Mitochondrial targeting of human 8-oxoguanine DNA glycosylase hOGG1 is impaired by a somatic mutation found in kidney cancer

Oxidative damage to mitochondrial DNA (mtDNA) has been implicated as a contributing factor to the origin of many pathological processes. Among the major DNA lesions generated by oxidative stress, 8-oxoguanine (8-oxoG) has a strong mutagenic potential. The main pathway for the repair of this lesion is the base excision repair (BER) initiated by the OGG1 DNA glycosylase. In human cells alternative splicing of the hOGG1 transcript yields two forms of the protein, alpha and beta, that are localised in the nucleus and the mitochondria, respectively. We describe here a hOGG1 somatic mutation, found in a kidney cancer, that modifies the intracellular localisation of beta-hOGG1. The glycine 12 to glutamic acid substitution does not affect the enzymatic activity of the enzyme but ties in what was predicted to be a mitochondrial targeting sequence (NITS). Immunocytochemical localisation experiments show that the G12E mutant protein has diffuse cytoplasmic distribution instead of the mitochondrial localisation found for the wild-type, providing an example of a single amino acid substitution capable of disrupting a MTS. These results imply that these cancer cells are deficient in their mitochondrial 8-oxoG DNA repair activity. (C) 2002 Elsevier Science B.V. All rights reserved.