1,3-Butadiene-Induced Adenine DNA Adducts Are Genotoxic but Only Weakly Mutagenic When Replicated in Escherichia Coli of Various Repair and Replication Backgrounds
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Author(s)
Seneviratne, Uthpala I.
Wu, Jie
Tretyakova, Natalia
Chang, Shiou-chi
Essigmann, John M
Date Issued
May 2017
Journal
Chemical Research in Toxicology
Publisher
American Chemical Society (ACS)
Citation
Chang, Shiou-chi et al. “1,3-Butadiene-Induced Adenine DNA Adducts Are Genotoxic but Only Weakly Mutagenic When Replicated in Escherichia Coli of Various Repair and Replication Backgrounds.” Chemical Research in Toxicology 30, 5 (April 2017): 1230–1239 © 2017 American Chemical Society
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Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1021/ACS.CHEMRESTOX.7B00064
