O⁶-methylguanine-DNA methyltransferase (MGMT) (MGMT)

O⁶-methylguanine-DNA methyltransferase (MGMT) is a specialized DNA repair enzyme responsible for the direct reversal of O6-alkylguanine lesions, which are highly mutagenic and cytotoxic [1, 4]. By transferring the alkyl group from the DNA to its own internal cysteine residue, MGMT prevents DNA cross-linking and mismatch-induced apoptosis [3]. In the context of oncology, MGMT plays a dual role: it protects normal cells from the carcinogenic effects of alkylating agents but also confers resistance to alkylating chemotherapies such as temozolomide in tumor cells [2]. The expression of MGMT is frequently regulated by the methylation status of its gene promoter; epigenetic silencing via promoter methylation results in low MGMT levels and improved clinical response to chemotherapy [2, 4]. Therefore, MGMT is both a critical mediator of drug resistance and a primary predictive biomarker for treatment efficacy in high-grade gliomas [2]. Pharmacological inhibitors like O6-benzylguanine have been developed to deplete MGMT levels and sensitize tumors to alkylating agents, though they often increase systemic toxicity [3]. Understanding MGMT status is essential for personalized treatment planning in neuro-oncology [2].

Other names

Methylated-DNA--protein-cysteine methyltransferaseO6-alkylguanine-DNA alkyltransferaseAGTAGAT

MGMT acts as a suicide enzyme that removes alkyl groups from the O6 position of guanine by transferring them to a cysteine residue in its active site, leading to irreversible self-inactivation and degradation [1, 3].