TFIIH kinase CDK7 drives cell proliferation through a common core transcription factor network

Sci Adv. 2025 Feb 28;11(9):eadr9660. doi: 10.1126/sciadv.adr9660.

Taylor Jones ¹, Junjie Feng ², Olivia Luyties ¹, Kira Cozzolino ¹, Lynn Sanford ³ ⁴, Jenna K Rimel ¹, Christopher C Ebmeier ¹, Grace S Shelby ¹, Lotte P Watts ¹ ⁴, Jessica Rodino ¹, Nisha Rajagopal ⁵, Shanhu Hu ⁵, Finn Brennan ¹, Zachary L Maas ³ ⁴, Sydney Alnemy ⁵, William F Richter ¹, Adrian F Koh ⁶, Nora B Cronin ⁷, Ameya Madduri ⁵, Jhuma Das ⁵, Elliot Cooper ⁵, Kristin B Hamman ⁵, John P Carulli ⁵, Mary A Allen ³ ⁴, Sabrina Spencer ¹ ⁴, Abhay Kotecha ⁶, Jason J Marineau ⁵, Basil J Greber ², Robin D Dowell ³ ⁴, Dylan J Taatjes ¹

Affiliations

1 Department of Biochemistry, University of Colorado, Boulder, CO 80303, USA.
2 Institute for Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.
3 Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80303, USA.
4 BioFrontiers Institute, University of Colorado, Boulder, CO 80303, USA.
5 Syros Pharmaceuticals, Cambridge, MA 02140, USA.
6 Materials and Structural Analysis Division, Thermo Fisher Scientific, Achtseweg Noord 5, 5651 Eindhoven, Netherlands.
7 London Consortium for High-Resolution Cryo-EM, The Francis Crick Institute, London NW1 1AT, UK.

PMID: 40020069 DOI: 10.1126/sciadv.adr9660

Abstract

How cyclin-dependent kinase 7 (CDK7) coordinately regulates the cell cycle and RNA polymerase II transcription remains unclear. Here, high-resolution cryo-electron microscopy revealed how two clinically relevant inhibitors block CDK7 function. In cells, CDK7 inhibition rapidly suppressed transcription, but constitutively active genes were disproportionately affected versus stimulus-responsive. Distinct transcription factors (TFs) regulate constitutive versus stimulus-responsive genes. Accordingly, stimulus-responsive TFs were refractory to CDK7 inhibition whereas constitutively active "core" TFs were repressed. Core TFs (n = 78) are predominantly promoter associated and control cell cycle and proliferative gene expression programs across cell types. Mechanistically, rapid suppression of core TF function can occur through CDK7-dependent phosphorylation changes in core TFs and RB1. Moreover, CDK7 inhibition depleted core TF protein levels within hours, consistent with durable target gene suppression. Thus, a major but unappreciated biological function for CDK7 is regulation of a TF cohort that drives proliferation, revealing an apparent universal mechanism by which CDK7 coordinates RNAPII transcription with cell cycle CDK regulation.

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