O-6-methylguanine-DNA methyltransferase (MGMT)

O‑6‑methylguanine-DNA methyltransferase (MGMT) is a critical human DNA repair enzyme that protects cells from mutagenesis and cytotoxicity caused by alkylating agents. It acts by directly removing harmful alkyl groups—primarily at the O^6 position on guanine bases—from damaged DNA. This process occurs via transfer of the offending group onto an internal cysteine residue within the protein itself, which irreversibly inactivates each molecule after one reaction ("suicide" mechanism). Loss or epigenetic silencing (e.g., via promoter hypermethylation) leads to increased mutation rates but also enhances tumor cell sensitivity to certain chemotherapies like temozolomide. Conversely, high levels confer therapeutic resistance. The gene encoding this protein (MGMT) serves as both a prognostic and predictive biomarker—especially relevant in brain tumors such as glioblastoma—and remains an important focus for overcoming chemotherapy resistance mechanisms in oncology.

Other names

Methylated-DNA–protein-cysteine methyltransferaseO^6^-alkylguanine DNA alkyltransferaseAGT

Alkylating agents such as temozolomide induce cytotoxic lesions at the O6 position of guanine; MGMT repairs these lesions by transferring the methyl group from DNA to its own cysteine residue ("suicide" mechanism), thereby reversing drug-induced damage and conferring drug resistance. Inhibition or silencing of MGMT increases tumor sensitivity to these drugs.