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

Abstract

Alkylation of DNA at the 0(6) position of guanine is regarded as one o f the most critical events leading to induction of mutations and cancers in organisms. Once 0(6)-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 0(6)-methylguanine in DNA. An enzyme, 0(6)-methylguanine-DNA methyltransferase, is present in various organism, from bacteria to human cells, and appears to be responsible for preventing the occurrence of such mutations. The enzyme transfers methyl groups from 0(6)-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 methyltransferase 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.