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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/31363
Title: The nitrosated bile acid DNA lesion O<sup>6</sup>-carboxymethylguanine is a substrate for the human DNA repair protein O<sup>6</sup>-methylguanine-DNA methyltransferase
Authors: Pattama Senthong
Christopher L. Millington
Oliver J. Wilkinson
Andrew S. Marriott
Amanda J. Watson
Onrapak Reamtong
Claire E. Eyers
David M. Williams
Geoffrey P. Margison
Andrew C. Povey
University of Manchester
Krebs Institute
Paterson Institute for Cancer Research
Manchester Institute of Biotechnology
Institute Génétique et Dévelopement de Rennes
University of Sussex
University of Liverpool
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Mar-2013
Citation: Nucleic Acids Research. Vol.41, No.5 (2013), 3047-3055
Abstract: The 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.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84876378991&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/31363
ISSN: 13624962
03051048
Appears in Collections:Scopus 2011-2015

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