O6-methylguanine DNA adduct (O6-MeG)

O6-methylguanine (O6-MeG) is a highly cytotoxic and mutagenic DNA adduct formed by the alkylation of the O6 position of guanine [5, 9]. It is the primary therapeutic lesion produced by methylating and chloroethylating chemotherapeutic agents, such as temozolomide and dacarbazine [3, 12]. Although it constitutes a minor percentage of total DNA alkylation, its biological impact is profound due to its tendency to mispair with thymine during DNA replication [11, 14]. This mispairing triggers the mismatch repair (MMR) pathway, which, in a futile attempt to correct the lesion, generates double-strand breaks that lead to cell cycle arrest and apoptosis [9, 12]. The persistence of O6-MeG is regulated by the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), which restores guanine by transferring the methyl group to itself [2, 11]. High levels of MGMT in tumors confer resistance to alkylating agents, making MGMT promoter methylation a critical predictive biomarker for treatment efficacy in cancers like glioblastoma [8, 13].

Other names

O6-MeGO6-methylguanineO6-alkylguanine DNA adductO6-MeG lesion

Induction of DNA damage through alkylation of the O6 position of guanine, leading to mismatch repair-mediated double-strand breaks and apoptosis.