title: Break-induced replication is a source of mutation clusters underlying kataegis.
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.
authors.affiliation: 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.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Sakofsky
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Roberts
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center and Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Malc
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center and Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Piotr A
authors.initials: PA
authors.lastname: Mieczkowski
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. Electronic address: gordenin@niehs.nih.gov.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Gordenin
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Malkova
mesh_terms: D053903:DNA Breaks, Double-Stranded; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000235:genetics; D016681:Genome, Fungal; D016296:Mutagenesis; D059645:Mutation Rate; D012441:Saccharomyces cerevisiae / Q000235:genetics*
chemical_list: D004277:DNA, Single-Stranded