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 lies in what was predicted to be a mitochondrial targeting sequence (MTS). 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.
Audebert
Marc
M
Département de Radiobiologie et Radiopathologie, UMR217 CNRS/CEA, Commissariat à l'Energie Atomique, BP6, F-92265 Fontenay aux Roses, France.
Charbonnier
J Baptiste
JB
Boiteux
Serge
S
Radicella
J Pablo
JP
D002467:Cell Nucleus / Q000378:metabolism; D043382:DNA-Formamidopyrimidine Glycosylase; D006367:HeLa Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000648:ultrastructure; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D009699:N-Glycosyl Hydrolases / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000235:genetics*; D017422:Sequence Analysis, DNA
D021382:Protein Sorting Signals; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase