Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage

DNA damage generated by oxidant byproducts of cellular metabolism has been proposed as a key factor in cancer and aging. Oxygen free radicals cause pr edominantly base damage in DNA, and the most frequent mutagenic base lesion is 7.8-dihydro-8-oxoguanine (8-oxoG). This altered base can pair with A as well as C residues, leading to a greatly increased frequency of spontaneou s C.C --> T.A transversion mutations in repair-deficient bacterial and yeas t cells. Eukaryotic cells use a specific DNA glycosylase. the product of th e OGG1 gene, to excise 8-oxoG from DNA. To assess the role of the mammalian enzyme in repair of DNA damage and prevention of carcinogenesis, we have g enerated homozygous ogg1(-/-) null mice. These animals are viable but accum ulate abnormal levels of 8-oxoG in their genomes, Despite this increase in potentially miscoding DNA lesions, OGG1-deficient mice exhibit only a moder ately, but significantly, elevated spontaneous mutation rate in nonprolifer ative tissues, do not develop malignancies, and show no marked pathological changes. Extracts of ogg1 null mouse tissues cannot excise the damaged bas e, but there is significant slow removal in vivo from proliferating cells. These findings suggest that in the absence of the DNA glycosylase, and in a pparent contrast to bacterial and yeast cells, an alternative repair pathwa y functions to minimize the effects of an increased load of 8-oxoG in the g enome and maintain a low endogenous mutation frequency.