Michael B. Yaffe, Ph.D.
Massachusetts Institute of Technology
NIEHS Grant R01ES015339
Researchers supported in part by the NIEHS, report evidence that an isoform of the bromodomain protein Brd4 can modulate the signaling response to DNA damage by insulating chromatin.
When DNA damage occurs, a network of signals directs various responses such as stopping the progression of the cell cycle, recruiting factors needed for DNA repair and/or prompting programmed cell death. Problems with the cell’s response to DNA damage can lead to tumor growth. The researchers studied the signaling and response of cells exposed to ionizing radiation damage, finding that Brd4 isoform b inhibited DNA damage response signaling. In cells with non-functioning Brd4 isoform b, the researchers observed a more relaxed chromatin structure and improved survival after irradiation.
Cells with functional Brd4 isoform b had more compact chromatin, lessened DNA damage response signaling, and enhanced radiation-induced lethality. From these findings the researchers conclude that Brd4 facilitates structural changes in chromatin that lessen the DNA signaling response to ionizing radiation.
Citation: 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. 2013. The bromodomain protein Brd4 insulates chromatin from DNA damage signaling. Nature. 498(7453):246-250.