title: Clusters of Multiple Mutations: Incidence and Molecular Mechanisms.
abstract: It has been long understood that mutation distribution is not completely random across genomic space and in time. Indeed, recent surprising discoveries identified multiple simultaneous mutations occurring in tiny regions within chromosomes while the rest of the genome remains relatively mutation-free. Mechanistic elucidation of these phenomena, called mutation showers, mutation clusters, or kataegis, in parallel with findings of abundant clustered mutagenesis in cancer genomes, is ongoing. So far, the combination of factors most important for clustered mutagenesis is the induction of DNA lesions within unusually long and persistent single-strand DNA intermediates. In addition to being a fascinating phenomenon, clustered mutagenesis also became an indispensable tool for identifying a previously unrecognized major source of mutation in cancer, APOBEC cytidine deaminases. Future research on clustered mutagenesis may shed light onto important mechanistic details of genome maintenance, with potentially profound implications for human health.
authors.affiliation: Mechanisms of Genome Dynamics Group, National Institute of Environmental Health Sciences, Department of Health and Human Services, National Institutes of Health, Durham, North Carolina 27709; email: kin.chan@nih.gov , gordenin@niehs.nih.gov.
authors.forename: Kin
authors.initials: K
authors.lastname: Chan
authors.affiliation: Mechanisms of Genome Dynamics Group, National Institute of Environmental Health Sciences, Department of Health and Human Services, National Institutes of Health, Durham, North Carolina 27709; email: kin.chan@nih.gov , gordenin@niehs.nih.gov.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Gordenin
mesh_terms: D000818:Animals; D004247:DNA; D004260:DNA Repair; D004277:DNA, Single-Stranded; D006801:Humans; D008817:Mice, Mutant Strains; D016296:Mutagenesis / Q000502:physiology*; D009154:Mutation; D000067552:Mutation Accumulation; D009369:Neoplasms / Q000235:genetics*; D018626:Retroelements / Q000235:genetics; D016615:Telomere / Q000235:genetics; D015003:Yeasts / Q000166:cytology / Q000235:genetics
chemical_list: D004277:DNA, Single-Stranded; D018626:Retroelements; D004247:DNA
keywords: cancer; evolution; genome instability; kataegis; mutagenesis; mutation showers