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Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition

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  • Nadine Czudnochowski

    (Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie
    Present address: Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.)

  • Christian A. Bösken

    (Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie)

  • Matthias Geyer

    (Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie)

Abstract

Phosphorylation of RNA polymerase II carboxy-terminal domain (CTD) in hepta-repeats YSPTSPS regulates eukaryotic transcription. Whereas Ser5 is phosphorylated in the initiation phase, Ser2 phosphorylation marks the elongation state. Here we show that the positive transcription elongation factor P-TEFb is a Ser5 CTD kinase that is unable to create Ser2/Ser5 double phosphorylations, while it exhibits fourfold higher activity on a CTD substrate pre-phosphorylated at Ser7 compared with the consensus hepta-repeat or the YSPTSPK variant. Mass spectrometry reveals an equal number of phosphorylations to the number of hepta-repeats provided, yet the mechanism of phosphorylation is distributive despite the repetitive nature of the substrate. Inhibition of P-TEFb activity is mediated by two regions in Hexim1 that act synergistically on Cdk9 and Cyclin T1. HIV-1 Tat/TAR abrogates Hexim1 inhibition to stimulate transcription of viral genes but does not change the substrate specificity. Together, these results provide insight into the multifaceted pattern of CTD phosphorylation.

Suggested Citation

  • Nadine Czudnochowski & Christian A. Bösken & Matthias Geyer, 2012. "Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1846
    DOI: 10.1038/ncomms1846
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    Cited by:

    1. Austin Hsu & Qiming Duan & Daniel S. Day & Xin Luo & Sarah McMahon & Yu Huang & Zachary B. Feldman & Zhen Jiang & Tinghu Zhang & Yanke Liang & Michael Alexanian & Arun Padmanabhan & Jonathan D. Brown , 2022. "Targeting transcription in heart failure via CDK7/12/13 inhibition," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. 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.
    3. Robert Düster & Kanchan Anand & Sophie C. Binder & Maximilian Schmitz & Karl Gatterdam & Robert P. Fisher & Matthias Geyer, 2024. "Structural basis of Cdk7 activation by dual T-loop phosphorylation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. 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.

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