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

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

doi:10.18632/oncotarget.26189

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.

Highlights

After millions of years of evolution, cells have evolved complex mechanisms to repair DNA breaks and prevent mutations
We recently reported that these bulky lesions can interfere with replication forks and induce double strand breaks (DSBs) that are repaired by Homologous Recombination (HR) involving Fanconi Anemia (FA) proteins (21)
We have recently reported that 5-azadC induces DNA damage that depends on active replication, which suggests that trapped DNA methyltransferases (DNMTs) collapses with oncoming replication forks into DSBs (21)

Summary

INTRODUCTION

After millions of years of evolution, cells have evolved complex mechanisms to repair DNA breaks and prevent mutations It has been known for many years that transcriptional stress plays an important role in genomic instability [1,2,3,4,5], it was in the mid-eighties when an additional DNA repair mechanism associated with transcriptionally active genes [6,7] was discovered. This specialized DNA repair processes, called Transcription-Coupled Repair (TCR), couples RNA polymerase blocks with the efficient removal of DNA lesions in the transcribed strand. We demonstrate that CSB and transcription act in the same pathway to repair 5-azadC-induced DNA lesions and promote survival

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS