DNA-repair methyltransferase as a molecular device for preventing mutation and cancer

Alkylation of DNA at the O⁶ position of guanine is regarded as one of the most critical events leading to induction of mutations and cancers in organisms. Once O⁶-methylguanine is formed, it can pair with thymine during DNA replication, the result being a conversion of the guanine·cytosine to an adenine·thymine pair in DNA, and such mutations are often found in tumors induced by alkylating agents. To counteract such effects, organisms possess a mechanism to repair O⁶-methylguanine in DNA. 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 cancers, animal models with altered levels of enzyme activity were generated. Transgenic mice carrying the foreign methyl-transferase gene with functional promoters had higher levels of methyltransferase activity and showed a decreased susceptibility to N-nitroso compounds in regard to liver carcinogenesis. Mouse lines deficient in the methyltransferase gene, which were established by gene targeting, exhibited an extraordinarily high sensitivity to an alkylating carcinogen.