Abstract

Proper signalling and repair of DNA double-strand breaks (DSB) is critical to prevent genome instability and diseases such as cancer. The packaging of DNA into chromatin, however, has evolved as a mere obstacle to these DSB responses. Posttranslational modifications and ATP-dependent chromatin remodelling help to overcome this barrier by modulating nucleosome structures and allow signalling and repair machineries access to DSBs in chromatin. Here we recap our current knowledge on how ATP-dependent SMARCA- and CHD-type chromatin remodellers alter chromatin structure during the signalling and repair of DSBs and discuss how their dysfunction impacts genome stability and human disease.This article is part of the themed issue ‘Chromatin modifiers and remodellers in DNA repair and signalling’.

Highlights

  • Our cells are exposed to various deleterious agents causing tens of thousands of lesions in the genome every day [1]

  • It has become clear that chromatin reorganization during the double-strand breaks (DSB) response is not a matter of switching chromatin from a ‘closed’ to ‘open’ state and vice versa

  • ATP-dependent chromatin remodellers induce chromatin structural changes that are crucial for these DSB responses

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Summary

Introduction

Our cells are exposed to various deleterious agents causing tens of thousands of lesions in the genome every day [1]. Of all the different DNA lesions that occur, DNA double-strand breaks (DSBs) are among the most toxic. If left unrepaired or repaired inaccurately, DSBs can lead to mutations and chromosomal translocations, thereby increasing predisposition to various human disorders such as cancer [2]. DSBs can be produced by exogenous sources such as ionizing radiation (IR) from cosmic radiation and medical treatments, or by chemical compounds such as bleomycin and cisplatin used in cancer chemotherapy. DSBs can be formed as by-products of intracellular metabolic activities producing reactive oxygen species (ROS), by the stalling and collapse of DNA replication forks and somatic recombination of antigen receptor loci [3,4,5]. Eukaryotic cells have evolved mechanisms collectively termed the DNA damage response (DDR) that detect, signal and repair DNA lesions such as DSBs to prevent genomic instability and human disease [2]

Detection and signalling of DNA double-strand breaks
Chromatin remodelling and the DNA doublestrand break response
The SMARCA class of chromatin remodellers
SMARCA2 and SMARCA4
SMARCA5
The CHD class of chromatin remodellers
15. Conclusion and future perspectives
19. Orthwein A et al 2015 A mechanism for the
22. Drane P et al 2017 TIRR regulates 53BP1 by
58. Luijsterburg MS et al 2016 PARP1 links
99. Gong F et al 2015 Screen identifies bromodomain
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