title: Damage-induced localized hypermutability.
abstract: Genome instability continuously presents perils of cancer, genetic disease and death of a cell or an organism. At the same time, it provides for genome plasticity that is essential for development and evolution. We address here the genome instability confined to a small fraction of DNA adjacent to free DNA ends at uncapped telomeres and double-strand breaks. We found that budding yeast cells can tolerate nearly 20 kilobase regions of subtelomeric single-strand DNA that contain multiple UV-damaged nucleotides. During restoration to the double-strand state, multiple mutations are generated by error-prone translesion synthesis. Genome-wide sequencing demonstrated that multiple regions of damage-induced localized hypermutability can be tolerated, which leads to the simultaneous appearance of multiple mutation clusters in the genomes of UV- irradiated cells. High multiplicity and density of mutations suggest that this novel form of genome instability may play significant roles in generating new alleles for evolutionary selection as well as in the incidence of cancer and genetic disease.
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC USA.
authors.forename: Lauranell H
authors.initials: LH
authors.lastname: Burch
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.forename: Joan F
authors.initials: JF
authors.lastname: Sterling
authors.forename: Steven A
authors.initials: SA
authors.lastname: Roberts
authors.forename: Frank G
authors.initials: FG
authors.lastname: Chao
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Leilei
authors.initials: L
authors.lastname: Zhang
authors.forename: Jesse
authors.initials: J
authors.lastname: Walsh
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
authors.forename: Piotr A
authors.initials: PA
authors.lastname: Mieczkowski
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Gordenin
mesh_terms: D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects*; D014644:Genetic Variation; D042822:Genomic Instability / Q000235:genetics*; D009154:Mutation / Q000528:radiation effects; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D004718:Saccharomycetales; D017422:Sequence Analysis, DNA; D016615:Telomere / Q000235:genetics / Q000528:radiation effects*; D034501:Telomere-Binding Proteins / Q000235:genetics; D014466:Ultraviolet Rays
chemical_list: C452219:Cdc13 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D034501:Telomere-Binding Proteins