title: Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions.
abstract: Mutations are typically perceived as random, independent events. We describe here nonrandom clustered mutations in yeast and in human cancers. Genome sequencing of yeast grown under chronic alkylation damage identified mutation clusters that extend up to 200 kb. A predominance of "strand-coordinated" changes of either cytosines or guanines in the same strand, mutation patterns, and genetic controls indicated that simultaneous mutations were generated by base alkylation in abnormally long single-strand DNA (ssDNA) formed at double-strand breaks (DSBs) and replication forks. Significantly, we found mutation clusters with analogous features in sequenced human cancers. Strand-coordinated clusters of mutated cytosines or guanines often resided near chromosome rearrangement breakpoints and were highly enriched with a motif targeted by APOBEC family cytosine-deaminases, which strongly prefer ssDNA. These data indicate that hypermutation via multiple simultaneous changes in randomly formed ssDNA is a general phenomenon that may be an important mechanism producing rapid genetic variation.
authors.affiliation: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Roberts
authors.forename: Joan
authors.initials: J
authors.lastname: Sterling
authors.forename: Cole
authors.initials: C
authors.lastname: Thompson
authors.forename: Shawn
authors.initials: S
authors.lastname: Harris
authors.forename: Deepak
authors.initials: D
authors.lastname: Mav
authors.forename: Ruchir
authors.initials: R
authors.lastname: Shah
authors.forename: Leszek J
authors.initials: LJ
authors.lastname: Klimczak
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Kryukov
authors.forename: Ewa
authors.initials: E
authors.lastname: Malc
authors.forename: Piotr A
authors.initials: PA
authors.lastname: Mieczkowski
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Gordenin
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D019175:DNA Methylation / Q000235:genetics; D004260:DNA Repair; D004271:DNA, Fungal / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D004277:DNA, Single-Stranded / Q000235:genetics*; D005800:Genes, Fungal; D017930:Genes, Reporter; D006801:Humans; D008741:Methyl Methanesulfonate; D009153:Mutagens; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics
chemical_list: D026923:Amino Acid Transport Systems, Basic; C502212:CAN1 protein, S cerevisiae; D004271:DNA, Fungal; D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D009153:Mutagens; D029701:Saccharomyces cerevisiae Proteins; C554167:URA3 protein, S cerevisiae; D008741:Methyl Methanesulfonate