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

TLDR

DNA damage from cellular oxidants, especially the mutagenic base lesion 8‑oxoG, is thought to drive cancer and aging, and eukaryotes rely on the OGG1 glycosylase to remove this lesion. The study aimed to determine whether loss of OGG1 impairs DNA repair and promotes carcinogenesis by creating homozygous ogg1‑/‑ null mice. The authors generated homozygous ogg1‑/‑ null mice to assess the enzyme’s role in DNA repair and cancer prevention. Despite accumulating high levels of 8‑oxoG, the ogg1‑/‑ mice remained viable, showed only a modest increase in spontaneous mutations, did not develop tumors or major pathology, and exhibited a slow in vivo removal of the lesion in proliferating cells, indicating an alternative repair pathway mitigates the mutagenic load.

Abstract

DNA damage generated by oxidant byproducts of cellular metabolism has been proposed as a key factor in cancer and aging. Oxygen free radicals cause predominantly 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 spontaneous G·C→T·A transversion mutations in repair-deficient bacterial and yeast cells. Eukaryotic cells use a specific DNA glycosylase, the product of the 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 generated homozygous ogg1 −/− null mice. These animals are viable but accumulate abnormal levels of 8-oxoG in their genomes. Despite this increase in potentially miscoding DNA lesions, OGG1-deficient mice exhibit only a moderately, but significantly, elevated spontaneous mutation rate in nonproliferative tissues, do not develop malignancies, and show no marked pathological changes. Extracts of ogg1 null mouse tissues cannot excise the damaged base, but there is significant slow removal in vivo from proliferating cells . These findings suggest that in the absence of the DNA glycosylase, and in apparent contrast to bacterial and yeast cells, an alternative repair pathway functions to minimize the effects of an increased load of 8-oxoG in the genome and maintain a low endogenous mutation frequency.