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RESEARCH PRODUCT

DNA Repair and Damage Response Following Exposure of Cells to Alkylating Carcinogens

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Abstract Alkylating carcinogens are widely distributed in the environment and are present in food, beverages and tobacco. They are also endogenously formed in stomach and gut. These agents induce a dozen different DNA lesions, and some of them have been identified to be carcinogenic, clastogenic, recombinogenic and cytotoxic. A critical DNA adduct is O6-methylguanine (O6MeG). This damage causes mutations and is responsible for most of the carcinogenic effects of simple alkylating agents. At the same time, O6MeG is a highly powerful cytotoxic lesion, giving rise to the induction of apoptosis, necrosis and autophagy. The damage is repaired by the suicide enzyme alkyltransferase (MGMT), which is a very important first-line defense mechanism and biomarker of alkylating drug resistance, both in normal tissue and tumors (therefore it also plays a key role in tumor therapy). MGMT knockout mice respond to alkylating agent treatment with a high yield of colon cancer. The same is true for MPG ko mice defective in b...