title: Cyclin-dependent kinase 7 controls mRNA synthesis by affecting stability of preinitiation complexes, leading to altered gene expression, cell cycle progression, and survival of tumor cells.
abstract: 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 G1/S and G2/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.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Institute of Molecular Tumor Biology, Westfalian Wilhelms University Muenster, Muenster, Germany.
authors.forename: Timothy W R
authors.initials: TW
authors.lastname: Kelso
authors.affiliation: Laboratory of Cellular and Molecular Biology, Institute of Molecular Tumor Biology, Westfalian Wilhelms University Muenster, Muenster, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Baumgart
authors.affiliation: Lead Discovery Center GmbH, Dortmund, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Eickhoff
authors.affiliation: Laboratory of Cellular and Molecular Biology, Institute of Molecular Tumor Biology, Westfalian Wilhelms University Muenster, Muenster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Albert
authors.affiliation: Laboratory of Cellular and Molecular Biology, Institute of Molecular Tumor Biology, Westfalian Wilhelms University Muenster, Muenster, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Antrecht
authors.affiliation: Laboratory of Cellular and Molecular Biology, Institute of Molecular Tumor Biology, Westfalian Wilhelms University Muenster, Muenster, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lemcke
authors.affiliation: Lead Discovery Center GmbH, Dortmund, Germany.
authors.forename: Bert
authors.initials: B
authors.lastname: Klebl
authors.affiliation: Laboratory of Cellular and Molecular Biology, Institute of Molecular Tumor Biology, Westfalian Wilhelms University Muenster, Muenster, Germany meistere@uni-muenster.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Meisterernst
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics*; D000077546:Roscovitine; D014227:Triazines / Q000494:pharmacology*; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: C000592925:LDC3140; C000592926:LDC4297; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D014227:Triazines; D000077546:Roscovitine; C000592924:BS-181; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human