Abstract
Oxygen radicals are produced through normal cellular metabolism, and formation of such radicals is enhanced further by ionizing radiation and by various chemicals. The oxygen radicals attack DNA and its precursor nucleotides, and consequently induce a various oxidized form of bases in DNA within normally growing cells. Among such modified bases, 8-oxo-7, 8-dihydroguanine (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, is a DNA glycosylase that excises adenine and 2-OH-A incorporated opposite guanine or 8-oxoG, thus expected to prevent G:C to T:A transversions in mammalian cells. To analyze mutagenesis in the mice, we constructed the Mutyh-deficient mice carrying the rpsL transgene as a mutation-reporter, and analyzed the mutation frequencies and spectra in Mutyh-deficient and wild type mice at the age of 24 weeks. Overall mutation frequencies observed in small intestines were not significantly different between the Mutyh-deficient and wild type mice. However, there are drastic differences between these two genotypes in class- and site-distributions of the rpsL- mutations recovered from the mice; an increase in the frequency of G:C to T:A transversions was evident in Mutyh-deficient mice. These results suggest the contribution of the Mutyh protein in counteracting the mutagenic oxidative lesions in DNA, such as 8-oxoG, and consequently in suppressing spontaneous tumorigenesis in the intestine.
