1,3-Butadiene-Induced Adenine DNA Adducts Are Genotoxic but only Weakly Mutagenic When Replicated in Escherichia coli of Various Repair and Replication Backgrounds

Shiou Chi Chang, Uthpala I. Seneviratne, Jie Wu, Natalia Tretyakova, John M. Essigmann

Research output: Contribution to journalArticle

Abstract

The adverse effects of the human carcinogen 1,3-butadiene (BD) are believed to be mediated by its DNA-reactive metabolites such as 3,4-epoxybut-1-ene (EB) and 1,2,3,4-diepoxybutane (DEB). The specific DNA adducts responsible for toxic and mutagenic effects of BD, however, have yet to be identified. Recent in vitro polymerase bypass studies of BD-induced adenine (BD-dA) adducts show that DEB-induced N6,N6-DHB-dA (DHB = 2,3-dihydroxybutan-1,4-diyl) and 1,N6-γ-HMHP-dA (HMHP = 2-hydroxy-3-hydroxymethylpropan-1,3-diyl) adducts block replicative DNA polymerases but are bypassed by human polymerases η and κ, leading to point mutations and deletions. In contrast, EB-induced N6-HB-dA (HB = 2-hydroxy-3-buten-1-yl) does not block DNA synthesis and is nonmutagenic. In the present study, we employed a newly established in vivo lesion-induced mutagenesis/genotoxicity assay via next-generation sequencing to evaluate the in vivo biological consequences of S-N6-HB-dA, R,R-N6,N6-DHB-dA, S,S-N6,N6-DHB-dA, and R,S-1,N6-γ-HMHP-dA. In addition, the effects of AlkB-mediated direct reversal repair, MutM and MutY catalyzed base excision repair, and DinB translesion synthesis on the BD-dA adducts in bacterial cells were investigated. BD-dA adducts showed the expected inhibition of DNA replication in vivo but were not substantively mutagenic in any of the genetic environments investigated. This result is in contrast with previous in vitro observations and opens the possibility that E. coli repair and bypass systems other than the ones studied here are able to minimize the mutagenic properties of BD-dA adducts.

Original languageEnglish (US)
Pages (from-to)1230-1239
Number of pages10
JournalChemical Research in Toxicology
Volume30
Issue number5
DOIs
StatePublished - May 15 2017

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DNA Adducts
Adenine
Escherichia coli
DNA
In Vitro Techniques
Repair
Poisons
DNA-Directed DNA Polymerase
DNA Replication
Point Mutation
Mutagenesis
DNA Repair
Carcinogens
Frangula
Cerebellar Ataxia
Insulin Infusion Systems
MSH Release-Inhibiting Hormone
Beryllium

ASJC Scopus subject areas

  • Toxicology

MeSH PubMed subject areas

  • Journal Article

Cite this

1,3-Butadiene-Induced Adenine DNA Adducts Are Genotoxic but only Weakly Mutagenic When Replicated in Escherichia coli of Various Repair and Replication Backgrounds. / Chang, Shiou Chi; Seneviratne, Uthpala I.; Wu, Jie; Tretyakova, Natalia; Essigmann, John M.

In: Chemical Research in Toxicology, Vol. 30, No. 5, 15.05.2017, p. 1230-1239.

Research output: Contribution to journalArticle

Chang, Shiou Chi; Seneviratne, Uthpala I.; Wu, Jie; Tretyakova, Natalia; Essigmann, John M. / 1,3-Butadiene-Induced Adenine DNA Adducts Are Genotoxic but only Weakly Mutagenic When Replicated in Escherichia coli of Various Repair and Replication Backgrounds.

In: Chemical Research in Toxicology, Vol. 30, No. 5, 15.05.2017, p. 1230-1239.

Research output: Contribution to journalArticle

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abstract = "The adverse effects of the human carcinogen 1,3-butadiene (BD) are believed to be mediated by its DNA-reactive metabolites such as 3,4-epoxybut-1-ene (EB) and 1,2,3,4-diepoxybutane (DEB). The specific DNA adducts responsible for toxic and mutagenic effects of BD, however, have yet to be identified. Recent in vitro polymerase bypass studies of BD-induced adenine (BD-dA) adducts show that DEB-induced N6,N6-DHB-dA (DHB = 2,3-dihydroxybutan-1,4-diyl) and 1,N6-γ-HMHP-dA (HMHP = 2-hydroxy-3-hydroxymethylpropan-1,3-diyl) adducts block replicative DNA polymerases but are bypassed by human polymerases η and κ, leading to point mutations and deletions. In contrast, EB-induced N6-HB-dA (HB = 2-hydroxy-3-buten-1-yl) does not block DNA synthesis and is nonmutagenic. In the present study, we employed a newly established in vivo lesion-induced mutagenesis/genotoxicity assay via next-generation sequencing to evaluate the in vivo biological consequences of S-N6-HB-dA, R,R-N6,N6-DHB-dA, S,S-N6,N6-DHB-dA, and R,S-1,N6-γ-HMHP-dA. In addition, the effects of AlkB-mediated direct reversal repair, MutM and MutY catalyzed base excision repair, and DinB translesion synthesis on the BD-dA adducts in bacterial cells were investigated. BD-dA adducts showed the expected inhibition of DNA replication in vivo but were not substantively mutagenic in any of the genetic environments investigated. This result is in contrast with previous in vitro observations and opens the possibility that E. coli repair and bypass systems other than the ones studied here are able to minimize the mutagenic properties of BD-dA adducts.",
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T1 - 1,3-Butadiene-Induced Adenine DNA Adducts Are Genotoxic but only Weakly Mutagenic When Replicated in Escherichia coli of Various Repair and Replication Backgrounds

AU - Chang,Shiou Chi

AU - Seneviratne,Uthpala I.

AU - Wu,Jie

AU - Tretyakova,Natalia

AU - Essigmann,John M.

PY - 2017/5/15

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N2 - The adverse effects of the human carcinogen 1,3-butadiene (BD) are believed to be mediated by its DNA-reactive metabolites such as 3,4-epoxybut-1-ene (EB) and 1,2,3,4-diepoxybutane (DEB). The specific DNA adducts responsible for toxic and mutagenic effects of BD, however, have yet to be identified. Recent in vitro polymerase bypass studies of BD-induced adenine (BD-dA) adducts show that DEB-induced N6,N6-DHB-dA (DHB = 2,3-dihydroxybutan-1,4-diyl) and 1,N6-γ-HMHP-dA (HMHP = 2-hydroxy-3-hydroxymethylpropan-1,3-diyl) adducts block replicative DNA polymerases but are bypassed by human polymerases η and κ, leading to point mutations and deletions. In contrast, EB-induced N6-HB-dA (HB = 2-hydroxy-3-buten-1-yl) does not block DNA synthesis and is nonmutagenic. In the present study, we employed a newly established in vivo lesion-induced mutagenesis/genotoxicity assay via next-generation sequencing to evaluate the in vivo biological consequences of S-N6-HB-dA, R,R-N6,N6-DHB-dA, S,S-N6,N6-DHB-dA, and R,S-1,N6-γ-HMHP-dA. In addition, the effects of AlkB-mediated direct reversal repair, MutM and MutY catalyzed base excision repair, and DinB translesion synthesis on the BD-dA adducts in bacterial cells were investigated. BD-dA adducts showed the expected inhibition of DNA replication in vivo but were not substantively mutagenic in any of the genetic environments investigated. This result is in contrast with previous in vitro observations and opens the possibility that E. coli repair and bypass systems other than the ones studied here are able to minimize the mutagenic properties of BD-dA adducts.

AB - The adverse effects of the human carcinogen 1,3-butadiene (BD) are believed to be mediated by its DNA-reactive metabolites such as 3,4-epoxybut-1-ene (EB) and 1,2,3,4-diepoxybutane (DEB). The specific DNA adducts responsible for toxic and mutagenic effects of BD, however, have yet to be identified. Recent in vitro polymerase bypass studies of BD-induced adenine (BD-dA) adducts show that DEB-induced N6,N6-DHB-dA (DHB = 2,3-dihydroxybutan-1,4-diyl) and 1,N6-γ-HMHP-dA (HMHP = 2-hydroxy-3-hydroxymethylpropan-1,3-diyl) adducts block replicative DNA polymerases but are bypassed by human polymerases η and κ, leading to point mutations and deletions. In contrast, EB-induced N6-HB-dA (HB = 2-hydroxy-3-buten-1-yl) does not block DNA synthesis and is nonmutagenic. In the present study, we employed a newly established in vivo lesion-induced mutagenesis/genotoxicity assay via next-generation sequencing to evaluate the in vivo biological consequences of S-N6-HB-dA, R,R-N6,N6-DHB-dA, S,S-N6,N6-DHB-dA, and R,S-1,N6-γ-HMHP-dA. In addition, the effects of AlkB-mediated direct reversal repair, MutM and MutY catalyzed base excision repair, and DinB translesion synthesis on the BD-dA adducts in bacterial cells were investigated. BD-dA adducts showed the expected inhibition of DNA replication in vivo but were not substantively mutagenic in any of the genetic environments investigated. This result is in contrast with previous in vitro observations and opens the possibility that E. coli repair and bypass systems other than the ones studied here are able to minimize the mutagenic properties of BD-dA adducts.

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