title: Kinetic models reveal the in vivo mechanisms of mutagenesis in microbes and man.
abstract: This review summarizes the evidence indicating that mutagenic mechanisms in vivo are essentially the same in all living cells. Unique metabolic reactions to a particular environmental stress apparently target specific genes for increased rates of transcription and mutation, resulting in higher mutation rates for those genes most likely to solve the problem. Kinetic models which have demonstrated predictive value are described and are shown to simulate mutagenesis in vivo in Escherichia coli, the p53 tumor suppressor gene, and somatic hypermutation. In all three models, direct correlations are seen between mutation frequencies and transcription rates. G and C nucleosides in single-stranded DNA (ssDNA) are intrinsically mutable, and G and C silent mutations in p53 and in VH framework regions provide compelling evidence for intrinsic mechanisms of mutability, since mutation outcomes are neutral and are not selected. During transcription, the availability of unpaired bases in the ssDNA of secondary structures is rate-limiting for, and determines the frequency of mutations in vivo. In vitro analyses also verify the conclusion that intrinsically mutable bases are in fact located in ssDNA loops of predicted stem-loop structures (SLSs).
authors.affiliation: Division of Biological Sciences, The University of Montana, Missoula, MT 59812, United States. Electronic address: barbara.wright@mso.umt.edu.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Wright
authors.affiliation: Division of Biological Sciences, The University of Montana, Missoula, MT 59812, United States.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Schmidt
authors.affiliation: Division of Biological Sciences, The University of Montana, Missoula, MT 59812, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Minnick
mesh_terms: D001419:Bacteria / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D016159:Tumor Suppressor Protein p53