Endogenous cytosine methylation and the formation of carcinogen carcinogen-DNA adducts.
Nucleic Acids Symp Ser (Oxf)
; (52): 49-50, 2008.
Article
em En
| MEDLINE
| ID: mdl-18776247
ABSTRACT
All CG dinucleotides along exons 5-8 of the p53 tumor suppressor gene contain endogenous 5-methylcytosine ((Me)C, X = Me in Scheme 1). The same sites (e.g. p53 codons 157, 158, 245, 248, and 273) are mutational hotspots in smoking induced lung cancer, suggesting that methylated CG dinucleotides may be preferentially targeted by the reactive metabolites of tobacco carcinogens. We employed a stable isotope labeling HPLC-ESI-MS/MS approach to demonstrate that methylated CG dinucleotides of the p53 gene are the preferred binding sites for the diolepoxide metabolites of bay region polycyclic aromatic hydrocarbons, e.g. benzo[a]pyrene diol epoxide (BPDE). In contrast, cytosine methylation was protective against O(6)-guanine alkylation by tobacco tobacco-specific nitrosamines, e.g. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), To investigate the mechanisms behind these effects, a series of structural analogs of (Me)C were prepared, and their effects on reactivity of base the paired dG towards BPDE was examined. We found that the presence of the C-5 substituent on cytosine influences the reactivity of its partner guanine towards BPDE and modifies the stereoisomeric composition of the resulting N(2)-BPDE-dG adducts.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido
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Carcinógenos
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Genes p53
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Adutos de DNA
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Ilhas de CpG
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5-Metilcitosina
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Desoxiguanosina
Idioma:
En
Revista:
Nucleic Acids Symp Ser (Oxf)
Ano de publicação:
2008
Tipo de documento:
Article