MGMT: Its role in cancer aetiology and cancer therapeutics

The DNA-repair protein O-6-alkylguanine DNA alkyltransferase (AGT) has a wide range of activity in normal tissues and its evolutionary conservation indicates a fundamental role in cell physiology and maintenance of the genome. Through removal of alkylating lesions at O6 of guanine, AGT protects against mutagenesis and malignant transformation. In tumours, AGT provides resistance to treatment with alkylating agents, unless expression is lost by methylation of the promoter of the gene encoding AGT - O-6-methylguanine-DNA-methyltransferase (MGMT) - or there is direct inhibition of AGT activity. When overexpressed in stem cells, MGMT serves as a drug-selection gene for gene therapy and protects normal tissues from the toxic effects of chemotherapy.