The dual role of DNA repair protein MGMT in cancer prevention and treatment

Alkylating agents are genotoxic chemicals that can induce and treat various types of cancer. This occurs through covalent bonding with cellular macromolecules, in particular DNA, leading to the loss of functional integrity under the persistence of modifications upon replication. O6-alkylguanine (O6-AlkylG) adducts are proposed to be the most potent DNA lesions induced by alkylating agents. If not repaired correctly, these adducts can result, at the molecular level, in DNA point mutations, chromosome aberrations, recombination, crosslinking, and singleand double-strand breaks (SSB/DSBs). At the cellular level, these lesions can result in malignant transformation, senescence, or cell death. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein capable of removing the alkyl groups from O6-AlkylG adducts in a damage reversal process that can prevent the adverse biological effects of DNA damage caused by guanine O6-alkylation. MGMT can thereby defend normal cells against tumor initiation, however it can also protect tumor cells against the beneficial effects of chemotherapy. Hence, MGMT can play an important role in both the prevention and treatment of cancer; thus, it can be considered as a double-edged sword. From a clinical perspective, MGMT is a therapeutic target, and it is important to explore the rational development of its clinical exploitation.