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

• DOI: 10.1126/sciadv.adr9660
• Publication Date: 2025-02-28T18:58:57Z
• Authors: Taylor Jones; Junjie Feng; Olivia Luyties; Kira Cozzolino; Lynn Sanford; Jenna K. Rimel; Christopher C. Eb...; Grace S. Shelby; Lotte P. Watts; Jessica Rodino; Nisha Rajagopal; Shanhu Hu; Finn Brennan; Zachary L. Maas; Sydney Alnemy; William F. Richter; Adrian F. Koh; Nora B. Cronin; Ameya Madduri; Jhuma Das; Elliot Cooper; Kristin B. Hamman; John P. Carulli; Mary A. Allen; Sabrina Spencer; Abhay Kotecha; Jason J. Marineau; Basil J. Greber; Robin D. Dowell; Dylan J. Taatjes
• Keywords: Cyclin-dependent kinase 7; RNA polymerase II; Transcription; CDK inhibitor

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, inhibition rapidly suppressed transcription, but constitutively active genes were disproportionately affected versus stimulus-responsive. Distinct factors (TFs) regulate constitutive stimulus-responsive genes. Accordingly, TFs refractory to whereas “core” repressed. Core (n = 78) are predominantly promoter associated control proliferative gene expression programs across types. Mechanistically, rapid suppression of core TF function can occur through CDK7-dependent phosphorylation changes in RB1. Moreover, depleted protein levels within hours, consistent with durable target suppression. Thus, a major unappreciated biological for is regulation cohort that drives proliferation, revealing an apparent universal mechanism by which coordinates RNAPII CDK regulation.