Brd4 as a Prognostic Indicator and Modulator of the Cell Response to DNA Damage

Technology

Alterations in chromatin structure are known to be important for the initiation and propagation of the DNA damage response, although the molecular details are unclear. The inventors monitored multiple time dependent checkpoint signaling and response events with a high-content multiplex image-based RNAi screen of chromatin modifying and interacting genes and discovered that Brd4 inhibits DNA damage signaling by binding to acetylated histones at sites of open chromatin and altering chromatin accessibility. Brd4 knockdown cells displayed altered chromatin structure, prolonged cell cycle checkpoint arrest and enhanced survival after irradiation, while overexpression of Brd4 isoformB results in enhanced radiation induced lethality. Therefore, drugs that inhibit Brd4 bromodomain binding or mis-localize Brd4 can serve as a radio-protective agents while therapies that up-regulate Brd4 isoformB expression can be used to increase the sensitivity of tumor cells to DNA damaging treatments such as ionizing radiation and chemotherapy. Lastly, it was discovered that assaying the levels of Brd4 isoformB expression in glioblastoma, and potentially other cancers, can be specifically used to predict which patients will have a good response to radiation. 

Problem Addressed

DNA damage activates a complex signaling network in cells that blocks cell cycle progression, recruits factors involved in DNA repair, and/or triggers programs that control senescence or programmed cell death. Despite this signaling network’s critical role in cancer pathogenesis, it is not fully understood. While investigating the role of chromatin structure in DNA damage response, it was discovered that Brd4, a double bromodomain-containing protein, is an endogenous inhibitor of DNA damage signaling and may be used for cancer treatment.  

Advantages 

• Prognostic indicator of DNA damage therapy response
• Sensitize tumors to DNA damage treatment
• Protect healthy cells from DNA damage treatment through inhibition

Publications

Zuber, Johannes, Johannes Shi, Emilija Wang, Lukas Rappaport, Christopher Herrmann, Alejandro E. Arruda, Sean S. M. Littlewood, et al. "The Bromodomain Protein Brd4 Insulates Chromatin from DNA Damage Signaling." Nature 498, no. 7453 (June 13, 2013): 246-250.