Oncotarget

Research Papers:

The Cockayne syndrome protein B is involved in the repair of 5-AZA-2′-deoxycytidine-induced DNA lesions

Estefanía Burgos-Morón, José Manuel Calderón-Montaño, Nuria Pastor, Andreas Höglund, Ángel Ruiz-Castizo, Inmaculada Domínguez, Miguel López- Lázaro, Nabil Hajji, Thomas Helleday, Santiago Mateos and Manuel Luis Orta _

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Oncotarget. 2018; 9:35069-35084. https://doi.org/10.18632/oncotarget.26189

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Abstract

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

Correspondence to:

Manuel Luis Orta, email: morta2@us.es

Keywords: CSB; 5-azadC; DNMT1; DNA damage; transcription

Received: March 02, 2018    Accepted: September 10, 2018    Published: October 12, 2018

ABSTRACT

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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