The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.

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2013-06-13

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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.

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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

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https://hdl.handle.net/10161/15937

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10.1038/nature12147

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Floyd, Scott R, Michael E Pacold, Qiuying Huang, Scott M Clarke, Fred C Lam, Ian G Cannell, Bryan D Bryson, Jonathan Rameseder, et al. (2013). The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature, 498(7453). pp. 246–250. 10.1038/nature12147 Retrieved from https://hdl.handle.net/10161/15937.

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Floyd

Scott Richard Floyd

Gary Hock and Lyn Proctor Associate Professor of Radiation Oncology

Diseases of the brain carry particular morbidity and mortality, given the fundamental function of the brain for human life and quality of life. Disease of the brain are also particularly difficult to study, given the complexity of the brain. Model systems that capture this complexity, but still allow for experiments to test therapies and mechanisms of disease are badly needed.  We have developed an experimental model system that uses slices made from rat and mouse brains to create a test platform to research new treatments for brain diseases such as stroke, Alzheimer's disease, Huntington's disease and brain tumors. This model system reduces the number of experimental animals used, and streamlines experiments so that final testing in laboratory animals is more efficient. We use this brainslice system and limited numbers of experimental animals to test drugs and genetic pathways to treat stroke, Alzheimer's disease, Huntington's disease and brain tumors. As many brain tumors are treated with radiation therapy, we have a particular interest in the cellular response to DNA damage caused by radiation. DNA damage signaling and repair are fundamental processes necessary for cells to maintain genomic integrity. Problems with these processes can lead to cancer. As many cancer cells have altered DNA damage and repair pathways, we can apply DNA damage as cancer therapy. Our knowledge of how normal and neoplastic cells handle DNA damage is still incomplete. A deeper understanding can lead to improved cancer treatment, and to better protection from the harmful effects of DNA damaging agents like radiation. To this end, we plan experiments that test the effects of radiation on normal animal tissues and animal models of cancer, as well as molecular pathways in brain diseases such as Alzheimer’s, Huntington’s and stroke.

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