MGMT: its role in cancer aetiology and cancer therapeutics

The DNA-repair protein O6-alkylguanine-DNA-alkyltransferase (AGT) is encoded by the gene O6-methylguanine-DNA-methyltransferase (MGMT).AGT removes alkylating lesions at position O6 of guanine and therefore has an important role in maintaining normal cell physiology and genomic stability.A broad range of expression of AGT is noted across tumours and normal tissues. Its expression also helps to prevent carcinogenesis and is a target for chemotherapy.Overexpression of MGMT reduces the risk of carcinogenesis and the risk of mutations after exposure to methylating agents.Loss of MGMT is associated with increased carcinogenic risk and increased sensitivity to methylating agents.MGMT-promoter methylation shuts off MGMT expression in tumours and increases responsiveness to chemotherapy.O6-benzylguanine is a specific inhibitor of AGT, but mutations in the active-site pocket of the protein can cause resistance to the drug.MGMT genes with such mutations are effective for use in gene therapy for transducing drug resistance into haematopoietic stem cells, to protect these cells from the toxic effects of chemotherapy.The physiological role of MGMT remains an area of active investigation.