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

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.

Effects of base excision repair proteins on mutagenesis by 8-oxo-7,8-dihydroguanine (8-hydroxyguanine) paired with cytosine and adenine

“…The four DNA glycosylases each function in the suppression of mutations by 8-oxo-Gua in DNA. The overlapped recognition of 8-oxo-Gua could explain the fact that single knock-out mice deficient in OGG1, MUTYH, NTH1, and NEIL1 show few tumor phenotypes [57,[65][66][67][68][69][70][71]. In contrast, there is evidence to support the view that polymorphisms in these DNA glycosylases are associated with human carcinogenesis (reviewed in 72).…”

Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

“…While Ogg1 2/2 mice have been shown to accumulate 8-oxoG in liver [Klungland et al, 1999;Osterod et al, 2001], most studies have not demonstrated them to be prone to spontaneous tumor formation relative to WT controls [Klungland et al, 1999]. Similarly, a novel model of OGG1 deficiency also reported a significant increase in 8-oxoG lesions, associated with increased mutagenesis of a transgenic gpt gene [Minowa et al, 2000;Arai et al, 2002Arai et al, , 2003].…”

Mitochondrial involvement in neurodegenerative diseases

“…Despite the progress in characterizing ROS effects on lipids (resulting in peroxidation), proteins (resulting in SH-group oxidation and formation of carbonyls), and DNA (formation of 8-OH guanosine and of single and double strand breaks) (29,30), the particular impact of potential sites relevant for cellular superoxide and hydrogen peroxide generation in brain tissue is less clear. Within the respiratory chain complex I, the FMN moiety (31,32), iron-sulfur clusters (33,34), and semiquinones (35) have been suggested to be responsible for mitochondrial superoxide production.…”