TFIIH kinase CDK7 drives cell proliferation through a common core transcription factor network
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.
Authors
- Sabrina L. Spencer (ORCID: https://orcid.org/0000-0002-5798-3007)
- Kristin B. Hamman
- Fujiet Koh (ORCID: https://orcid.org/0000-0001-6682-4449)
- William F. Richter (ORCID: https://orcid.org/0000-0003-4469-6428)
- Dylan J. Taatjes (ORCID: https://orcid.org/0000-0003-4444-5688)
- Frank R. Brennan
- Nisha Rajagopal
- Jhuma Das (ORCID: https://orcid.org/0000-0003-3548-3105)
- Lotte P. Watts (ORCID: https://orcid.org/0000-0002-1364-4345)
- Abhay Kotecha (ORCID: https://orcid.org/0000-0002-4480-5439)
- Sydney Alnemy
- Robin D. Dowell (ORCID: https://orcid.org/0000-0001-7665-9985)
- Mary A. Allen (ORCID: https://orcid.org/0000-0001-7490-0165)
- Nora Cronin (ORCID: https://orcid.org/0000-0002-4249-7313)
- Christopher C. Ebmeier (ORCID: https://orcid.org/0000-0001-7940-6190)
- Jenna K. Rimel
- Lynn Sanford (ORCID: https://orcid.org/0000-0002-1255-556X)
- Shanhu Hu
- Olivia Luyties (ORCID: https://orcid.org/0000-0002-3806-9340)
- Zachary L. Maas (ORCID: https://orcid.org/0009-0008-5645-2811)
- Kira Cozzolino
- Jason Marineau (ORCID: https://orcid.org/0000-0002-4321-0038)
- Taylor Jones (ORCID: https://orcid.org/0000-0002-8591-2847)
- Basil J. Greber (ORCID: https://orcid.org/0000-0001-9379-7159)
- Elliot R. Cooper
- Junjie Feng (ORCID: https://orcid.org/0009-0001-5861-2742)
- Abhinav B Madduri
- John P. Carulli (ORCID: https://orcid.org/0000-0001-9959-597X)
- Jessica Rodino (ORCID: https://orcid.org/0009-0009-6935-4441)
- Grace S. Shelby
Institutions
- Institute of Cancer Research (GB)
- University of Colorado Boulder (US)
- The Francis Crick Institute (GB)
- Thermo Fisher Scientific (Netherlands) (NL)
Publication Details
- Journal
- Science Advances
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1126/sciadv.adr9660
- Citations
- 6
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 4.84
Funders
- Medical Research Council