Multiple P-TEFbs cooperatively regulate the release of promoter-proximally paused RNA polymerase II.
Multiple P-TEFbs cooperatively regulate the release of promoter-proximally paused RNA polymerase II.
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多个 P-TEFb 协同调节启动子近端暂停的 RNA 聚合酶 II 的释放。
DOI：
10.1093/nar/gkw571
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发表时间：
2016-08-19
影响因子：
14.9
通讯作者：
Chen R
中科院分区：
文献类型：
--
作者：
Lu X;Zhu X;Li Y;Liu M;Yu B;Wang Y;Rao M;Yang H;Zhou K;Wang Y;Chen Y;Chen M;Zhuang S;Chen LF;Liu R;Chen R
DSIF和NELF与启动的RNA聚合酶II（Pol II）的关联是诱导Pol II启动子近端暂停的一般机制。然而，在很大程度上仍然不清楚暂停的Pol II是如何响应刺激而释放的。在这里，我们表明，暂停的Pol II的释放是由多个P-TEFbs，这是由含溴结构域的蛋白Brd 4和超延伸复合物（SEC）通过不同的招募机制招募合作调节。在刺激后，Brd 4通过由Med 1、Med 23和Tat-SF 1组成的募集途径将P-TEFb募集到Spt 5/DSIF，而SEC分别通过Paf 1c和Med 26将P-TEFb募集到NELF-A和NELF-E。P-TEFb介导的Spt 5、NELF-A和NELF-E的磷酸化导致NELF从Pol II解离，从而将转录从暂停转变为延伸。此外，我们证明，P-TEFb介导的Ser 2磷酸化的Pol II的暂停释放是不稳定的。因此，我们的研究揭示了Brd 4和SEC通过介体和Paf 1c协调的招募网络招募多个P-TEFbs来调节转录暂停释放的共调节机制。
The association of DSIF and NELF with initiated RNA Polymerase II (Pol II) is the general mechanism for inducing promoter-proximal pausing of Pol II. However, it remains largely unclear how the paused Pol II is released in response to stimulation. Here, we show that the release of the paused Pol II is cooperatively regulated by multiple P-TEFbs which are recruited by bromodomain-containing protein Brd4 and super elongation complex (SEC) via different recruitment mechanisms. Upon stimulation, Brd4 recruits P-TEFb to Spt5/DSIF via a recruitment pathway consisting of Med1, Med23 and Tat-SF1, whereas SEC recruits P-TEFb to NELF-A and NELF-E via Paf1c and Med26, respectively. P-TEFb-mediated phosphorylation of Spt5, NELF-A and NELF-E results in the dissociation of NELF from Pol II, thereby transiting transcription from pausing to elongation. Additionally, we demonstrate that P-TEFb-mediated Ser2 phosphorylation of Pol II is dispensable for pause release. Therefore, our studies reveal a co-regulatory mechanism of Brd4 and SEC in modulating the transcriptional pause release by recruiting multiple P-TEFbs via a Mediator- and Paf1c-coordinated recruitment network.
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