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

Taylor Jones1, Junjie Feng2, Olivia Luyties1

  • 1Department of Biochemistry, University of Colorado, Boulder, CO 80303, USA.

Science Advances
|February 28, 2025
PubMed

Insights

Cyclin-dependent kinase 7 (CDK7) regulates cell cycle and transcription by repressing core transcription factors (TFs). CDK7 inhibition affects constitutive genes more than stimulus-responsive ones, revealing a key role in proliferation control.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The precise mechanisms by which cyclin-dependent kinase 7 (CDK7) regulates both the cell cycle and RNA polymerase II (RNAPII) transcription are not fully understood.
  • CDK7 is a target for cancer therapeutics, necessitating a deeper understanding of its cellular functions.

Purpose of the Study:

  • To elucidate how CDK7 inhibitors function at a molecular level.
  • To investigate the differential impact of CDK7 inhibition on constitutive versus stimulus-responsive gene expression.
  • To identify the specific transcription factors (TFs) regulated by CDK7 and their role in cell proliferation.

Main Methods:

  • High-resolution cryo-electron microscopy to visualize inhibitor binding to CDK7.
  • Cellular assays to assess the effects of CDK7 inhibition on transcription and TF activity.
  • Phosphoproteomic analysis to identify CDK7-dependent phosphorylation events.
  • Protein level analysis to quantify TF abundance following CDK7 inhibition.

Main Results:

  • CDK7 inhibition rapidly suppressed RNAPII transcription, with a disproportionate effect on constitutively active genes.
  • Stimulus-responsive TFs remained active, while constitutively active "core" TFs (n=78) were repressed.
  • CDK7 inhibition led to phosphorylation changes in core TFs and RB1, and subsequent depletion of core TF protein levels.
  • Core TFs are primarily promoter-associated and control cell cycle and proliferation genes.

Conclusions:

  • CDK7 plays a critical role in regulating a cohort of core TFs that drive cell proliferation.
  • CDK7 coordinates RNAPII transcription with cell cycle regulation through its control over these core TFs.
  • This study reveals a previously unappreciated function of CDK7 in maintaining proliferative gene expression programs.

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