title: Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination.
abstract: How chromatin shapes pathways that promote genome-epigenome integrity in response to DNA damage is an issue of crucial importance. We report that human bromodomain (BRD)-containing proteins, the primary "readers" of acetylated chromatin, are vital for the DNA damage response (DDR). We discovered that more than one-third of all human BRD proteins change localization in response to DNA damage. We identified ZMYND8 (zinc finger and MYND [myeloid, Nervy, and DEAF-1] domain containing 8) as a novel DDR factor that recruits the nucleosome remodeling and histone deacetylation (NuRD) complex to damaged chromatin. Our data define a transcription-associated DDR pathway mediated by ZMYND8 and the NuRD complex that targets DNA damage, including when it occurs within transcriptionally active chromatin, to repress transcription and promote repair by homologous recombination. Thus, our data identify human BRD proteins as key chromatin modulators of the DDR and provide novel insights into how DNA damage within actively transcribed regions requires chromatin-binding proteins to orchestrate the appropriate response in concordance with the damage-associated chromatin context.
authors.affiliation: Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA;
authors.forename: Fade
authors.initials: F
authors.lastname: Gong
authors.affiliation: Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA;
authors.forename: Li-Ya
authors.initials: LY
authors.lastname: Chiu
authors.affiliation: Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA;
authors.forename: Ben
authors.initials: B
authors.lastname: Cox
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Université de Toulouse/Université Paul Sabatier, 31062 Toulouse, France. Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Centre National de la Recherche Scientifique (CNRS), 31062 Toulouse, France.
authors.forename: François
authors.initials: F
authors.lastname: Aymard
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Université de Toulouse/Université Paul Sabatier, 31062 Toulouse, France. Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Centre National de la Recherche Scientifique (CNRS), 31062 Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clouaire
authors.affiliation: Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA;
authors.forename: Justin W
authors.initials: JW
authors.lastname: Leung
authors.affiliation: Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Cammarata
authors.affiliation: Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA;
authors.forename: Mercedes
authors.initials: M
authors.lastname: Perez
authors.affiliation: Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA;
authors.forename: Poonam
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Brodbelt
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Université de Toulouse/Université Paul Sabatier, 31062 Toulouse, France. Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Centre National de la Recherche Scientifique (CNRS), 31062 Toulouse, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Legube
authors.affiliation: Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA; kyle.miller@austin.utexas.edu.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Miller
mesh_terms: D001324:Autoantigens / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D004249:DNA Damage; D005786:Gene Expression Regulation; D020868:Gene Silencing; D059765:Homologous Recombination / Q000235:genetics*; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport / Q000235:genetics; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
chemical_list: D001324:Autoantigens; C115323:CHD4 protein, human; D002843:Chromatin; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C000617312:ZMYND8 protein, human; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex
keywords: DNA damage; ZMYND8; bromodomain; chromatin; histone acetylation