O6-alkylguanine and O4-alkylthymine DNA adducts (O6-AG/O4-AT)

O6-alkylguanine and O4-alkylthymine DNA adducts are covalent modifications of DNA bases formed by the action of alkylating agents, such as temozolomide, dacarbazine, and nitrosoureas (Pegg, 2000, NIH). These adducts are highly cytotoxic and mutagenic; O6-methylguanine, for instance, frequently mispairs with thymine during replication, which triggers the mismatch repair (MMR) system and leads to double-strand breaks and apoptosis (Duckett et al., 1996, UNC). O4-alkylthymine adducts, though formed in smaller quantities, are also potent inducers of mutations and are repaired with varying efficiency by alkyltransferases (Pegg, 2000, NIH). The repair of these lesions is primarily mediated by the enzyme O6-methylguanine-DNA methyltransferase (MGMT), which removes the alkyl group in a stoichiometric, suicide reaction (Dolan, 1995, NIH). Because MGMT can confer resistance to alkylating chemotherapies, its expression levels and promoter methylation status are critical biomarkers for predicting treatment efficacy in cancers like glioblastoma (Hegi et al., 2005, NEJM). While these adducts are essential for the therapeutic effect of certain drugs, their mutagenic potential in non-cancerous cells also poses a risk for secondary malignancies and other toxicities (Pegg, 1990, Cancer Research).

Other names

O6-methylguanineO4-methylthymineO6-meGO4-meTAlkylated DNA basesO6-alkyl-GO4-alkyl-TO6-alkylguanine DNA lesions

Formation of cytotoxic and mutagenic DNA adducts that lead to base mispairing and trigger mismatch repair-mediated cell death.