Oxygen-induced DNA Damage and its Repair Mechanisms

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8-Oxo-dGTP (8-oxo-7,8-dihydrodeoxyguanosine triphosphate) is a potent mutagenic substrate for DNA synthesis. The accumulation of 8-oxo-dGTP in the nucleotide pool induces G : C to T : A transversion as well as A : T to C : G transversion, and Escherichia coli cells possess mechanisms for preventing such mutations. The mutT gene product specifically hydrolyzes 8-oxo-dGTP to the monophosphate form while the mutM and the mutY gene products function to correct misincorporation of 8-oxo-guanine into DNA.From analyzes odf forward mutations incuced in cells lacking 8-oxo-dGTPase (MutT protein) and/or repair enzymes that suppress mutations caused by 8-oxo-guanine in DNA (MutM and MutY proteins), cooperative functions of these proteins in control of the spontqneous mutagenesis became evident. In mutator strains lacking MutT and/or MutM proteins, 8-oxo-duanine of DNA increased to a concentration expected from the increased rate of mutaion.Human cells contain enzyme activity that hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP,therby preventing occurence of mutations, caused by misincorporation. When the cDNA for human 8-oxo-dGTPase was expressed in E.coli mutT^- mutant cells devoid of self 8-oxo-dGTPase activity, the elevated level of spontaneous A : T to C : G mutastion frequency reverted to normal. We isolated the genomic sequence encoding the enzyme and named the gene MTH1 (for mutT human homologue). This gene is composed of at least 4 exons, spans approximately 9 kb, and is located on human chromosome 7p22.