Break-induced replication is a source of mutation clusters underlying kataegis

Cynthia J Sakofsky; Steven A Roberts; Ewa Malc; Piotr A Mieczkowski; Michael A Resnick; Dmitry A Gordenin; Anna Malkova

doi:10.1016/j.celrep.2014.04.053

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Break-induced replication is a source of mutation clusters underlying kataegis

Journal article

Open access

Peer reviewed

Break-induced replication is a source of mutation clusters underlying kataegis

Cynthia J Sakofsky, Steven A Roberts, Ewa Malc, Piotr A Mieczkowski, Michael A Resnick, Dmitry A Gordenin and Anna Malkova

Cell reports (Cambridge), Vol.7(5), pp.1640-1648

06/12/2014

DOI: 10.1016/j.celrep.2014.04.053

PMCID: PMC4274036

PMID: 24882007

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Abstract

Clusters of simultaneous multiple mutations can be a source of rapid change during carcinogenesis and evolution. Such mutation clusters have been recently shown to originate from DNA damage within long single-stranded DNA (ssDNA) formed at resected double-strand breaks and dysfunctional replication forks. Here, we identify double-strand break (DSB)-induced replication (BIR) as another powerful source of mutation clusters that formed in nearly half of wild-type yeast cells undergoing BIR in the presence of alkylating damage. Clustered mutations were primarily formed along the track of DNA synthesis and were frequently associated with additional breakage and rearrangements. Moreover, the base specificity, strand coordination, and strand bias of the mutation spectrum were consistent with mutations arising from damage in persistent ssDNA stretches within unconventional replication intermediates. Altogether, these features closely resemble kataegic events in cancers, suggesting that replication intermediates during BIR may be the most prominent source of mutation clusters across species.

DNA, Single-Stranded - genetics

Genome, Fungal

Mutagenesis

Saccharomyces cerevisiae - genetics

DNA Replication

Mutation Rate

DNA Breaks, Double-Stranded

Details

Title: Subtitle: Break-induced replication is a source of mutation clusters underlying kataegis
Creators: Cynthia J Sakofsky - Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242-1324, USA; Department of Biology, School of Science, IUPUI, Indianapolis, IN 46202-5132, USA
Steven A Roberts - National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
Ewa Malc - Department of Genetics, Lineberger Comprehensive Cancer Center and Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA
Piotr A Mieczkowski - Department of Genetics, Lineberger Comprehensive Cancer Center and Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA
Michael A Resnick - National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
Dmitry A Gordenin - National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. Electronic address: gordenin@niehs.nih.gov
Anna Malkova - Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242-1324, USA; Department of Biology, School of Science, IUPUI, Indianapolis, IN 46202-5132, USA. Electronic address: anna-malkova@uiowa.edu
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.7(5), pp.1640-1648
DOI: 10.1016/j.celrep.2014.04.053
PMID: 24882007
PMCID: PMC4274036
NLM abbreviation: Cell Rep
ISSN: 2211-1247
eISSN: 2211-1247
Publisher: United States
Grant note: R00 ES022633 / NIEHS NIH HHS P30 ES010126 / NIEHS NIH HHS GM084242 / NIGMS NIH HHS R01 GM084242 / NIGMS NIH HHS Z01 ES065073 / Intramural NIH HHS R01 GM052319 / NIGMS NIH HHS K99ES022633-01 / NIEHS NIH HHS 5R01GM052319-17 / NIGMS NIH HHS
Language: English
Date published: 06/12/2014
Academic Unit: Biology
Record Identifier: 9983991932902771

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