Interaction of Cyclin-Dependent Kinase 12/CrkRS with Cyclin K1 Is Required for the Phosphorylation of the C-Terminal Domain of RNA Polymerase II
Open accessAbstract
CrkRS (Cdc2-related kinase, Arg/Ser), or cyclin-dependent kinase 12 (CKD12), is a serine/threonine kinase believed to coordinate transcription and RNA splicing. While CDK12/CrkRS complexes were known to phosphorylate the C-terminal domain (CTD) of RNA polymerase II (RNA Pol II), the cyclin regulating this activity was not known. Using immunoprecipitation and mass spectrometry, we identified a 65-kDa isoform of cyclin K (cyclin K1) in endogenous CDK12/CrkRS protein complexes. We show that cyclin K1 complexes isolated from mammalian cells contain CDK12/CrkRS but do not contain CDK9, a presumed partner of cyclin K. Analysis of extensive RNA-Seq data shows that the 65-kDa cyclin K1 isoform is the predominantly expressed form across numerous tissue types. We also demonstrate that CDK12/CrkRS is dependent on cyclin K1 for its kinase activity and that small interfering RNA (siRNA) knockdown of CDK12/CrkRS or cyclin K1 has similar effects on the expression of a luciferase reporter gene. Our data suggest that cyclin K1 is the primary cyclin partner for CDK12/CrkRS and that cyclin K1 is required to activate CDK12/CrkRS to phosphorylate the CTD of RNA Pol II. These properties are consistent with a role of CDK12/CrkRS in regulating gene expression through phosphorylation of RNA Pol II.
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CDK12, a known CR8 target whose activity requires cycK, is a crucial component for CR8-induced destabilization of cycKeGFP.
“In addition, we identified cyclin-dependent kinase 12 (CDK12), which is a known target of CR819 and whose activity depends on the interaction with cycK20, as a crucial component for CR8-induced cycKeGFP destabilisation (Fig. 1g, Extended Data Fig. 2h–k).”
From The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K (2020) · cites this paper as [20]
To execute their functions, CDK12 and CDK13 form two separate complexes with CCNK.
“To execute their functions, CDK12 and CDK13 form two separate complexes with CCNK (Blazek et al., 2011; Cheng et al., 2012).”
From Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation (2020) · cites this paper as Cheng et al., 2012
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Self-citation
- Authors
- Cheng, S.-W. G., Kuzyk, M. A., Moradian, A., Ichu, T.-A., Chang, V. C.-D., Tien, J. F., Vollett, S. E., Griffith, M., Marra, M. A., & Morin, G. B.
- Affiliations
- BC Cancer Agency (CA)
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2012-11-01
- Volume
- 32
- Issue
- 22
- Pages
- 4691-4704
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC3486194
- OpenAlex
- W2109885069
- Semantic Scholar
- 81efaf8b333c2a183eac5d42648c3fc7c6fb3934
- Cited by
- 124
- References
- 68
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 11 · 2023: 8 · 2022: 10 · 2021: 5 · 2020: 20 · 2019: 8 · 2018: 10 · 2017: 4 · 2016: 6 · 2015: 8 · 2014: 7 · 2013: 7 · 2012: 1
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- BC Cancer Agency
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- RNA polymerase II C-terminal domain, CTD phosphorylation, cyclin-dependent kinases, CDK9, transcriptional regulation, RNA splicing, kinase activation, gene expression regulation
- MeSH terms
- Binding Sites, Gene Expression Regulation, HeLa Cells, Humans, Luciferases, Phosphorylation, Protein Binding, RNA Polymerase II, Mass Spectrometry, Signal Transduction, Cyclins, Protein Structure, Tertiary, Genes, Reporter, Cyclin-Dependent Kinases, Protein Isoforms, RNA, Small Interfering, Immunoprecipitation, HEK293 Cells
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