Pattama SenthongChristopher L. MillingtonOliver J. WilkinsonAndrew S. MarriottAmanda J. WatsonOnrapak ReamtongClaire E. EyersDavid M. WilliamsGeoffrey P. MargisonAndrew C. PoveyUniversity of ManchesterKrebs InstitutePaterson Institute for Cancer ResearchManchester Institute of BiotechnologyInstitute Génétique et Dévelopement de RennesUniversity of SussexUniversity of LiverpoolMahidol University2018-10-192018-10-192013-03-01Nucleic Acids Research. Vol.41, No.5 (2013), 3047-305513624962030510482-s2.0-84876378991https://repository.li.mahidol.ac.th/handle/20.500.14594/31363The consumption of red meat is a risk factor in human colorectal cancer (CRC). One hypothesis is that red meat facilitates the nitrosation of bile acid conjugates and amino acids, which rapidly convert to DNA-damaging carcinogens. Indeed, the toxic and mutagenic DNA adduct O6-carboxymethylguanine (O6-CMG) is frequently present in human DNA, increases in abundance in people with high levels of dietary red meat and may therefore be a causative factor in CRC. Previous reports suggested that O6-CMG is not a substrate for the human version of the DNA damage reversal protein O6-methylguanine-DNA methyltransferase (MGMT), which protects against the genotoxic effects of other O6-alkylguanine lesions by removing alkyl groups from the O6-position. We now show that synthetic oligodeoxyribonucleotides containing the known MGMT substrate O6-methylguanine (O6-MeG) or O6-CMG effectively inactivate MGMT in vitro (IC50 0.93 and 1.8 nM, respectively). Inactivation involves the removal of the O6-alkyl group and its transfer to the active-site cysteine residue of MGMT. O6-CMG is therefore an MGMT substrate, and hence MGMT is likely to be a protective factor in CRC under conditions where O6-CMG is a potential causative agent. © The Author(s) 2013.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1093/nar/gks1476