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Fukuoka Igaku Zasshi. 2004 Jan;95(1):17-30.

Functional cooperation of Ogg1 and Mutyh in preventing G: C-->T: a transversions in mice.

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  • 1Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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.

PMID:
15031996
[PubMed - indexed for MEDLINE]
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