Metabolic fate of oxidized guanine ribonucleotides in mammalian cells

8-Oxo-7,8-dihydroguanine- (8-oxoguanine-) containing nucleotides are genera ted in the cellular nucleotide pool by the action of oxygen radicals produc ed during normal cellular metabolism. We examined the interconversion and m etabolic fate of 8-oxoguanine-containing ribonucleotides in mammalian cells . (1) 8-OxoGTP can be generated not only by direct oxidation of GTP but als o by phosphorylation of 8-oxoGDP by nucleotide diphosphate kinase, and the 8-oxoGTP thus formed can serve as a substrate for RNA polymerase II to indu ce transcription errors. (2) MTH1 protein carrying intrinsic 8-oxo-dGTPase activity has the potential to hydrolyze 8-oxoGTP to 8-oxoGMP, thus preventi ng misincorporation of 8-oxoguanine into RNA. 8-OxoGMP, the degradation pro duce, cannot be reutilized, since guanylate kinase, which has the potential to phosphorylate both GMP and dGMP, is inactive on 8-oxoGMP. (3) Ribonucle otide reductase, which catalyzes reduction of four naturally occurring ribo nucleoside diphosphates, cannot convert 8-oxoguanine-containing ribonucleot ide to the deoxyribonucleotide. This step appears to serve as a gatekeeper to prevent formation of mutagenic substrates for DNA synthesis from oxidize d ribonucleotides.