Repair of oxidative DNA damage in Mammalian cells

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Endonuclease III, encoded by nth in Escherichia coli, removes thymine glycols, a toxic oxidative DNA lesion. To determine the biological significance of this repair in mammals, we established a mouse mutated in mNth1, a homologue of nth, by gene targeting. The homozygous mNth1 mutant mouse showed no detectable phenotypic abnormality so far analyzed. Embryonic cells with or without wild-type mNth1 showed no difference in sensitivity to menadione or hydrogen peroxide. Thymine glycols produced in the mutant mouse liver DNA by X-ray irradiation disappeared with time, though more slowly than in wild-type mouse. In extracts from mutant mouse liver, we found, instead of mNTH1 activity, at least two novel DNA glycosylase activities against thymine glycols. One activity is significantly higher in the mutant than in wild-type mouse in mitochondria, while the other is another nuclear glycosylase, for thymine glycols. These results underscore the importance of base excision repair of thymine glycols both in the nuclei and in the mitochondria in mammals.