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Structure of paused transcription complex Pol II–DSIF–NELF

Author

Listed:
  • Seychelle M. Vos

    (Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology)

  • Lucas Farnung

    (Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology)

  • Henning Urlaub

    (Max Planck Institute for Biophysical Chemistry, Bioanalytical Mass Spectrometry
    University Medical Center Göttingen, Institute of Clinical Chemistry, Bioanalytics Group)

  • Patrick Cramer

    (Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology)

Abstract

Metazoan gene regulation often involves the pausing of RNA polymerase II (Pol II) in the promoter-proximal region. Paused Pol II is stabilized by the protein complexes DRB sensitivity-inducing factor (DSIF) and negative elongation factor (NELF). Here we report the cryo-electron microscopy structure of a paused transcription elongation complex containing Sus scrofa Pol II and Homo sapiens DSIF and NELF at 3.2 Å resolution. The structure reveals a tilted DNA–RNA hybrid that impairs binding of the nucleoside triphosphate substrate. NELF binds the polymerase funnel, bridges two mobile polymerase modules, and contacts the trigger loop, thereby restraining Pol II mobility that is required for pause release. NELF prevents binding of the anti-pausing transcription elongation factor IIS (TFIIS). Additionally, NELF possesses two flexible ‘tentacles’ that can contact DSIF and exiting RNA. These results define the paused state of Pol II and provide the molecular basis for understanding the function of NELF during promoter-proximal gene regulation.

Suggested Citation

  • Seychelle M. Vos & Lucas Farnung & Henning Urlaub & Patrick Cramer, 2018. "Structure of paused transcription complex Pol II–DSIF–NELF," Nature, Nature, vol. 560(7720), pages 601-606, August.
    • Handle: RePEc:nat:nature:v:560:y:2018:i:7720:d:10.1038_s41586-018-0442-2
    DOI: 10.1038/s41586-018-0442-2
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    Cited by:

    1. Abdallah Gaballa & Anneli Gebhardt-Wolf & Bastian Krenz & Greta Mattavelli & Mara John & Giacomo Cossa & Silvia Andreani & Christina Schülein-Völk & Francisco Montesinos & Raphael Vidal & Carolin Kast, 2024. "PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Simona Pilotto & Michal Sýkora & Gwenny Cackett & Christopher Dulson & Finn Werner, 2024. "Structure of the recombinant RNA polymerase from African Swine Fever Virus," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Michael DeBerardine & Gregory T. Booth & Philip P. Versluis & John T. Lis, 2023. "The NELF pausing checkpoint mediates the functional divergence of Cdk9," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Seina Ohe & Yuji Kubota & Kiyoshi Yamaguchi & Yusuke Takagi & Junichiro Nashimoto & Hiroko Kozuka-Hata & Masaaki Oyama & Yoichi Furukawa & Mutsuhiro Takekawa, 2022. "ERK-mediated NELF-A phosphorylation promotes transcription elongation of immediate-early genes by releasing promoter-proximal pausing of RNA polymerase II," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Heeyoun Bunch & Deukyeong Kim & Masahiro Naganuma & Reiko Nakagawa & Anh Cong & Jaehyeon Jeong & Haruhiko Ehara & Hongha Vu & Jeong Ho Chang & Matthew J. Schellenberg & Shun-ichi Sekine, 2023. "ERK2-topoisomerase II regulatory axis is important for gene activation in immediate early genes," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Anniina Vihervaara & Philip Versluis & Samu V. Himanen & John T. Lis, 2023. "PRO-IP-seq tracks molecular modifications of engaged Pol II complexes at nucleotide resolution," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    7. Vladyslava Gorbovytska & Seung-Kyoon Kim & Filiz Kuybu & Michael Götze & Dahun Um & Keunsoo Kang & Andreas Pittroff & Theresia Brennecke & Lisa-Marie Schneider & Alexander Leitner & Tae-Kyung Kim & Cl, 2022. "Enhancer RNAs stimulate Pol II pause release by harnessing multivalent interactions to NELF," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    8. Roberto Bandiera & Rebecca E. Wagner & Thiago Britto-Borges & Christoph Dieterich & Sabine Dietmann & Susanne Bornelöv & Michaela Frye, 2021. "RN7SK small nuclear RNA controls bidirectional transcription of highly expressed gene pairs in skin," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    9. Rina Hirano & Haruhiko Ehara & Tomoya Kujirai & Tamami Uejima & Yoshimasa Takizawa & Shun-ichi Sekine & Hitoshi Kurumizaka, 2022. "Structural basis of RNA polymerase II transcription on the chromatosome containing linker histone H1," Nature Communications, Nature, vol. 13(1), pages 1-11, 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. Jieqiong Zhang & Zhenhua Hu & Hwa Hwa Chung & Yun Tian & Kah Weng Lau & Zheng Ser & Yan Ting Lim & Radoslaw M. Sobota & Hwei Fen Leong & Benjamin Jieming Chen & Clarisse Jingyi Yeo & Shawn Ying Xuan T, 2023. "Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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