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- Title
Repair of multiple simultaneous double-strand breaks causes bursts of genome-wide clustered hypermutation.
- 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.
- 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.
- Subjects
SOMATIC mutation; APOLIPOPROTEIN B; DNA damage; DEAMINASES; NUCLEIC acids
- Publication
PLoS Biology, 2019, Vol 17, Issue 9, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3000464