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.