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. Author manuscript; available in PMC: 2015 Jan 29.
Published in final edited form as: Chem Rev. 2013 Jun 24;113(11):8567–8582. doi: 10.1021/cr400120z

Fig. 4. Brd4 is a potent suppressor of Tat-transactivation and BET bromodomain inhibitor JQ1 efficiently antagonizes this suppressive effect.

Fig. 4

A. In the absence of JQ1, the promoter-bound Brd4 (through interacting with acetylated histones or Ac) competitively blocks the interaction between P-TEFb and Tat. Likewise, methylation of Tat by SETDB1 and PRMT6 also prevents this interaction. Meanwhile, most of cellular P-TEFb are sequestered in the inactive 7SK snRNP. All of these inhibit the ability of Tat to form on the HIV TAR RNA a functional SEC that is essential for activated viral transcription. B. JQ1 dissociates Brd4 from the HIV promoter and increases the local concentration of active P-TEFb for Tat to assemble into the SEC for efficient phosphorylation of the Pol II CTD, DSIF and NELF and activation of productive elongation. Additionally, JQ1 inhibits the expressions of SETDB1 and PRMT6 while promoting the production of SIRT1, which deacetylates Tat to enhance the Tat-P-TEFb interaction. Finally, JQ1 also disrupts the 7SK snRNP to release P-TEFb, providing another source of P-TEFb for SEC assembly at the HIV promoter.