Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase

Oxygen radicals, which can be produced through normal cellular metabolism, are thought to play an important role in mutagenesis and tumorigenesis. Amo ng various classes of oxidative DNA damage, 8-oxo-7,8-dihydroguanine (8-oxo G) is most important because of its abundance and mutagenicity. The MTH1 ge ne encodes an enzyme that hydrolyzes 8-oxo-dGTP to monophosphate in the nuc leotide pool, thereby preventing occurrence of transversion mutations. By m eans of gene targeting, we have established MTH1 gene-knockout cell lines a nd mice. When examined 18 months after birth, a greater number of tumors we re formed in the lungs, livers, and stomachs of MTH1-deficient mice, as com pared with wild-type mice. The MTH1-deficient mouse will provide a useful m odel for investigating the role of the MTH1 protein in normal conditions an d under oxidative stress.