title: The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.
abstract: DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Floyd
authors.forename: Michael E
authors.initials: ME
authors.lastname: Pacold
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Huang
authors.forename: Scott M
authors.initials: SM
authors.lastname: Clarke
authors.forename: Fred C
authors.initials: FC
authors.lastname: Lam
authors.forename: Ian G
authors.initials: IG
authors.lastname: Cannell
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Bryson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rameseder
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lee
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Blake
authors.forename: Anna
authors.initials: A
authors.lastname: Fydrych
authors.forename: Richard
authors.initials: R
authors.lastname: Ho
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Greenberger
authors.forename: Grace C
authors.initials: GC
authors.lastname: Chen
authors.forename: Amanda
authors.initials: A
authors.lastname: Maffa
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Del Rosario
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Anne E
authors.initials: AE
authors.lastname: Carpenter
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
authors.forename: Forest M
authors.initials: FM
authors.lastname: White
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yaffe
mesh_terms: D000107:Acetylation; D000251:Adenosine Triphosphatases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000528:radiation effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism* / Q000528:radiation effects; D042002:Chromatin Assembly and Disassembly / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000528:radiation effects; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects; D014157:Transcription Factors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D008239:Lysine; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D020033:Protein Isoforms; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C468783:H2AX protein, human; C108312:condensin complexes