Document Detail


Effect of CpG methylation at different sequence context on acrolein- and BPDE-DNA binding and mutagenesis.
MedLine Citation:
PMID:  23042304     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Acrolein (Acr), an α,β-unsaturated aldehyde, is abundant in tobacco smoke and cooking and exhaust fumes. Acr induces mutagenic α- and γ- hydroxy-1,N(2)-cyclic propano-deoxyguanosine adducts in normal human bronchial epithelial cells. Our earlier work has found that Acr-induced DNA damage preferentially occurs at lung cancer p53 mutational hotspots that contain CpG sites and that methylation at CpG sites enhances Acr-DNA binding at these sites. Based on these results, we hypothesized that this enhancement of Acr-DNA binding leads to p53 mutational hotspots in lung cancer. In this study, using a shuttle vector supF system, we tested this hypothesis by determining the effect of CpG methylation on Acr-DNA binding and the mutations in human lung fibroblasts. We found that CpG methylation enhances Acr-induced mutations significantly. Although CpG methylation enhances Acr-DNA binging at all CpG sites, it enhances mutations at selective--TCGA--sites. Similarly, we found that CpG methylation enhances benzo(a)pyrene diol epoxide binding at all -CpG- sites. However, the methylated CpG sequences in which benzo(a)pyrene diol epoxide-induced mutations are enhanced are different from the CpG sequences in which Acr-induced mutations are enhanced. CpG methylation greatly increases Acr-induced G to T and G to A mutation frequency to levels similar to these types of mutations found in the CpG sites in the p53 gene in tobacco smoke-related lung cancer. These results indicate that both CpG sequence context and the chemical nature of the carcinogens are crucial factors for determining the effect of CpG methylation on mutagenesis.
Authors:
Hsiang-Tsui Wang; Mao-wen Weng; Wen-chi Chen; Michael Yobin; Jishen Pan; Fung-Lung Chung; Xue-Ru Wu; William Rom; Moon-shong Tang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-06
Journal Detail:
Title:  Carcinogenesis     Volume:  34     ISSN:  1460-2180     ISO Abbreviation:  Carcinogenesis     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-03     Completed Date:  2013-02-25     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  England    
Other Details:
Languages:  eng     Pagination:  220-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / metabolism*
Acrolein / metabolism,  toxicity*
Base Sequence
Cells, Cultured
CpG Islands*
DNA / drug effects,  genetics
DNA Adducts / metabolism*
DNA Methylation*
DNA Primers
Humans
Molecular Sequence Data
Mutagens / metabolism,  toxicity*
Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
CA114541/CA/NCI NIH HHS; CA99007/CA/NCI NIH HHS; ES00260/ES/NIEHS NIH HHS; ES014641/ES/NIEHS NIH HHS; P30 CA016087/CA/NCI NIH HHS; U01 CA086137/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA Adducts; 0/DNA Primers; 0/Mutagens; 0/benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; 55097-80-8/7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; 7864XYD3JJ/Acrolein; 9007-49-2/DNA
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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