McNamara Ryan P, McCann Jennifer L, Gudipaty Swapna Aravind, D'Orso Iván
Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9048, USA.
Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9048, USA.
Cell Rep. 2013 Dec 12;5(5):1256-68. doi: 10.1016/j.celrep.2013.11.003. Epub 2013 Dec 5.
The transition from transcription initiation into elongation is controlled by transcription factors, which recruit positive transcription elongation factor b (P-TEFb) to promoters to phosphorylate RNA polymerase II. A fraction of P-TEFb is recruited as part of the inhibitory 7SK small nuclear ribonucleoprotein particle (snRNP), which inactivates the kinase and prevents elongation. However, it is unclear how P-TEFb is captured from the promoter-bound 7SK snRNP to activate elongation. Here, we describe a mechanism by which transcription factors mediate the enzymatic release of P-TEFb from the 7SK snRNP at promoters to trigger activation in a gene-specific manner. We demonstrate that Tat recruits PPM1G/PP2Cγ to locally disassemble P-TEFb from the 7SK snRNP at the HIV promoter via dephosphorylation of the kinase T loop. Similar to Tat, nuclear factor (NF)-κB recruits PPM1G in a stimulus-dependent manner to activate elongation at inflammatory-responsive genes. Recruitment of PPM1G to promoter-assembled 7SK snRNP provides a paradigm for rapid gene activation through transcriptional pause release.
从转录起始到延伸的转变由转录因子控制，这些转录因子将正性转录延伸因子b（P-TEFb）募集到启动子上，使RNA聚合酶II磷酸化。一部分P-TEFb作为抑制性7SK小核核糖核蛋白颗粒（snRNP）的一部分被募集，该颗粒使激酶失活并阻止延伸。然而，尚不清楚P-TEFb如何从与启动子结合的7SK snRNP中被捕获以激活延伸。在这里，我们描述了一种机制，通过该机制转录因子介导P-TEFb在启动子处从7SK snRNP上酶促释放，以基因特异性方式触发激活。我们证明，Tat通过激酶T环的去磷酸化将PPM1G/PP2Cγ募集到HIV启动子处，使P-TEFb从7SK snRNP上局部解离。与Tat类似，核因子（NF）-κB以刺激依赖的方式募集PPM1G，以激活炎症反应基因处的延伸。将PPM1G募集到启动子组装的7SK snRNP上为通过转录暂停释放实现快速基因激活提供了一个范例。
