Base excision repair of 8-hydroxyguanine protects DNA from endogenous oxidative stress

A particularly important stress for all cells is the one produced by reactive oxygen species (ROS) that are formed as a byproduct of endogenous metabolism or the exposure to environmental oxidizing agents. An oxidatively damaged guanine, 8-hydroxyguanine (8-OH-G), is abundantly produced in DNA exposed to ROS. The biological relevance of this kind of DNA damage has been unveiled by the study of two mutator genes in E, coli, fpg and mutY. Both genes code for DNA glycosylases that cooperate to prevent the mutagenic effects of 8-OH-G. Inactivation of any of those two genes leads to a spontaneous mutator phenotype characterized by the exclusive increase in G:C to T:A transversions. in the simple eukaryote Saccharomyces cerevisiae, the OGG1 gene encodes an 8-OH-G DNA glycosylase which is the functional homolog of the bacterial fpg gene product. Moreover, the inactivation of OGG1 in yeast creates a mutator phenotype that is also specific for the generation of G:C to T:A transversions. The presence of such system in mammals has been confirmed by the cloning of the OGG1 gene coding for a human homolog of the yeast enzyme. Human cells also possess a MutY homolog encoded by the MYH gene. Analysis of the human OGG1 gene and its transcripts in normal and tumoral tissues reveals alternative splicing, polymorphisms and somatic mutations. The aim of this review is to summarize recent findings dealing with the biochemical properties and the biological functions of 8-OH-G DNA glycosylases in bacterial, yeast, insect and mammalian cells. These results point to 8-OH-G as an endogenous source of mutations and to its likely involvement in the process of carcinogenesis. (C) Societe francaise de biochimie et biologie moleculaire / Elsevier, Paris.