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

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-diepoxybuta...

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Autores principales: Chesner, Lisa N., Degner, Amanda, Sangaraju, Dewakar, Yomtoubian, Shira, Wickramaratne, Susith, Malayappan, Bhaskar, Tretyakova, Natalia, Campbell, Colin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454995/
https://www.ncbi.nlm.nih.gov/pubmed/28524082
http://dx.doi.org/10.3390/ijms18051086
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author Chesner, Lisa N.
Degner, Amanda
Sangaraju, Dewakar
Yomtoubian, Shira
Wickramaratne, Susith
Malayappan, Bhaskar
Tretyakova, Natalia
Campbell, Colin
author_facet Chesner, Lisa N.
Degner, Amanda
Sangaraju, Dewakar
Yomtoubian, Shira
Wickramaratne, Susith
Malayappan, Bhaskar
Tretyakova, Natalia
Campbell, Colin
author_sort Chesner, Lisa N.
collection PubMed
description 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.
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spelling pubmed-54549952017-06-08 Cellular Repair of DNA–DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane Chesner, Lisa N. Degner, Amanda Sangaraju, Dewakar Yomtoubian, Shira Wickramaratne, Susith Malayappan, Bhaskar Tretyakova, Natalia Campbell, Colin Int J Mol Sci Article 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. MDPI 2017-05-18 /pmc/articles/PMC5454995/ /pubmed/28524082 http://dx.doi.org/10.3390/ijms18051086 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chesner, Lisa N.
Degner, Amanda
Sangaraju, Dewakar
Yomtoubian, Shira
Wickramaratne, Susith
Malayappan, Bhaskar
Tretyakova, Natalia
Campbell, Colin
Cellular Repair of DNA–DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane
title Cellular Repair of DNA–DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane
title_full Cellular Repair of DNA–DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane
title_fullStr Cellular Repair of DNA–DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane
title_full_unstemmed Cellular Repair of DNA–DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane
title_short Cellular Repair of DNA–DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane
title_sort cellular repair of dna–dna cross-links induced by 1,2,3,4-diepoxybutane
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454995/
https://www.ncbi.nlm.nih.gov/pubmed/28524082
http://dx.doi.org/10.3390/ijms18051086
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