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Repair of multiple simultaneous double-strand breaks causes bursts of genome-wide clustered hypermutation.
- Source :
- PLoS Biology; 9/30/2019, Vol. 17 Issue 9, p1-32, 32p, 1 Diagram, 5 Graphs
- Publication Year :
- 2019
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- SOMATIC mutation
APOLIPOPROTEIN B
DNA damage
DEAMINASES
NUCLEIC acids
Subjects
Details
- Language :
- English
- ISSN :
- 15449173
- Volume :
- 17
- Issue :
- 9
- Database :
- Complementary Index
- Journal :
- PLoS Biology
- Publication Type :
- Academic Journal
- Accession number :
- 138873718
- Full Text :
- https://doi.org/10.1371/journal.pbio.3000464