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

Elisabeth M. Loecken, Surendra Dasari, Salisha Hill, David L. Tabb, F. Peter Guengerich

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 O6-alkylguanine alkyltransferase (AGT) enhances bis-electrophileinduced 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.

Original languageEnglish (US)
Pages (from-to)1069-1076
Number of pages8
JournalChemical Research in Toxicology
Volume22
Issue number6
DOIs
StatePublished - Jun 15 2009
Externally publishedYes

Fingerprint

Mutagenesis
Histones
DNA
Ethylene Dibromide
Alkyl and Aryl Transferases
Glyceraldehyde-3-Phosphate Dehydrogenases
Escherichia coli
erythritol anhydride
Proteins
DNA Adducts
Nuclear Proteins
Liver
Industry
Cells
Oxidation

ASJC Scopus subject areas

  • Toxicology

Cite this

The bis-electrophile diepoxybutane cross-links DNA to human histones but does not result in enhanced mutagenesis in recombinant systems. / Loecken, Elisabeth M.; Dasari, Surendra; Hill, Salisha; Tabb, David L.; Guengerich, F. Peter.

In: Chemical Research in Toxicology, Vol. 22, No. 6, 15.06.2009, p. 1069-1076.

Research output: Contribution to journalArticle

Loecken, Elisabeth M. ; Dasari, Surendra ; Hill, Salisha ; Tabb, David L. ; Guengerich, F. Peter. / The bis-electrophile diepoxybutane cross-links DNA to human histones but does not result in enhanced mutagenesis in recombinant systems. In: Chemical Research in Toxicology. 2009 ; Vol. 22, No. 6. pp. 1069-1076.
@article{467d1c95570a4844acfb4ee0d7938ee4,
title = "The bis-electrophile diepoxybutane cross-links DNA to human histones but does not result in enhanced mutagenesis in recombinant systems",
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 O6-alkylguanine alkyltransferase (AGT) enhances bis-electrophileinduced 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.",
author = "Loecken, {Elisabeth M.} and Surendra Dasari and Salisha Hill and Tabb, {David L.} and Guengerich, {F. Peter}",
year = "2009",
month = "6",
day = "15",
doi = "10.1021/tx900037u",
language = "English (US)",
volume = "22",
pages = "1069--1076",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "6",

}

TY - JOUR

T1 - The bis-electrophile diepoxybutane cross-links DNA to human histones but does not result in enhanced mutagenesis in recombinant systems

AU - Loecken, Elisabeth M.

AU - Dasari, Surendra

AU - Hill, Salisha

AU - Tabb, David L.

AU - Guengerich, F. Peter

PY - 2009/6/15

Y1 - 2009/6/15

N2 - 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 O6-alkylguanine alkyltransferase (AGT) enhances bis-electrophileinduced 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.

AB - 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 O6-alkylguanine alkyltransferase (AGT) enhances bis-electrophileinduced 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.

UR - http://www.scopus.com/inward/record.url?scp=67449113183&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67449113183&partnerID=8YFLogxK

U2 - 10.1021/tx900037u

DO - 10.1021/tx900037u

M3 - Article

VL - 22

SP - 1069

EP - 1076

JO - Chemical Research in Toxicology

JF - Chemical Research in Toxicology

SN - 0893-228X

IS - 6

ER -