| Effect of CpG methylation at different sequence context on acrolein- and BPDE-DNA binding and mutagenesis. | |
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MedLine Citation:
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PMID: 23042304 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-10-06 |
Journal Detail:
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Title: Carcinogenesis Volume: 34 ISSN: 1460-2180 ISO Abbreviation: Carcinogenesis Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-01-03 Completed Date: 2013-02-25 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 8008055 Medline TA: Carcinogenesis Country: England |
Other Details:
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Languages: eng Pagination: 220-7 Citation Subset: IM |
Affiliation:
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Department of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo Park, New York 10987, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
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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:
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CA114541/CA/NCI NIH HHS; CA99007/CA/NCI NIH HHS; ES00260/ES/NIEHS NIH HHS; ES014641/ES/NIEHS NIH HHS; U01 CA086137/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA Adducts; 0/DNA Primers; 0/Mutagens; 0/benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; 107-02-8/Acrolein; 55097-80-8/7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; 9007-49-2/DNA |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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