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. Author manuscript; available in PMC: 2022 Dec 1.
Published in final edited form as: Pharmacol Ther. 2021 Jun 23;228:107922. doi: 10.1016/j.pharmthera.2021.107922

Figure 1. TMZ induced DNA damage repair.

Figure 1.

TMZ is hydrolyzed to its active metabolite, 3-methyl-(triazen-1-yl) imidazole-4-carboxamide (MTIC), and then splits into monomethyl diazonium ions and 5-aminoimidazole-4-carboxamide (AIC). TMZ causes methyl adducts specifically at the N1-methyladenine (N1meA) and N3-methylcytosine (N3meC) (2%); N7-methylguanine (N7-meG) (80%–85%); N3-methyladenine (N3-meA) or N3-methylguanine (N3-meG) (8%), and O6-methylguanine (O6-meG) (8%). ALKBH2 and ALKBH3 remove N1meA and N3meC, accompanying with oxidative decarboxylation of 2-oxoglutarate (α-ketoglutarate, αKG) to succinate (Suc). MGMT is responsible for repairing O6-meG lesions. MGMT transfers the methyl group from O6-meG to its cysteine residue, resulting in the methylation and degradation of itself. If O6-meG adducts fail to be removed by MGMT, it will mispair with thymine. O6-meG-T mismatches are recognized by MMR components MSH2 and MSH6. MMR components MLH1 and PMS2 further removes the thymine residue and leave the O6-meG adduct unrepaired. The futile repair cycles lead to the accumulation of DNA strand breaks and eventually apoptosis. N7-meG and N3-meA adducts account for about 80% of TMZ-induced DNA adducts. BER system efficiently fixes these lesions. MPG is responsible for the detection and removal of aberrantly N7-meG and N3-meA. APE recognizes the abasic site, cleaves the 5’ end of the DNA, and triggers PARP1 to undergo patch repair. Patch repair can be completed by DNA polymerase, DNA ligase III, and XRCC1 (short patch) or FEN1 and DNA ligase I (long patch).