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Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase II

Author

Listed:
  • Huasong Lu

    (Xiamen University
    University of California)

  • Dan Yu

    (University of California)

  • Anders S. Hansen

    (University of California)

  • Sourav Ganguly

    (University of California)

  • Rongdiao Liu

    (Xiamen University)

  • Alec Heckert

    (University of California)

  • Xavier Darzacq

    (University of California)

  • Qiang Zhou

    (University of California)

Abstract

Hyperphosphorylation of the C-terminal domain (CTD) of the RPB1 subunit of human RNA polymerase (Pol) II is essential for transcriptional elongation and mRNA processing1–3. The CTD contains 52 heptapeptide repeats of the consensus sequence YSPTSPS. The highly repetitive nature and abundant possible phosphorylation sites of the CTD exert special constraints on the kinases that catalyse its hyperphosphorylation. Positive transcription elongation factor b (P-TEFb)—which consists of CDK9 and cyclin T1—is known to hyperphosphorylate the CTD and negative elongation factors to stimulate Pol II elongation1,4,5. The sequence determinant on P-TEFb that facilitates this action is currently unknown. Here we identify a histidine-rich domain in cyclin T1 that promotes the hyperphosphorylation of the CTD and stimulation of transcription by CDK9. The histidine-rich domain markedly enhances the binding of P-TEFb to the CTD and functional engagement with target genes in cells. In addition to cyclin T1, at least one other kinase—DYRK1A 6 —also uses a histidine-rich domain to target and hyperphosphorylate the CTD. As a low-complexity domain, the histidine-rich domain also promotes the formation of phase-separated liquid droplets in vitro, and the localization of P-TEFb to nuclear speckles that display dynamic liquid properties and are sensitive to the disruption of weak hydrophobic interactions. The CTD—which in isolation does not phase separate, despite being a low-complexity domain—is trapped within the cyclin T1 droplets, and this process is enhanced upon pre-phosphorylation by CDK7 of transcription initiation factor TFIIH1–3. By using multivalent interactions to create a phase-separated functional compartment, the histidine-rich domain in kinases targets the CTD into this environment to ensure hyperphosphorylation and efficient elongation of Pol II.

Suggested Citation

  • Huasong Lu & Dan Yu & Anders S. Hansen & Sourav Ganguly & Rongdiao Liu & Alec Heckert & Xavier Darzacq & Qiang Zhou, 2018. "Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase II," Nature, Nature, vol. 558(7709), pages 318-323, June.
  • Handle: RePEc:nat:nature:v:558:y:2018:i:7709:d:10.1038_s41586-018-0174-3
    DOI: 10.1038/s41586-018-0174-3
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    Cited by:

    1. Rui Chen & Xinyao Shi & Xiangrui Yao & Tong Gao & Guangyu Huang & Duo Ning & Zemin Cao & Youxin Xu & Weizheng Liang & Simon Zhongyuan Tian & Qionghua Zhu & Liang Fang & Meizhen Zheng & Yuhui Hu & Huan, 2024. "Specific multivalent molecules boost CRISPR-mediated transcriptional activation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Prathama Talukdar & Sujay Pal & Debabrata Biswas, 2024. "Post-translational modification-dependent oligomerization switch in regulation of global transcription and DNA damage repair during genotoxic stress," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    3. Marta Vicioso-Mantis & Raquel Fueyo & Claudia Navarro & Sara Cruz-Molina & Wilfred F. J. Ijcken & Elena Rebollo & Álvaro Rada-Iglesias & Marian A. Martínez-Balbás, 2022. "JMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Jiaxing Jin & Hui Bai & Han Yan & Ting Deng & Tianyu Li & Ruijing Xiao & Lina Fan & Xue Bai & Hanhan Ning & Zhe Liu & Kai Zhang & Xudong Wu & Kaiwei Liang & Ping Ma & Xin Gao & Deqing Hu, 2023. "PRMT2 promotes HIV-1 latency by preventing nucleolar exit and phase separation of Tat into the Super Elongation Complex," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Yucheng Tian & Yixiao Chen & Sai Wang & Xianfeng Wang & Jianyong Yu & Shichao Zhang & Bin Ding, 2024. "Ultrathin aerogel-structured micro/nanofiber metafabric via dual air-gelation synthesis for self-sustainable heating," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    6. Katerina Linhartova & Francesco Luca Falginella & Martin Matl & Marek Sebesta & Robert Vácha & Richard Stefl, 2024. "Sequence and structural determinants of RNAPII CTD phase-separation and phosphorylation by CDK7," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Hossein Salari & Geneviève Fourel & Daniel Jost, 2024. "Transcription regulates the spatio-temporal dynamics of genes through micro-compartmentalization," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. Hui Wang & Boyuan Li & Linyu Zuo & Bo Wang & Yan Yan & Kai Tian & Rong Zhou & Chenlu Wang & Xizi Chen & Yongpeng Jiang & Haonan Zheng & Fangfei Qin & Bin Zhang & Yang Yu & Chao-Pei Liu & Yanhui Xu & J, 2022. "The transcriptional coactivator RUVBL2 regulates Pol II clustering with diverse transcription factors," Nature Communications, Nature, vol. 13(1), pages 1-26, December.
    9. Lisa-Marie Appel & Vedran Franke & Melania Bruno & Irina Grishkovskaya & Aiste Kasiliauskaite & Tanja Kaufmann & Ursula E. Schoeberl & Martin G. Puchinger & Sebastian Kostrhon & Carmen Ebenwaldner & M, 2021. "PHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    10. Ines H. Kaltheuner & Kanchan Anand & Jonas Moecking & Robert Düster & Jinhua Wang & Nathanael S. Gray & Matthias Geyer, 2021. "Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    11. David Flores-Solis & Irina P. Lushpinskaia & Anton A. Polyansky & Arya Changiarath & Marc Boehning & Milana Mirkovic & James Walshe & Lisa M. Pietrek & Patrick Cramer & Lukas S. Stelzl & Bojan Zagrovi, 2023. "Driving forces behind phase separation of the carboxy-terminal domain of RNA polymerase II," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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