Alkylation of DNA at the O6-position of guanine is one of the most critical events leading to induction of mutation as well as cancer. An enzyme, O6-methylguanine-DNA methyltransferase, is present in various organisms, from bacteria to human cells, and appears to be responsible for preventing the occurrence of such mutations. The enzyme transfers methyl groups from O6-methylguanine and other methylated moieties of the DNA to its own molecule, thereby repairing DNA lesions in a single-step reaction. To elucidate the role of methyltransferase in preventing cancer, animal models with altered levels of enzyme activity were generated. Transgenic mice carrying extra copies of the foreign methyltransferase gene showed a decreased susceptibility to alkylating carcinogens, with regard to tumor formation. By means of gene targeting, mouse lines defective in both alleles of the methyltransferase gene were established. Administration of metkylnitrosourea to these gene-targeted mice led to early death while normal mice treated in the same manner showed no untoward effects. Numerous tumors were formed in the gene-defective mice exposed to a low dose of methylnitrosourea, while none or only few tumors were induced in the methyltransferase-proficient mice. It seems apparent that the DNA repair methyltransferase plays an important role in lowering a risk of occurrence of cancer in organisms.
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