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Title: The bis-electrophile diepoxybutane cross-links DNA to human histones but does not result in enhanced mutagenesis in recombinant systems.

Authors: Loecken, Elisabeth M; Dasari, Surendra; Hill, Salisha; Tabb, David L; Guengerich, F Peter

Published In Chem Res Toxicol, (2009 Jun)

Abstract: 1,2-Dibromoethane and 1,3-butadiene are cancer suspects present in the environment and have been used widely in industry. The mutagenic properties of 1,2-dibromoethane and the 1,3-butadiene oxidation product diepoxybutane are thought to be related to the bis-electrophilic character of these chemicals. The discovery that overexpression of O(6)-alkylguanine alkyltransferase (AGT) enhances bis-electrophile-induced mutagenesis prompted a search for other proteins that may act by a similar mechanism. A human liver screen for nuclear proteins that cross-link with DNA in the presence of 1,2-dibromoethane identified histones H2b and H3 as candidate proteins. Treatment of isolated histones H2b and H3 with diepoxybutane resulted in DNA-protein cross-links and produced protein adducts, and DNA-histone H2b cross-links were identified (immunochemically) in Escherichia coli cells expressing histone H2b. However, heterologous expression of histone H2b in E. coli failed to enhance bis-electrophile-induced mutagenesis. These results are similar to those found with the cross-link candidate glyceraldehyde 3-phosphate dehydrogenase (GAPDH) [ Loecken , E. M. and Guengerich , F. P. ( 2008 ) Chem. Res. Toxicol. 21 , 453 - 458 ], but in contrast to GAPDH, histone H2b bound DNA with even higher affinity than AGT. The extent of DNA cross-linking of isolated histone H2b was similar to that of AGT, suggesting that differences in postcross-linking events explain the difference in mutagenesis.

PubMed ID: 19364102 Exiting the NIEHS site

MeSH Terms: Alkyl and Aryl Transferases/metabolism; Cross-Linking Reagents/chemistry*; Cross-Linking Reagents/toxicity; DNA/chemistry*; DNA/metabolism; Epoxy Compounds/chemistry*; Epoxy Compounds/toxicity; Histones/chemistry*; Histones/metabolism; Humans; Mutagenesis; Mutagens/chemistry*; Mutagens/toxicity; Peptide Fragments/analysis; Recombinant Proteins/metabolism

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