MERIT Award Recipient: Anthony Pegg, Ph.D.
Persistence of Alkylated DNA in Carcinogeneis
Alkylating agents are of major importance in cancer. Many environmental carcinogens, including N-nitroso- compounds, are alkylating agents or are converted to them by metabolism. Secondly, the alkylating agents form an important class of therapeutically valuable anti-cancer drugs. Alkylating agents interact with DNA at a number of sites to produce adducts that cause cytotoxicity and mutations. One site of particular interest is the O6-position of guanine. DNA adducts at this position are highly mutagenic and also cause cytotoxicity. The DNA repair alkyltransferase proteins (AGT) that are the focus of these studies play a major role in protecting cells from the toxic effects of alkylating agents by removing these adducts. AGT is also a significant factor in the resistance of some established tumors to therapy with alkylating agents. AGT repairs DNA in a unique manner by transferring the alkyl group from the guanine O6-position to an acceptor site located in the AGT protein. This AGT activity provides resistance both to cell killing and to mutagenesis and the initiation of tumors. AGT acts alone to repair DNA but it is not an enzyme since the alkylated acceptor site is not regenerated and each AGT protein molecule can therefore act only once. Rapid repair of O6-alkylguanine is thus limited in extent to the number of available AGT molecules. Studies are being carried out on a number of aspects of AGT including its structure, substrate specificity and mechanism of action; the regulation of AGT content and activity; the fate of the inactive alkylated form of the protein; and the effect on AGT activity of human polymorphic variants. These results will be of great value in maximizing the potential of therapeutic alkylating agents and in designing procedures and screening methods to reduce the risks associated with exposure to environmental alkylating agents.