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Int. J. Mol. Sci. 2017, 18(5), 1086; doi:10.3390/ijms18051086

Cellular Repair of DNA–DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane

1
Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
2
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Mateus Webba da Silva
Received: 31 March 2017 / Revised: 4 May 2017 / Accepted: 11 May 2017 / Published: 18 May 2017
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

Xenobiotic-induced interstrand DNA–DNA cross-links (ICL) interfere with transcription and replication and can be converted to toxic DNA double strand breaks. In this work, we investigated cellular responses to 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) cross-links induced by 1,2,3,4-diepoxybutane (DEB). High pressure liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI+-MS/MS) assays were used to quantify the formation and repair of bis-N7G-BD cross-links in wild-type Chinese hamster lung fibroblasts (V79) and the corresponding isogenic clones V-H1 and V-H4, deficient in the XPD and FANCA genes, respectively. Both V-H1 and V-H4 cells exhibited enhanced sensitivity to DEB-induced cell death and elevated bis-N7G-BD cross-links. However, relatively modest increases of bis-N7G-BD adduct levels in V-H4 clones did not correlate with their hypersensitivity to DEB. Further, bis-N7G-BD levels were not elevated in DEB-treated human clones with defects in the XPA or FANCD2 genes. Comet assays and γ-H2AX focus analyses conducted with hamster cells revealed that ICL removal was associated with chromosomal double strand break formation, and that these breaks persisted in V-H4 cells as compared to control cells. Our findings suggest that ICL repair in cells with defects in the Fanconi anemia repair pathway is associated with aberrant re-joining of repair-induced double strand breaks, potentially resulting in lethal chromosome rearrangements. View Full-Text
Keywords: interstrand DNA-DNA crosslink; DNA repair; Fanconi anemia; nucleotide excision repair; homologous recombination; Chinese hamster lung fibroblast; 1,2,3,4-diepoxybutane; DNA double strand break interstrand DNA-DNA crosslink; DNA repair; Fanconi anemia; nucleotide excision repair; homologous recombination; Chinese hamster lung fibroblast; 1,2,3,4-diepoxybutane; DNA double strand break
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Chesner, L.N.; Degner, A.; Sangaraju, D.; Yomtoubian, S.; Wickramaratne, S.; Malayappan, B.; Tretyakova, N.; Campbell, C. Cellular Repair of DNA–DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane. Int. J. Mol. Sci. 2017, 18, 1086.

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