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

Loecken EM, Dasari S, Hill S, Tabb DL, Guengerich FP
Chem Res Toxicol. 2009 22 (6): 1069-76

PMID: 19364102 · PMCID: PMC2696559 · DOI:10.1021/tx900037u

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.

MeSH Terms (10)

Alkyl and Aryl Transferases Cross-Linking Reagents DNA Epoxy Compounds Histones Humans Mutagenesis Mutagens Peptide Fragments Recombinant Proteins

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