Repair of multiple simultaneous double-strand breaks causes bursts of genome-wide clustered hypermutation.

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ID: 61144
2019
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Abstract
A single cancer genome can harbor thousands of clustered mutations. Mutation signature analyses have revealed that the origin of clusters are lesions in long tracts of single-stranded (ss) DNA damaged by apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases, raising questions about molecular mechanisms that generate long ssDNA vulnerable to hypermutation. Here, we show that ssDNA intermediates formed during the repair of gamma-induced bursts of double-strand breaks (DSBs) in the presence of APOBEC3A in yeast lead to multiple APOBEC-induced clusters similar to cancer. We identified three independent pathways enabling cluster formation associated with repairing bursts of DSBs: 5' to 3' bidirectional resection, unidirectional resection, and break-induced replication (BIR). Analysis of millions of mutations in APOBEC-hypermutated cancer genomes revealed that cancer tolerance to formation of hypermutable ssDNA is similar to yeast and that the predominant pattern of clustered mutagenesis is the same as in resection-defective yeast, suggesting that cluster formation in cancers is driven by a BIR-like mechanism. The phenomenon of genome-wide burst of clustered mutagenesis revealed by our study can play an important role in generating somatic hypermutation in cancers as well as in noncancerous cells.
Reference Key
sakofsky2019repairplos Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Sakofsky, Cynthia J;Saini, Natalie;Klimczak, Leszek J;Chan, Kin;Malc, Ewa P;Mieczkowski, Piotr A;Burkholder, Adam B;Fargo, David;Gordenin, Dmitry A;
Journal plos biology
Year 2019
DOI
10.1371/journal.pbio.3000464
URL
Keywords
homologous recombination break-induced replication dna double-strand breaks fancm rad52 common fragile sites replication stress

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