The Versatile Attributes of MGMT: Its Repair Mechanism, Crosstalk with Other DNA Repair Pathways, and Its Role in Cancer

Abstract

O6-methylguanine-DNA methyltransferase (MGMT or AGT) is a DNA repair protein with the capability to remove alkyl groups from O6-AlkylG adducts. Moreover, MGMT plays a crucial role in repairing DNA damage induced by methylating agents like temozolomide and chloroethylating agents such as carmustine, and thereby contributes to chemotherapeutic resistance when these agents are used. This review delves into the structural roles and repair mechanisms of MGMT, with emphasis on the potential structural and functional roles of the N-terminal domain of MGMT. It also explores the development of cancer therapeutic strategies that target MGMT. Finally, it discusses the intriguing crosstalk between MGMT and other DNA repair pathways.

MGMT ProFWise: Unlocking a New Application for Combined Feature Selection and the Rank-Based Weighting Method to Link MGMT Methylation Status to Serum Protein Expression in Patients with Glioblastoma

“…The improvement in outcomes observed in MGMT promoter methylated patients has been attributed to its role as a repair enzyme and its activity in relationship to the administration of TMZ, specifically for GBM [13]. However, its action in direct DNA repair, which constitutes less than 10% of the damage inflicted by TMZ [14,38], as well as its relevance to the presence of RT alone [39] and to other malignancies, and in the prevention of cancer development [40] suggest a broader role of the MGMT promoter. Further, the outcome is linked to several facets, including methylation patterns of CpGs associated with prognosis [41].…”

The interplay mechanism between IDH mutation, MGMT-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory

“…Although the sensitivity of MGMT -methylated tumors to chemotherapeutic agents varies, MGMT -promoter is considered the most relevant for the action of TMZ [ 13 , 14 ]. Its relationship with G4 astrocytoma treatment modalities and clinical outcomes showed provocative results [ 15 ].…”

“…The effect of IDH products on the MGM- promoter and PRMT5 was rarely investigated. MGMT , which is a DNA repair protein that removes alkyl groups from several residues, particularly the O6-position of guanine, is considered the most relevant for the action of TMZ [ 13 , 14 ]. The relationship between MGMT- promotor methylation and IDH mutation with treatment modalities and survival rates also showed controversial results [ 15 ].…”

Prospects of marine-derived compounds as potential therapeutic agents for glioma

“…However, TMZ treatment faces challenges due to factors such as the BBB, tumour heterogeneity, GSCs, drug efflux pumps, DNA damage repair mechanisms, and high expression of the MGMT gene, all of which contribute to resistance to TMZ therapy (Angom et al. 2023 ; Fang 2024 ). Compounds derived from marine sources exhibit various origins and mechanisms, inhibiting glioma cell growth and migration through various means, such as inducing multiple modes of cell death and regulating immune cell activity.…”