The bis-electrophile diepoxybutane cross-links DNA to human histones but does not result in enhanced mutagenesis in recombinant systems.
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.
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Elisabeth M
EM
Loecken
Surendra
S
Dasari
Salisha
S
Hill
David L
DL
Tabb
F Peter
FP
Guengerich
D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000737:chemistry* / Q000633:toxicity; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004852:Epoxy Compounds / Q000737:chemistry* / Q000633:toxicity; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D016296:Mutagenesis; D009153:Mutagens / Q000737:chemistry* / Q000633:toxicity; D010446:Peptide Fragments / Q000032:analysis; D011994:Recombinant Proteins / Q000378:metabolism
D003432:Cross-Linking Reagents; D004852:Epoxy Compounds; D006657:Histones; D009153:Mutagens; D010446:Peptide Fragments; D011994:Recombinant Proteins; C007366:diepoxybutane; D004247:DNA; D019883:Alkyl and Aryl Transferases