抄録
Reactive oxygen species attack DNA and its precursor nucleotides, and consequently induce various oxidized forms of bases in DNA within normally growing cells. Among such modified bases, 8-oxoguanine (8-oxoG) and 2-hydroxyadenine (2-OH-A) are highly mutagenic lesions, if not repaired, in DNA. MUTYH, a mammalian homolog of E. coli MutY protein, is a DNA glycosylase that excises adenine and 2-OH-A incorporated opposite guanine or 8-oxoG from DNA, thus expected to prevent G:C to T:A transversion mutation in mammalian cells. To investigate the role of the MUTYH gene in mutagenesis, we introduced the rpsL transgene to the MUTYH-null and wild-type mice by crossing. Using rpsL gene as a reporter, we compared the mutation frequencies and spectra between these two genotypes at the age of 24 weeks. The analysis of mutation spectra revealed that the frequency of G:C to T:A transversion was significantly increased in MUTYH-null mice compared to that of wild-type mice. This result suggests that MUTYH prevents occurrence of G:C to T:A transversion spontaneously induced by oxidative damage. Consistent with this notion, oral administration of KBrO3, an oxidizing reagent, to the mice resulted in a significant increased frequency of G:C to T:A transversion in MUTYH-null mice. Our observations indicate that MUTYH prevents mutagenesis caused by oxidative damage in mammals.
