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Journal Article

CDK7 kinase activity promotes RNA polymerase II promoter escape by facilitating initiation factor release

MPS-Authors
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Velychko,  Taras       
Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Mohammad,  Eusra
Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Parfentev,  Iwan
Research Group of Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Werner,  Marcel
Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Schwalb,  Björn
Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Urlaub,  Henning
Research Group of Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Cramer,  Patrick       
Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Lidschreiber,  Michael       
Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Citation

Velychko, T., Mohammad, E., Ferrer-Vicens, I., Parfentev, I., Werner, M., Studniarek, C., et al. (2024). CDK7 kinase activity promotes RNA polymerase II promoter escape by facilitating initiation factor release. Molecular Cell, 84(12), 2287-2303.e10. doi:10.1016/j.molcel.2024.05.007.


Cite as: https://hdl.handle.net/21.11116/0000-000F-5BE6-8
Abstract
Cyclin-dependent kinase 7 (CDK7), part of the general transcription factor TFIIH, promotes gene transcription by phosphorylating the C-terminal domain of RNA polymerase II (RNA Pol II). Here, we combine rapid CDK7 kinase inhibition with multi-omics analysis to unravel the direct functions of CDK7 in human cells. CDK7 inhibition causes RNA Pol II retention at promoters, leading to decreased RNA Pol II initiation and immediate global downregulation of transcript synthesis. Elongation, termination, and recruitment of co-transcriptional factors are not directly affected. Although RNA Pol II, initiation factors, and Mediator accumulate at promoters, RNA Pol II complexes can also proceed into gene bodies without promoter-proximal pausing while retaining initiation factors and Mediator. Further downstream, RNA Pol II phosphorylation increases and initiation factors and Mediator are released, allowing recruitment of elongation factors and an increase in RNA Pol II elongation velocity. Collectively, CDK7 kinase activity promotes the release of initiation factors and Mediator from RNA Pol II, facilitating RNA Pol II escape from the promoter.