Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 34, Issue 19, Pages 3675-3688Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00595-14
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Funding
- German Ministry for Research and Technology (BMBF) [0313860D]
- IZKF of Faculty of Medicine of the Westfalian Wilhelms University (WWU) Muenster
- Max Planck Foundation, Munich, Germany
- Excellency initiative Cells in Motion
- Cell Dynamics and Disease graduate school
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Cyclin-dependent kinase 7 (CDK7) activates cell cycle CDKs and is a member of the general transcription factor TFIIH. Although there is substantial evidence for an active role of CDK7 in mRNA synthesis and associated processes, the degree of its influence on global and gene-specific transcription in mammalian species is unclear. In the current study, we utilize two novel inhibitors with high specificity for CDK7 to demonstrate a restricted but robust impact of CDK7 on gene transcription in vivo and in in vitro-reconstituted reactions. We distinguish between relative low- and high-dose responses and relate them to distinct molecular mechanisms and altered physiological responses. Low inhibitor doses cause rapid clearance of paused RNA polymerase II (RNAPII) molecules and sufficed to cause genome-wide alterations in gene expression, delays in cell cycle progression at both the G(1)/S and G(2)/M checkpoints, and diminished survival of human tumor cells. Higher doses and prolonged inhibition led to strong reductions in RNAPII carboxyl-terminal domain (CTD) phosphorylation, eventual activation of the p53 program, and increased cell death. Together, our data reason for a quantitative contribution of CDK7 to mRNA synthesis, which is critical for cellular homeostasis.
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