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The NELF pausing checkpoint mediates the functional divergence of Cdk9

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Listed:
  • Michael DeBerardine

    (Cornell University)

  • Gregory T. Booth

    (Cornell University
    Kanvas Biosciences)

  • Philip P. Versluis

    (Cornell University)

  • John T. Lis

    (Cornell University)

Abstract

Promoter-proximal pausing by RNA Pol II is a rate-determining step in gene transcription that is hypothesized to be a prominent point at which regulatory factors act. The pausing factor NELF is known to induce and stabilize pausing, but not all kinds of pausing are NELF-mediated. Here, we find that NELF-depleted Drosophila melanogaster cells functionally recapitulate the NELF-independent pausing we previously observed in fission yeast (which lack NELF). Critically, only NELF-mediated pausing establishes a strict requirement for Cdk9 kinase activity for the release of paused Pol II into productive elongation. Upon inhibition of Cdk9, cells with NELF efficiently shutdown gene transcription, while in NELF-depleted cells, defective, non-productive transcription continues unabated. By introducing a strict checkpoint for Cdk9, the evolution of NELF was likely critical to enable increased regulation of Cdk9 in higher eukaryotes, as Cdk9 availability can be restricted to limit gene transcription without inducing wasteful, non-productive transcription.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38359-y
    DOI: 10.1038/s41467-023-38359-y
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    References listed on IDEAS

    as
    1. Saskia Gressel & Björn Schwalb & Patrick Cramer, 2019. "The pause-initiation limit restricts transcription activation in human cells," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    2. Gregory T. Booth & Pabitra K. Parua & Miriam Sansó & Robert P. Fisher & John T. Lis, 2018. "Cdk9 regulates a promoter-proximal checkpoint to modulate RNA polymerase II elongation rate in fission yeast," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    3. 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.
    4. Seychelle M. Vos & Lucas Farnung & Marc Boehning & Christoph Wigge & Andreas Linden & Henning Urlaub & Patrick Cramer, 2018. "Structure of activated transcription complex Pol II–DSIF–PAF–SPT6," Nature, Nature, vol. 560(7720), pages 607-612, August.
    5. Anthony C. Bishop & Jeffrey A. Ubersax & Dejah T. Petsch & Dina P. Matheos & Nathanael S. Gray & Justin Blethrow & Eiji Shimizu & Joe Z. Tsien & Peter G. Schultz & Mark D. Rose & John L. Wood & David , 2000. "A chemical switch for inhibitor-sensitive alleles of any protein kinase," Nature, Nature, vol. 407(6802), pages 395-401, September.
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    1. Krzysztof Kuś & Loic Carrique & Tea Kecman & Marjorie Fournier & Sarah Sayed Hassanein & Ebru Aydin & Cornelia Kilchert & Jonathan M. Grimes & Lidia Vasiljeva, 2025. "DSIF factor Spt5 coordinates transcription, maturation and exoribonucleolysis of RNA polymerase II transcripts," Nature Communications, Nature, vol. 16(1), pages 1-19, December.

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