The nitrosated bile acid DNA lesion O6-carboxymethylguanine is a substrate for the human DNA repair protein O6-methylguanine-DNA methyltransferase

Research output: Contribution to journalArticle

  • External 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

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 O 6-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 O 6-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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)3047-3055
Number of pages8
JournalNucleic acids research.
Volume41
Issue number5
DOIs
Publication statusPublished - Mar 2013