3' end formation of pre-mRNA and phosphorylation of Ser2 on the RNA polymerase II CTD are reciprocally coupled in human cells.
3' end formation of pre-mRNA and phosphorylation of Ser2 on the RNA polymerase II CTD are reciprocally coupled in human cells.
复制标题
3'RNA聚合酶II CTD上Ser2的前MRNA的末端形成和在人类细胞中相互耦合。
DOI：
10.1101/gad.231274.113
复制
发表时间：
2014-02-15
影响因子：
10.5
通讯作者：
West S
中科院分区：
文献类型：
--
作者：
Davidson L;Muniz L;West S
前体mRNA 3′末端的形成通过RNA Pol II C-末端结构域（CTD）与转录偶联。然而，转录和前mRNA成熟在人类中是如何协调的还知之甚少。在这里，West及其同事表明，Pol II暂停通过Cdk 12促进Ser 2 p，Cdk 12招募CPA因子CstF 77，并且是最佳3′端加工所需的。这项研究描绘了poly（A）位点加工的早期步骤和Pol II Ser 2 p之间的相互关系，确保了人类细胞中有效的前mRNA 3′端形成。前体mRNA的3′末端形成通过RNA聚合酶II（Pol II）的C末端结构域（CTD）与其转录偶联。几乎所有的蛋白质编码转录物都是通过切割和多聚腺苷酸化（CPA）而成熟的，这在疾病中经常被错误调节。因此，了解转录如何与人类细胞中的CPA协调非常重要。我们发现CTD在poly（A）（pA）信号处的Ser 2（Ser 2 p）上严重磷酸化，这与CstF 77 CPA因子的募集一致。Ser 2激酶Cdk 12的耗尽损害Ser 2 p、CstF 77募集和CPA，强烈表明这些过程是相互关联的，就像它们在芽殖酵母中一样。重要的是，我们还发现3′端的高Ser 2 p信号依赖于pA信号功能。CPA的下调导致3′ Ser 2 p峰的丢失，而当CPA被重新诱导时形成新的峰。最后，高Ser 2 p信号由Pol II暂停产生，这是PA位点识别的众所周知的特征。因此，pA位点加工的早期步骤和Ser 2 p之间的相互关系确保了有效的3′末端形成。
Pre-mRNA 3′ end formation is coupled to transcription via the RNA Pol II C-terminal domain (CTD). However, how transcription and pre-mRNA maturation are coordinated in humans is poorly understood. Here, West and colleagues show that Pol II pausing promotes Ser2p by Cdk12, which recruits CPA factor CstF77 and is required for optimal 3′ end processing. This study delineates a reciprocal relationship between early steps in poly(A) site processing and Pol II Ser2p that ensures efficient pre-mRNA 3′ end formation in human cells. 3′ end formation of pre-mRNAs is coupled to their transcription via the C-terminal domain (CTD) of RNA polymerase II (Pol II). Nearly all protein-coding transcripts are matured by cleavage and polyadenylation (CPA), which is frequently misregulated in disease. Understanding how transcription is coordinated with CPA in human cells is therefore very important. We found that the CTD is heavily phosphorylated on Ser2 (Ser2p) at poly(A) (pA) signals coincident with recruitment of the CstF77 CPA factor. Depletion of the Ser2 kinase Cdk12 impairs Ser2p, CstF77 recruitment, and CPA, strongly suggesting that the processes are linked, as they are in budding yeast. Importantly, we additionally show that the high Ser2p signals at the 3′ end depend on pA signal function. Down-regulation of CPA results in the loss of a 3′ Ser2p peak, whereas a new peak is formed when CPA is induced de novo. Finally, high Ser2p signals are generated by Pol II pausing, which is a well-known feature of pA site recognition. Thus, a reciprocal relationship between early steps in pA site processing and Ser2p ensures efficient 3′ end formation.
登录
查看更多内容
影响因子：
23.9
作者：
Brookes, Emily;de Santiago, Ines;Hebenstreit, Daniel;Morris, Kelly J.;Carroll, Tom;Xie, Sheila Q.;Stock, Julie K.;Heidemann, Martin;Eick, Dirk;Nozaki, Naohito;Kimura, Hiroshi;Ragoussis, Jiannis;Teichmann, Sarah A.;Pombo, Ana
通讯作者：
Pombo, Ana
影响因子：
7
作者：
Grosso AR;de Almeida SF;Braga J;Carmo-Fonseca M
通讯作者：
Carmo-Fonseca M
影响因子：
16.8
作者：
de Almeida, Sergio Fernandes;Grosso, Ana Rita;Carmo-Fonseca, Maria
通讯作者：
Carmo-Fonseca, Maria
影响因子：
64.5
作者：
Dye, MJ;Proudfoot, NJ
通讯作者：
Proudfoot, NJ
影响因子：
10.5
作者：
Bartkowiak, Bartlomiej;Liu, Pengda;Greenleaf, Arno L.
通讯作者：
Greenleaf, Arno L.