DNA-REPAIR METHYLTRANSFERASE AS A MOLECULAR DEVICE FOR PREVENTING MUTATION AND CANCER

Alkylation of DNA at the O-6 position of guanine is regarded as one of the most critical events leading to induction of mutations and cancer s in organisms. Once O-6-methylguanine is formed, it can pair with thy mine during DNA replication, the result being a conversion of the guan ine . cytosine to an adenine thymine pair in DNA, and such mutations a re often found in tumors induced by alkylating agents. To counteract s uch effects, organisms possess a mechanism to repair O-6-methylguanine in DNA. An enzyme, O-6-methylguanine-DNA methyltransferase, is presen t in various organisms, from bacteria to human cells, and appears to b e responsible for preventing the occurrence of such mutations. The enz yme transfers methyl groups from O-6-methylguanine and other methylate d moieties of the DNA to its own molecule, thereby repairing DNA lesio ns in a single-step reaction. To elucidate the role of methyltransfera se in preventing cancers, animal models with altered levels of enzyme activity were generated. Transgenic mice carrying the foreign methyltr ansferase gene with functional promoters had higher levels of methyltr ansferase 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 carcino gen.