PolⅡ磷酸化調節轉錄起始和剪接之間的轉換

PolⅡ磷酸化調節轉錄起始和剪接之間的轉換

作者：

小柯機器人

發布時間：2019/8/22 16:02:24

美國懷特黑德生物醫學研究所Richard A. Young研究組取得進展。他們的研究發現Pol Ⅱ磷酸化調控轉錄和剪接復合物之間的轉換。該研究成果發表在2019年8月22日出版的《自然》上。

課題組人員通過研究Pol Ⅱ C末端結構域的磷酸化，是否調節PolⅡ摻入與轉錄起始和剪接相關複合物的相分離，發現具有低磷酸化C末端的Pol Ⅱ與轉錄中介複合物結合，並且由細胞周期蛋白依賴性激酶磷酸化的Pol Ⅱ會減少了這種結合。研究人員還發現，過度磷酸化C末端結構域的Pol Ⅱ會優先進入由剪接因子形成的複合物中。結果表明，PolⅡ C末端結構域的磷酸化驅動從轉錄起始複合物到RNA加工複合物的轉換，這暗示磷酸化作為調節Pol Ⅱ結合不同複合物偏好性的機制。

RNA聚合酶 Ⅱ（Pol  Ⅱ）合成前體mRNA包括轉錄起始複合物的形成到延伸複合物的轉換。Pol Ⅱ的大亞基含有無序的C末端結構域，其在從起始到延伸的過渡期間被細胞周期蛋白依賴性激酶磷酸化，從而影響C末端結構域與起始複合物的不同組分或RNA-剪接體的相互作用。最近的研究表明，該模型僅揭示了C-末端結構域磷酸化部分的作用機制。轉錄起始複合物和剪接複合物都可以形成相分離的液滴，這些液滴含有大量的元件分子如：數百個Pol Ⅱ和mediator分子在超級增強子區形成相分離液滴，大量的剪接因子集中在核斑點區，其中一些出現在高度活躍的轉錄位點。

附：英文原文

Title: Pol II phosphorylation regulates a switch between transcriptional and splicing condensates

Author: Yang Eric Guo, John C. Manteiga, Jonathan E. Henninger, Benjamin R. Sabari, Alessandra Dall』Agnese, Nancy M. Hannett, Jan-Hendrik Spille, Lena K. Afeyan, Alicia V. Zamudio, Krishna Shrinivas, Brian J. Abraham, Ann Boija, Tim-Michael Decker, Jenna K. Rimel, Charli B. Fant, Tong Ihn Lee, Ibrahim I. Cisse, Phillip A. Sharp, Dylan J. Taatjes, Richard A. Young

Issue&Volume:Volume 572 Issue 7770

Abstract: The synthesis of pre-mRNA by RNA polymerase II (Pol II) involves the formation of a transcription initiation complex, and a transition to an elongation complex. The large subunit of Pol II contains an intrinsically disordered C-terminal domain that is phosphorylated by cyclin-dependent kinases during the transition from initiation to elongation, thus influencing the interaction of the C-terminal domain with different components of the initiation or the RNA-splicing apparatus. Recent observations suggest that this model provides only a partial picture of the effects of phosphorylation of the C-terminal domain. Both the transcription-initiation machinery and the splicing machinery can form phase-separated condensates that contain large numbers of component molecules: hundreds of molecules of Pol II and mediator are concentrated in condensates at super-enhancers, and large numbers of splicing factors are concentrated in nuclear speckles, some of which occur at highly active transcription sites. Here we investigate whether the phosphorylation of the Pol II C-terminal domain regulates the incorporation of Pol II into phase-separated condensates that are associated with transcription initiation and splicing. We find that the hypophosphorylated C-terminal domain of Pol II is incorporated into mediator condensates and that phosphorylation by regulatory cyclin-dependent kinases reduces this incorporation. We also find that the hyperphosphorylated C-terminal domain is preferentially incorporated into condensates that are formed by splicing factors. These results suggest that phosphorylation of the Pol II C-terminal domain drives an exchange from condensates that are involved in transcription initiation to those that are involved in RNA processing, and implicates phosphorylation as a mechanism that regulates condensate preference.

DOI: 10.1038/s41586-019-1464-0

Source:https://www.nature.com/articles/s41586-019-1464-0