Oxygen-induced DNA damage and its repair mechamism

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Oxygen radicals, which can be produced through normal cellular metabolism, are thought to play an important role in mutagenesis and tumorigenesis. Among various classes of oxidative DNA damage, 8-oxo-7,8-dihydroguanine (8-oxoG) is most important because of its abundance and mutagenicity.The MTH1 gene encodes an enzyme that hydrolyzes 8-oxo-dGTP to monophosphate in the nucleotide pool, thereby preventing occurrence of transversion mutations. By means of gene targeting, we have established MTH1 gene-knockout cell lines and mice. When examined 18 months after birth, a greater number of tumors were formed in the lungs, livers and stomachs of MTH1-deficient mice, as compared with wild-type mice. The MTH1-deficient mouse will provide a useful model for investigating the role of the MTH1 protein in normal conditions and under oxidative stress.Recent studies showed that the human MTH1 protein hydrolyzed 2-hydroxy-dATP more efficiently and with higher affinity than 8-oxo-dGTP.Current studies on mutagenesis with MTH1-null mutant mice will provide more insight into the role of the sanitizing enzyme, MTH1.We found a single nucleotide polymorphism in human MTH1 gene which alters splicing patterns of its transcripts, and that a novel MTH1 polypeptide with an additional mitochondrial targeting signal is produced from the altered MTH1 mRNA.We further characterized expression and intracellular localization of 8-oxoG DNA glycosylase (OGG1) and 2-OH-A/adenine DNA DNA glycosylase (MYH) in human cells. The authentic OGG1 and MYH proteins present in mitochondria as well as in nuclei, and their intracellular localization were found to be regulated by alternative splicing of each transcript.