The Bromodomain Protein Brd4 Insulates Chromatin from DNA Damage Signaling

DNA damage activates a signaling network that blocks cell cycle progression, recruits DNA repair factors, and/or triggers senescence or programmed cell death.1 Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response (DDR).2 We further investigated the role of chromatin structure in the DDR by monitoring ionizing radiation-induced signaling and response events with a high-content multiplex RNAi screen of chromatin modifying and interacting genes. We discovered that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DDR signaling by recruiting the condensin II chromatin ¶Correspondence and requests for materials should be addressed to M.B.Y. (myaffe@mit.edu). Author Contributions S.R.F. and M.B.Y. designed the study, supervised the experiments, analysed the data, and wrote the manuscript. D.E.R., W.C.H., and D.M.S. were involved in the design and preparation of the lentiviral shRNA library. SRF, MEP, an