Cellular Repair of DNA–DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane
AbstractXenobiotic-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
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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.
Chesner LN, 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. International Journal of Molecular Sciences. 2017; 18(5):1086.Chicago/Turabian Style
Chesner, Lisa N.; Degner, Amanda; Sangaraju, Dewakar; Yomtoubian, Shira; Wickramaratne, Susith; Malayappan, Bhaskar; Tretyakova, Natalia; Campbell, Colin. 2017. "Cellular Repair of DNA–DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane." Int. J. Mol. Sci. 18, no. 5: 1086.
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