The bromodomain protein Brd4 insulates chromatin from DNA damage signalling
Program in Systems Biology
Acetylation; Adenosine Triphosphatases; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Chromatin; *Chromatin Assembly and Disassembly; *DNA Damage; DNA Repair; DNA-Binding Proteins; Histones; Humans; Lysine; Multiprotein Complexes; Nuclear Proteins; Phosphorylation; Positive Transcriptional Elongation Factor B; Protein Isoforms; Radiation, Ionizing; *Signal Transduction; Transcription Factors
Biochemistry | Cell Biology | Computational Biology | Molecular Biology | Molecular Genetics | Systems Biology
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.
DNA damage response, Chromatin remodelling, Checkpoint signalling
DOI of Published Version
Floyd SR, Pacold ME, Huang Q, Clarke SM, Lam FC, Cannell IG, Bryson BD, Rameseder J, Lee MJ, Blake EJ, Fydrych A, Ho R, Greenberger BA, Chen GC, Maffa A, Del Rosario AM, Root DE, Carpenter AE, Hahn WC, Sabatini DM, Chen CC, White FM, Bradner JE, Yaffe MB. The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature. 2013 Jun 13;498(7453):246-50. doi: 10.1038/nature12147. Link to article on publisher's site
Floyd, Scott R.; Pacold, Michael E.; Huang, Qiuying; Clarke, Scott M.; Lam, Fred C.; Cannell, Ian G.; Bryson, Bryan D.; Rameseder, Jonathan; Lee, Michael J.; Blake, Emily J.; Fydrych, Anna; Ho, Richard; Greenberger, Benjamin A.; Chen, Grace C.; Maffa, Amanda; Del Rosario, Amanda M.; Root, David E.; Carpenter, Anne E.; Hahn, William C.; Sabatini, David M.; Chen, Clark C.; White, Forest M.; Bradner, James E.; and Yaffe, Michael B., "The bromodomain protein Brd4 insulates chromatin from DNA damage signalling" (2013). Program in Systems Biology Publications and Presentations. 38.