Excision repair of 8-oxoguanine in eukaryotes - The ogg1 proteins

7,8-Dihydro-8-oxoguanine (8-OxoG) is a major mutagenic lesion produced on DNA by the endogenous oxidative stress. In eukaryotes, this modified base can be removed by specific DNA glycosylases/AP lyases, the Ogg1 proteins. The OGG1 gene of Saccharomyces cerevisiae encodes a protein of 376 amino acids with a molecular mass of 43-kDa. The yOgg1 protein catalyses the excision of 8-OxoG and the nicking of DNA at AP sites using a beta-elimination reaction. The ogg1 mutant strains exhibit a mutator phenotype characterized by an exclusive increase in G/C to T/A transversions, attributed to unrepaired 8-OxoG in DNA. Using the yeast OGG1 sequence, two human cDNAs coding for proteins showing >30% identity with yOgg1 were identified. The predicted proteins have 345 and 424 amino acids and a molecular mass of 39- and 47-kDa, respectively. These two proteins, alpha-hOgg1 and beta-hOgg1, result from an alternative splicing of a single transcript. The alpha-hOgg1 protein has nuclear localization and is ubiquitously expressed in human tissues. Both, alpha-hOgg1 and beta-hOgg1, release 8-OxoG and nick DNA at AP sites. Moreover, when they are expressed in a bacterial fpg mutY mutant strain, they complement the mutator phenotype. The human OGG1 gene was localized to chromosome 3p25. The mouse Ogg1 gene was also identified and localized to chrosome 6E. The mOgg1 protein contains 345 amino acids and is 84% identical to alpha-hOgg1. In addition to hOgg1 proteins, human cells also possess a MutY homolog and possibly use nucleotide excision repair to excise 8-OxoG from DNA. The results show that repair enzymes involved in the excision of 8-OxoG are highly conserved in eukaryotes and suggest an important impact of oxidative DNA damage on the process of carcinogenesis.