Regulatory mechanisms for mutagenesis and carcinogenesis

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Oxygen radicals, which can be produced through normal cellular metabolism, play important roles in mutagenesis and carcinogenesis. Among various classes of oxidative DNA damage, 8-oxoguanine (8-oxo-7,8-dihydroguanine) 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 monthe after birth, a greater number of tumors were formed in the lungs, livers and stomachs of MTH1-deficient mice. The MTH1-defient mice will provide a useful model for investigating the role of oxygen radicals in spontaneous carcinogenesis. We also found that the persistence of 8-oxoguanine in messenger RNA causes translational errors. To prevent this outcome, at least two gene products act in Escherichia coli cells. It is of interest to know if similar mechanisms function in mammalian cells.