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      DNA repair goes hip-hop: SMARCA and CHD chromatin remodellers join the break dance

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          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’.

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          Most cited references73

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          The biology of chromatin remodeling complexes.

          The packaging of chromosomal DNA by nucleosomes condenses and organizes the genome, but occludes many regulatory DNA elements. However, this constraint also allows nucleosomes and other chromatin components to actively participate in the regulation of transcription, chromosome segregation, DNA replication, and DNA repair. To enable dynamic access to packaged DNA and to tailor nucleosome composition in chromosomal regions, cells have evolved a set of specialized chromatin remodeling complexes (remodelers). Remodelers use the energy of ATP hydrolysis to move, destabilize, eject, or restructure nucleosomes. Here, we address many aspects of remodeler biology: their targeting, mechanism, regulation, shared and unique properties, and specialization for particular biological processes. We also address roles for remodelers in development, cancer, and human syndromes.
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            Somatic generation of antibody diversity.

            In the genome of a germ-line cell, the genetic information for an immunoglobulin polypeptide chain is contained in multiple gene segments scattered along a chromosome. During the development of bone marrow-derived lymphocytes, these gene segments are assembled by recombination which leads to the formation of a complete gene. In addition, mutations are somatically introduced at a high rate into the amino-terminal region. Both somatic recombination and mutation contribute greatly to an increase in the diversity of antibody synthesized by a single organism.
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              ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex.

              The ataxia-telangiectasia mutated (ATM) kinase signals the presence of DNA double-strand breaks in mammalian cells by phosphorylating proteins that initiate cell-cycle arrest, apoptosis, and DNA repair. We show that the Mre11-Rad50-Nbs1 (MRN) complex acts as a double-strand break sensor for ATM and recruits ATM to broken DNA molecules. Inactive ATM dimers were activated in vitro with DNA in the presence of MRN, leading to phosphorylation of the downstream cellular targets p53 and Chk2. ATM autophosphorylation was not required for monomerization of ATM by MRN. The unwinding of DNA ends by MRN was essential for ATM stimulation, which is consistent with the central role of single-stranded DNA as an evolutionarily conserved signal for DNA damage.
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                Author and article information

                Journal
                Philos Trans R Soc Lond B Biol Sci
                Philos. Trans. R. Soc. Lond., B, Biol. Sci
                RSTB
                royptb
                Philosophical Transactions of the Royal Society B: Biological Sciences
                The Royal Society
                0962-8436
                1471-2970
                5 October 2017
                28 August 2017
                28 August 2017
                : 372
                : 1731 , Theme issue ‘Chromatin modifiers and remodellers in DNA repair and signalling’ compiled and edited by Penelope A. Jeggo, Jessica A. Downs and Susan M. Gasser
                : 20160285
                Affiliations
                Department of Human Genetics, Leiden University Medical Center , Einthovenweg 20, 2333 ZC Leiden, The Netherlands
                Author notes
                Author information
                http://orcid.org/0000-0001-8590-0240
                Article
                rstb20160285
                10.1098/rstb.2016.0285
                5577463
                28847822
                f2da0a60-00c2-46b5-a086-a6c27a775072
                © 2017 The Authors.

                Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

                History
                : 7 April 2017
                Funding
                Funded by: H2020 European Research Council, http://dx.doi.org/10.13039/100010663;
                Award ID: 617485
                Categories
                1001
                15
                33
                197
                129
                Articles
                Review Article
                Custom metadata
                October 5, 2017

                Philosophy of science
                dna double-strand break (dsb),dsb signalling,dsb repair,chromatin remodellers,smarca,chd

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