The Cockayne syndrome protein B is involved in the repair of 5-AZA-2′-deoxycytidine-induced DNA lesions
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Estefanía Burgos-Morón2,*, José Manuel Calderón-Montaño2,*, Nuria Pastor1, Andreas Höglund3,5, Ángel Ruiz-Castizo1, Inmaculada Domínguez1, Miguel López-Lázaro2, Nabil Hajji4, Thomas Helleday3, Santiago Mateos1 and Manuel Luis Orta1
1Department of Cell Biology, Faculty of Biology, University of Seville, 41012 Seville, Spain
2Department of Pharmacology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
3Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21 Stockholm, Sweden
4Department of Medicine, Division of Experimental Medicine, Centre for Pharmacology & Therapeutics, Toxicology Unit, Imperial College London, Hammersmith Campus, London, W12 0NN UK
5Present address: Sprint Bioscience AB, 141 57 Huddinge, Sweden
*The authors contributed equally to this work and should be regarded as joint First Authors
Manuel Luis Orta, email: email@example.com
Keywords: CSB; 5-azadC; DNMT1; DNA damage; transcription
Received: March 02, 2018 Accepted: September 10, 2018 Published: October 12, 2018
The Cockayne Syndrome Protein B (CSB) plays an essential role in Transcription-Coupled Nucleotide Excision Repair (TC-NER) by recruiting repair proteins once transcription is blocked with a DNA lesion. In fact, CSB-deficient cells are unable to recover from transcription-blocking DNA lesions. 5-Aza-2′-deoxycytidine (5-azadC) is a nucleoside analogue that covalently traps DNA methyltransferases (DNMTs) onto DNA. This anticancer drug has a double mechanism of action: it reverts aberrant hypermethylation in tumour-suppressor genes, and it induces DNA damage. We have recently reported that Homologous Recombination and XRCC1/PARP play an important role in the repair of 5-azadC-induced DNA damage. However, the mechanisms involved in the repair of the DNMT adducts induced by azadC remain poorly understood. In this paper, we show for the first time the importance of CSB in the repair of azadC-induced DNA lesions. We propose a model in which CSB initiates a signalling pathway to repair transcription blocks induced by incorporated 5-azadC. Indeed, CSB-deficient cells treated with 5-azadC show a delay in the repair of trapped DNMT1, increased levels of DNA damage and reduced survival.
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