confidence: 99%

Remarkably Long-Tract Gene Conversion Induced by Fragile Site Instability inSaccharomyces cerevisiae

Chumki¹,

Dunn²,

Coates³

et al. 2016

Genetics

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Replication stress causes breaks at chromosomal locations called common fragile sites. Deletions causing loss of heterozygosity (LOH) in human tumors are strongly correlated with common fragile sites, but the role of gene conversion in LOH at fragile sites in tumors is less well studied. Here, we investigated gene conversion stimulated by instability at fragile site FS2 in the yeast Saccharomyces cerevisiae. In our screening system, mitotic LOH events near FS2 are identified by production of red/white sectored colonies. We analyzed single nucleotide polymorphisms between homologs to determine the cause and extent of LOH. Instability at FS2 increases gene conversion 48-to 62-fold, and conversions unassociated with crossover represent 6-7% of LOH events. Gene conversion can result from repair of mismatches in heteroduplex DNA during synthesis-dependent strand annealing (SDSA), double-strand break repair (DSBR), and from break-induced replication (BIR) that switches templates [double BIR (dBIR)]. It has been proposed that SDSA and DSBR typically result in shorter gene-conversion tracts than dBIR. In cells under replication stress, we found that bidirectional tracts at FS2 have a median length of 40.8 kb and a wide distribution of lengths; most of these tracts are not crossover-associated. Tracts that begin at the fragile site FS2 and extend only distally are significantly shorter. The high abundance and long length of noncrossover, bidirectional gene-conversion tracts suggests that dBIR is a prominent mechanism for repair of lesions at FS2, thus this mechanism is likely to be a driver of common fragile site-stimulated LOH in human tumors.KEYWORDS loss of heterozygosity; gene conversion; BIR; fragile site; homologous recombination D NA integrity is frequently challenged by chemical, environmental, and physical agents, as well as by endogenous factors. Common fragile sites are one source of endogenous damage, causing DNA instability and breaks under conditions of replication stress when DNA replication is partially inhibited (Durkin and Glover 2007;Sarni and Kerem 2016). Replication stress has typically been induced experimentally by treating cells with the polymerase inhibitor aphidicolin (Glover et al. 1984) or by genetically lowering the levels of DNA polymerases Lemoine et al. 2008). In vivo, replication stress has been observed early in the process of tumor development as a result of alteration of replication fork progression and nucleotide deficiency caused by activation of oncogenes (Di Micco et al. 2006;Bester et al. 2011). In cancer cells, human common fragile sites are hotspots for chromosomal deletions, amplifications, and rearrangements (Burrow et al. 2009;Drusco et al. 2011; OzeriGalai et al. 2011 OzeriGalai et al. , 2012, and a large-scale screen of deletions in 746 cancer cell lines reported that many areas of unexplained deletions are in fragile sites (Bignell et al. 2010).The alterations at human common fragile sites in cancer cells are proposed to result from the processes of DNA repair at...

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Section: Discussionmentioning

confidence: 99%

Remarkably Long-Tract Gene Conversion Induced by Fragile Site Instability inSaccharomyces cerevisiae

Chumki¹,

Dunn²,

Coates³

et al. 2016

Genetics

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“…Homologous recombination (HR) at stalled or collapsed forks can either suppress or promote genomic instability 6,7 . To study repair at stalled mammalian replication forks, we previously adapted the Escherichia coli Tus/ Ter replication fork barrier (RFB) 8,9 to trigger locus-specific fork stalling and HR on a mammalian chromosome 10 .…”

mentioning

confidence: 99%

Mechanism of tandem duplication formation in BRCA1-mutant cells

Willis

Frock

Menghi

et al. 2017

Nature

117

154

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Summary Small ~10 kb microhomology-mediated tandem duplications (“Group 1 TDs”) are abundant in BRCA1-linked but not BRCA2-linked breast cancer genomes. Here, we define the mechanism underlying this “rearrangement signature”. We show that BRCA1, but not BRCA2, suppresses TDs at a Tus/Ter site-specific chromosomal replication fork barrier in primary mammalian cells. BRCA1 has no equivalent role at chromosomal double strand breaks, indicating specificity for the stalled fork response. Tandem duplications in BRCA1 mutant cells arise by a “replication restart-bypass” mechanism terminated by end joining or by microhomology-mediated template switching, the latter forming complex TD breakpoints. We show that solitary DNA ends form directly at Tus/Ter, implicating misrepair of these lesions in TD formation. We find that BRCA1 inactivation is strongly associated with Group 1 TDs in ovarian cancer. The Group 1 TD phenotype may be a general signature of BRCA1-deficient cancer.

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“…Interestingly, a recent study demonstrated that BIR-driven mutagenic synthesis at broken replication forks can be restricted by either a converging replication fork or Mus81, an endonuclease that cleaves the D loop. This study suggests an elegant strategy by which cells maintain their genomic integrity during error-prone DNA synthesis at breaks harboring one-sided homology (Mayle et al 2015). This begs the question of how often BIR ensues at genomic locations that lie in between replication origins.…”

Section: Rad51-dependent Birmentioning

confidence: 93%

“…It will be interesting to examine whether LTGC products obtained at the stalled replication fork are dependent on Pol D3. A further question of interest is the relative usage of BIR in comparison with the repair of a locus by a converging replication fork, which has also been shown to limit BIR-mediated synthesis (Mayle et al 2015).…”

Section: Bir-mediated Synthesis During Replication Stressmentioning

confidence: 99%

Noncanonical views of homology-directed DNA repair

2016

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DNA repair is essential to maintain genomic integrity and initiate genetic diversity. While gene conversion and classical nonhomologous end-joining are the most physiologically predominant forms of DNA repair mechanisms, emerging lines of evidence suggest the usage of several noncanonical homology-directed repair (HDR) pathways in both prokaryotes and eukaryotes in different contexts. Here we review how these alternative HDR pathways are executed, specifically focusing on the determinants that dictate competition between them and their relevance to cancers that display complex genomic rearrangements or maintain their telomeres by homology-directed DNA synthesis.

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Mus81 and converging forks limit the mutagenicity of replication fork breakage

Cited by 162 publications

References 31 publications

Remarkably Long-Tract Gene Conversion Induced by Fragile Site Instability inSaccharomyces cerevisiae

Remarkably Long-Tract Gene Conversion Induced by Fragile Site Instability inSaccharomyces cerevisiae

Mechanism of tandem duplication formation in BRCA1-mutant cells

Noncanonical views of homology-directed DNA repair

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