Disrupting the Cdk9/Cyclin T1 heterodimer of 7SK snRNP for the Brd4 and AFF1/4 guided reconstitution of active P-TEFb.
Disrupting the Cdk9/Cyclin T1 heterodimer of 7SK snRNP for the Brd4 and AFF1/4 guided reconstitution of active P-TEFb.
复制标题
破坏 7SK snRNP 的 Cdk9/Cyclin T1 异二聚体，用于 Brd4 和 AFF1/4 引导活性 P-TEFb 的重建。
DOI：
10.1093/nar/gkab1228
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发表时间：
2022-01-25
影响因子：
14.9
通讯作者：
Liu M
中科院分区：
文献类型：
--
作者：
Zhou K;Zhuang S;Liu F;Chen Y;Li Y;Wang S;Li Y;Wen H;Lin X;Wang J;Huang Y;He C;Xu N;Li Z;Xu L;Zhang Z;Chen LF;Chen R;Liu M
P-TEFb通过与负调节因子和正调节因子的交替相互作用来调节RNA聚合酶II的延伸。虽然非活性P-TEFbs主要以无染色质状态被隔离在7SK snRNP复合物中，但其大多数活性形式与其募集因子Brd 4和SEC以染色质相关状态复合。因此，从失活的7SK snRNP转换为活性P-TEFb（Brd 4/P-TEFb或SEC/P-TEFb）对于整体基因表达是必需的。尽管已经显示细胞信号传导刺激7SK snRNP的破坏，释放去磷酸化和催化失活的P-TEFb，但是关于失活的释放的P-TEFb如何被重新激活知之甚少。在这里，我们表明，Cdk 9/CycT 1异源二聚体从7SK snRNP释放完全解离成单体在应激反应。然后Brd 4或SEC募集单体化的Cdk 9和CycT 1以重新组装核心P-TEFb。同时，单体去磷酸化的Cdk 9与Brd 4或SEC的结合诱导Cdk 9的T186的自磷酸化。最后，在诺考达唑释放进入细胞周期的早期G1期期间采用相同的机制。因此，我们的研究证明了一种新的机制，Cdk 9和CycT 1单体在染色质上重新组装，形成活性P-TEFb，通过其与Brd 4或SEC的相互作用来调节转录。
P-TEFb modulates RNA polymerase II elongation through alternative interaction with negative and positive regulation factors. While inactive P-TEFbs are mainly sequestered in the 7SK snRNP complex in a chromatin-free state, most of its active forms are in complex with its recruitment factors, Brd4 and SEC, in a chromatin-associated state. Thus, switching from inactive 7SK snRNP to active P-TEFb (Brd4/P-TEFb or SEC/P-TEFb) is essential for global gene expression. Although it has been shown that cellular signaling stimulates the disruption of 7SK snRNP, releasing dephosphorylated and catalytically inactive P-TEFb, little is known about how the inactive released P-TEFb is reactivated. Here, we show that the Cdk9/CycT1 heterodimer released from 7SK snRNP is completely dissociated into monomers in response to stress. Brd4 or SEC then recruits monomerized Cdk9 and CycT1 to reassemble the core P-TEFb. Meanwhile, the binding of monomeric dephosphorylated Cdk9 to either Brd4 or SEC induces the autophosphorylation of T186 of Cdk9. Finally, the same mechanism is employed during nocodazole released entry into early G1 phase of cell cycle. Therefore, our studies demonstrate a novel mechanism by which Cdk9 and CycT1 monomers are reassembled on chromatin to form active P-TEFb by its interaction with Brd4 or SEC to regulate transcription.
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影响因子：
16
作者：
He N;Liu M;Hsu J;Xue Y;Chou S;Burlingame A;Krogan NJ;Alber T;Zhou Q
通讯作者：
Zhou Q
影响因子：
5.6
作者：
Ramakrishnan, Rajesh;Rice, Andrew P.
通讯作者：
Rice, Andrew P.
DOI：
10.1126/science.1181421
发表时间：
2010-01-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Nechaev S;Fargo DC;dos Santos G;Liu L;Gao Y;Adelman K
通讯作者：
Adelman K
影响因子：
11.4
作者：
Baumli, Sonja;Lolli, Graziano;Johnson, Louise N.
通讯作者：
Johnson, Louise N.
影响因子：
4.8
作者：
Hu, Xiangming;Lu, Xiaodong;Chen, Ruichuan
通讯作者：
Chen, Ruichuan