Abstract
Oxygen radicals are produced through normal cellular metabolism, and formation of such radicals is further enhanced by ionizing radiation and by various chemicals. Among various classes of oxidative DNA damage, 8-oxo-7,8-dihydroguanine (8-oxoG) is the most abundant, and appears to play important roles in mutagenesis and carcinogenesis. Enzymatic activities that may be responsible for preventing 8-oxoG-evoked mutations were identified in mammalian cells. We have focused on following the two enzymes. MTH1 (Mth1) protein is the mammalian counterpart of E. coli MutT protein, which hydrolyzes 8-oxo-dGTP to its monophosphate form in the nucleotide pool, thereby preventing the incorporation of the mutagenic substrate into DNA. On the other hand, MUTYH (Mutyh) protein, a counterpart of E. coli MutY protein, having adenine/2-hydroxyadenine DNA glycosylase activity, is expected to prevent G:C to T:A transversions, by excising adenine from G:A mismatches induced by 8-oxoG and 2-OH-A. To analyze the function of the mammalian Mth1 and Mutyh proteins in vivo, we established gene-knockout mice for these two enzymes by gene targeting, and investigated spontaneous tumorigenesis as well as mutagenesis. Here we discuss our recent progress on spontaneous and oxidative stress-induced mutagenesis with these mutant mouse lines.
