title: Functional cooperation of Ogg1 and Mutyh in preventing G: C-->T: a transversions in mice.
abstract: Oxygen radicals generated through normal cellular metabolism induce a variety of types of oxidative damage into DNA and its precursors. Among such types of oxidative damage, 7, 8-dihydro-8-oxoguanine (8-oxoG), an oxidized form of guanine, is known to be abundant and highly mutagenic. 8-OxoG can pair with adenine as well as cytosine, thus causing G: C to T: A transversions after DNA replication, if not repaired. Organisms are equipped with elaborate systems to avoid such mutations caused by 8-oxoG. In Escherichia coli, two DNA glycosylases have been identified to suppress these mutations. One is MutM, an 8-oxoguanine DNA glycosylase that removes 8-oxoG from 8-oxoG: C base pairs. The other is MutY, an adenine DNA glycosylase that excises adenine from 8-oxoG: A mismatches. Mammals also have such DNA glycosylases; OGG1 (Ogg1) is the functional counterpart of MutM, and MUTYH (Mutyh) is the MutY homologue. In order to investigate the roles of these two enzymes in the avoidance of 8-oxoG-related mutagenesis in mammals, we analyzed spontaneous mutagenesis in the small intestine of Ogg1-deficient (Ogg1-/-) and Ogg1-, Mutyh-double deficient (Ogg1-/-; Mutyh-/-) mice at the age of 4-5 weeks using the prokaryotic rpsL transgene as a reporter. The observed mutation frequency was 1.00 x 10(-5) in both wild type and Ogg1-/- mice, and 1.91 x 10(-5) in Ogg1-/-; Mutyh-/- mice, indicating that the overall spontaneous mutation frequency was increased in Ogg1-/-; Mutyh-/- mice, but not in Ogg1-/- mice. Analysis of the mutation spectrum revealed that the frequency of G: C to T: A transversions were significantly increased in both Ogg1-/- and Ogg1-/-; Mutyh-/- mice; a 5-fold increase in Ogg1-/- mice, and a 41-fold increase in Ogg1-/-; Mutyh-/- mice when compared with wild type mice. A previous study in our laboratory indicated that a defect in Mutyh caused a 4-fold increase in the frequency of G: C to T: A transversions in mice. Combined, these observations suggest that a cooperative function between Ogg1 and Mutyh exists to prevent 8-oxoG-related mutagenesis in mammals.
authors.affiliation: Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Isogawa
mesh_terms: D000818:Animals; D004249:DNA Damage / Q000235:genetics; D045647:DNA Glycosylases / Q000502:physiology*; D004261:DNA Replication / Q000235:genetics; D029968:Escherichia coli Proteins; D005260:Female; D016368:Frameshift Mutation / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D005787:Gene Frequency; D005838:Genotype; D006151:Guanosine / Q000031:analogs & derivatives* / Q000502:physiology / Q000633:toxicity; D007421:Intestine, Small; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis / Q000187:drug effects / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D000091243:Ribosomal Protein S9
chemical_list: D029968:Escherichia coli Proteins; D000091243:Ribosomal Protein S9; C000717190:RpsI protein, E coli; D006151:Guanosine; C046215:8-hydroxyguanosine; D045647:DNA Glycosylases; C483741:OGG1 protein, rat; C061738:mutY adenine glycosylase