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Lookup NU author(s): Dr Mauro Santibanez Koref
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The repair of specific types of DNA alkylation damage by O6 -alkylguanine-DNA alkyltransferase (MGMT) is a major mechanism of resistance to the carcinogenic and chemotherapeutic effects of certain alkylating agents. MGMT expression levels vary widely between individuals but the underlying causes of this variability are not known. To address this, we used an expressed single nucleotide polymorphism (SNP) and demonstrated that the MGMT alleles are frequently expressed at different levels in peripheral blood mononuclear cells (PBMC). This suggests that there is a genetic component of inter-allelic variation of MGMT levels that maps close to or within the MGMT locus. We then used quantitative trait locus (QTL) analysis using intragenic SNPs and found that there are at least two sites influencing inter-individual variation in PBMC MGMT activity. One is characterized by an SNP at the 3′ end of the first intron and the second by two SNPs in the last exon. The latter are in perfect disequilibrium and both result in amino acid substitutions - one of them, Ile143Val, affecting an amino acid close to the Cys145 residue at the active site of MGMT. Using in vitro assays, we further showed that while the Val143 variant did not affect the activity of the protein on methylated DNA substrate, it was more resistant to inactivation by the MGMT pseudosubstrate, O6-(4-bromothenyl)guanine. These findings suggest that further investigations of the potential epidemiological and clinical significance of inherited differences in MGMT expression and activity are warranted. © Oxford University Press 2005; All rights reserved.
Author(s): Margison GP, Heighway J, Pearson S, McGown G, Thorncroft MR, Watson AJ, Harrison KL, Lewis SJ, Rohde K, Barber PV, O'Donnell P, Povey AC, Santibanez-Koref MF
Publication type: Article
Publication status: Published
Journal: Carcinogenesis
Year: 2005
Volume: 26
Issue: 8
Pages: 1473-1480
Print publication date: 01/08/2005
ISSN (print): 0143-3334
ISSN (electronic): 1460-2180
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/carcin/bgi087
DOI: 10.1093/carcin/bgi087
PubMed id: 15831531
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