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Alkylated S-Cysteine MGMT Adducts As Biomarkers of Mutagenic Agents in the Colon
Project Code: N12008
Povey, A ; Cooper, D; Lees, N; Margison, G
Promoter methylation of the DNA repair protein, MGMT, is associated with K-ras GC ®AT transition mutations in colorectal cancer implicating alkylating agent exposure as a key aetiological factor in this mutagenic event. As alkyl groups of O6-alkylguanines are specifically transferred to a cysteine acceptor group (position 145) in MGMT, the measurement of these alkylated S-cysteine residues will provide a direct record of mutagen exposure. In this pilot study, alkylated S-cysteine MGMT standards will be synthesised and adducts detected by mass spectroscopic analysis of intact MGMT and enzymatically released peptides. To demonstrate the feasibility of this approach, alkylated S-cysteine residues will be measured in tissues obtained from animals treated with alkylating agents and from human colorectal tissues. This new approach will enable the rapid and cost-effective identification of those genotoxic agents that cause MGMT-repairable DNA alkylation and lead to a better understanding of dietary factors that determining colorectal cancer susceptibility.
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