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

Ira, Grzegorz; Pham, Nhung; Yan, Zhong; Haber, James E.; Malkova, Anna

doi:10.1101/2020.02.28.969154

Cited by 2 publications

(2 citation statements)

References 71 publications

(63 reference statements)

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“…We therefore estimated mutation rates to understand if the mutational process is also impacted and variable across genetic backgrounds. DNA synthesis during mitotic recombination is considered to be mutagenic (39) and this effect is suggested to be amplified in heterozygous genomes (49,50). In the 169 MA lines, we identified 912 single nucleotide mutations (SNMs) and 14 multi-nucleotide mutations (MNMs), of which 83 and 2 are homozygous, respectively (Supplementary file 5).…”

Section: Mutation Rate Is Constant Across Heterozygous Diploid Backgroundsmentioning

confidence: 99%

“…By contrast, T-LOH events result from mitotic crossovers and break-induced replication (BIR) mechanisms frequently spanning large chromosomal regions greater than 100 kb (37,38). BIR is a homologous recombination (HR) pathway that repairs only one-ended DSBs and suppressed at two ended DSBs (39). Despite their high fidelity relative to other repair pathways, recent findings have demonstrated that HR pathways promote genome instability through an increased load of mutagenesis and chromosomal rearrangements (40)(41)(42).…”

Section: Introductionmentioning

confidence: 99%

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Loss of heterozygosity results in rapid but variable genome homogenization across yeast genetic backgrounds

Dutta

Dutreux

Schacherer

2021

eLife

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The dynamics and diversity of the appearance of genetic variants play an essential role in the evolution of the genome and the shaping of biodiversity. Recent population-wide genome sequencing surveys have highlighted the importance of loss-of-heterozygosity (LOH) events and have shown that they are a neglected part of the genetic diversity landscape. To assess the extent, variability, and spectrum, we explored the accumulation of LOH events in 169 heterozygous diploid Saccharomyces cerevisiae mutation accumulation lines across nine genetic backgrounds. In total, we detected a large set of 22,828 LOH events across distinct genetic backgrounds with a heterozygous level ranging from 0.1 to 1%. LOH events are very frequent with a rate consistently much higher than the mutation rate, showing their importance for genome evolution. We observed that the interstitial LOH (I-LOH) events, resulting in internal short LOH tracts, were much frequent (n = 19,660) than the terminal LOH (T-LOH) events, i.e., tracts extending to the end of the chromosome (n = 3,168). However, the spectrum, the rate, and the fraction of the genome under LOH vary across genetic backgrounds. Interestingly, we observed that the more the ancestors were heterozygous, the more they accumulated T-LOH events. In addition, frequent short I-LOH tracts are a signature of the lines derived from hybrids with low spore fertility. Finally, we found lines showing almost complete homozygotization during vegetative progression. Overall, our results highlight that the variable dynamics of the LOH accumulation across distinct genetic backgrounds might lead to rapid differential genome evolution during vegetative growth.

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Section: Mutation Rate Is Constant Across Heterozygous Diploid Backgroundsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of heterozygosity results in rapid but variable genome homogenization across yeast genetic backgrounds

Dutta

Dutreux

Schacherer

2021

eLife

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Comprehensive analysis of cis- and trans-acting factors affecting Break-Induced Replication

Uribe-Calvillo

Maestroni

Marsolier

et al. 2022

Preprint

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Break-induced replication (BIR) is a highly mutagenic eukaryotic homologous DNA recombination pathway that repairs one-ended DNA double strand breaks such as broken DNA replication forks and eroded telomeres. While searching for cis-acting factors regulating BIR efficiency, we found that BIR efficiency is the highest close to chromosome ends. The variations of BIR efficiency as a function of the length of DNA to replicate can be described as a combination of two decreasing exponential functions, a property in line with repeated cycles of strand invasion, elongation and dissociation that characterize BIR. Interestingly, the apparent processivity of BIR depends on the length of DNA already synthesized. BIR is more susceptible to disruption during the synthesis of the first ∼35-40 kb of DNA than later, notably when the template chromatid is being transcribed or heterochromatic. Finally, we show that the Srs2 helicase promotes BIR from both telomere proximal and telomere distal regions in diploid cells but only from telomere proximal sites in haploid cells. Altogether, we bring new light on the factors impacting a last resort DNA repair pathway.

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

Cited by 2 publications

References 71 publications

Loss of heterozygosity results in rapid but variable genome homogenization across yeast genetic backgrounds

Loss of heterozygosity results in rapid but variable genome homogenization across yeast genetic backgrounds

Comprehensive analysis of cis- and trans-acting factors affecting Break-Induced Replication

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