Affinage

CDK7

Cyclin-dependent kinase 7 · UniProt P50613

Length
346 aa
Mass
39.0 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDK7 is a serine/threonine kinase that couples cell-cycle control to transcription by functioning in two distinct biochemical settings (PMID:8069918, PMID:8001135). As the catalytic subunit of the CDK-activating kinase (CAK), it assembles with cyclin H and MAT1 into a trimeric complex (PMID:8069918, PMID:8078587, PMID:8617234) that phosphorylates the T-loop threonine of cell-cycle CDKs — CDK2 and CDC2/CDK1 (PMID:8069918, PMID:8344251), CDK4 and CDK6 (PMID:23622515), and CDK5 (PMID:14586172) — to activate them; immunodepletion and metazoan genetics establish CDK7 as the genuine, essential CAK in vivo (PMID:8344251, PMID:9450931, PMID:9315098). Within the TFIIH transcription/repair factor, CDK7 instead phosphorylates the RNA polymerase II CTD to drive promoter escape, release of initiation factors and Mediator, capping enzyme and SETD1A/B recruitment, and the transition to productive elongation (PMID:8001135, PMID:26257281, PMID:28768201, PMID:38821049). Substrate selection is governed by complex context: MAT1 and the TFIIH core shift specificity from CDKs toward the CTD (PMID:9130709, PMID:10801852), while CAK dissociation from TFIIH licenses phosphorylation of broader targets including the transcriptional kinases CDK9, CDK12 and CDK13 and the splicing factors SF3B1 and U2AF2 (PMID:33060135). CDK7 activity is itself regulated by dual T-loop phosphorylation (pS164 then pT170), which stabilizes the complex and selectively boosts activity toward non-CDK substrates such as the CTD and SPT5 without altering CAK function (PMID:11447116, PMID:39097586), and by MAT1, which can position the T-loop in its active conformation independently of phosphorylation (PMID:33055219). Beyond core transcription, CDK7 phosphorylates regulators including p53 at Ser33 (PMID:9372954), MED1 at T1457 to support androgen-receptor super-enhancer transcription (PMID:31466944), and YAP/TAZ to block their ubiquitin-mediated degradation and promote organ growth and tumorigenesis (PMID:31857346, PMID:37582812). Selective covalent and chemical-genetic inhibitors have separated CDK7's direct G1/S and E2F-driven cell-cycle role from CTD-phosphorylation effects previously attributed to it, and link CDK7 inhibition to senescence and to therapeutic vulnerability in cancer (PMID:30905681, PMID:37977119).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1994 High

    Established the founding identity of CDK7 as the catalytic subunit of CAK, answering how cell-cycle CDKs themselves become activated.

    Evidence Protein purification, cDNA cloning, in vitro reconstitution with cyclin H and mutagenesis of the conserved T-loop threonine; immunodepletion from Xenopus extracts with functional recovery

    PMID:7935441 PMID:8069918 PMID:8078587 PMID:8344251

    Open questions at the time
    • Did not resolve how the same kinase is partitioned between CAK and transcription roles
    • Structural basis of CDK substrate recognition not yet defined
  2. 1994 High

    Connected CDK7 to transcription and DNA repair by placing it in TFIIH and identifying the RNA pol II CTD as a substrate, revealing a kinase that bridges cell cycle, transcription, and repair.

    Evidence Biochemical association studies and in vitro/in vivo nucleotide-excision-repair assays

    PMID:8001135

    Open questions at the time
    • Mechanism switching CDK7 between CDK and CTD substrates not yet defined
    • Functional consequences of CTD phosphorylation on transcription steps unresolved
  3. 1996 High

    Defined the trimeric CAK architecture and showed MAT1 as a stimulatory assembly factor, and that TFIIH-associated CDK7 is downregulated by UV, linking the kinase to stress responses.

    Evidence Biochemical fractionation, reciprocal co-IP, in vitro kinase assays under UV irradiation

    PMID:8617234

    Open questions at the time
    • How MAT1 reshapes the active site was not structurally defined
    • Physiological signal controlling free vs TFIIH-bound CAK unknown
  4. 1997 High

    Showed that MAT1 and the TFIIH core context act as substrate-specificity switches, explaining how one kinase serves both CDK activation and CTD phosphorylation.

    Evidence In vitro kinase assays comparing free CAK and TFIIH-associated kinase across multiple substrates (CTD, CDK2, TFIIE, TFIIF), plus p53 Ser33 phosphorylation with site mutagenesis

    PMID:9130709 PMID:9372954

    Open questions at the time
    • Quantitative contribution of each context to in vivo specificity not established
    • p53 Ser33 phosphorylation's physiological output not resolved here
  5. 1998 High

    Genetic proof in a metazoan that cdk7 is the bona fide CAK required for CDK activation and cell division, and that its CTD activity is repressed at mitosis.

    Evidence Drosophila null and temperature-sensitive alleles with in vivo CAK assays; mitotic kinase and in vitro transcription assays with p21 rescue

    PMID:9450931 PMID:9488463

    Open questions at the time
    • Direct kinase responsible for mitotic CDK7 inhibition in vivo not fully defined
    • Coupling of transcriptional repression to mitotic CDK7 shutdown mechanistic detail incomplete
  6. 2001 High

    Defined T-loop phosphorylation (Ser164/Thr170) as a substrate-selective regulator that boosts CTD activity via increased kcat while sparing CDK activation, distinguishing CAK from transcriptional functions.

    Evidence Drosophila phosphosite mutants, co-IP, in vitro kinase kinetics

    PMID:11447116

    Open questions at the time
    • Upstream kinase priming T-loop phosphorylation not identified here
    • Structural basis of substrate-selective activation not resolved
  7. 2004 High

    Provided the first atomic view of CDK7, showing an inactive conformation with phosphorylated Thr170 and that CDK7 is not dephosphorylated by KAP, refining models of its activation.

    Evidence X-ray crystallography of CDK7-ATP at 3 Å with in vitro kinase assays

    PMID:15530371

    Open questions at the time
    • Structure of the active trimeric CAK not yet captured
    • Cyclin H/MAT1 contacts not visualized in this structure
  8. 2013 High

    Extended CDK7 substrate range to CDK4/CDK6 and revealed a continuous-activation requirement during G1, defining a mitogen-driven CDK-activation cascade distinct from CDK1/CDK2.

    Evidence Analog-sensitive CDK7 chemical genetics, in vitro kinase assays, synchronization and phosphorylation analysis

    PMID:23622515

    Open questions at the time
    • Why CDK4/6 require continuous vs transient CDK7 input mechanistically unresolved
    • Direct in vivo ordering of CDK7-CDK4 phosphorylation not fully isolated from feedback
  9. 2015 High

    Dissected CDK7's role across transcription steps in vitro — CTD phosphorylation, capping, pausing, and elongation — showing it acts after initiation.

    Evidence In vitro transcription with nuclear extract and THZ1 inhibitor, RNA pol II phosphorylation assays

    PMID:26257281

    Open questions at the time
    • THZ1 off-target effects on CDK12/13 not yet accounted for
    • Direct vs indirect effects on pausing not fully separated in this assay
  10. 2017 High

    Linked CDK7-dependent CTD phosphorylation to a chromatin 'code' that recruits capping enzymes and SETD1A/B, connecting transcription initiation to histone methylation patterning.

    Evidence Analog-sensitive CDK7 cells, ChIP-seq, mass spectrometry, in vitro nucleosome methylation assays

    PMID:28768201

    Open questions at the time
    • Causal chain from CTD marks to H3K4me3 spreading not fully reconstituted
    • Generality across gene classes not established
  11. 2019 High

    Identified CDK7 as the master upstream kinase shaping diverse outputs — MED1/AR super-enhancer transcription and YAP/TAZ stabilization — broadening its role into oncogenic transcriptional programs.

    Evidence ChIP-seq, phosphoproteomics, site mutagenesis and ubiquitination assays, Drosophila genetics, xenograft models with THZ1

    PMID:31466944 PMID:31857346

    Open questions at the time
    • Whether these phosphorylations occur via free CAK or TFIIH-bound CDK7 not resolved
    • Direct vs indirect contribution of CDK7 to these substrates in vivo incompletely separated
  12. 2019 High

    Selective covalent inhibitor with rescue mutant proved CDK7's direct G1/S and E2F role and reassigned much CTD-phosphorylation phenotype to CDK12/13, correcting earlier inhibitor-based interpretations.

    Evidence Covalent inhibitor YKL-5-124 with on-target rescue mutant, cell-cycle and expression profiling, comparison to selective CDK12/13 inhibitor

    PMID:30905681

    Open questions at the time
    • Quantitative split between CDK7 and CDK12/13 contributions to CTD phosphorylation context-dependent and unresolved
    • Direct CDK7 cell-cycle substrates driving E2F arrest not fully enumerated
  13. 2020 High

    Established CDK7 as the activating kinase for transcriptional CDK9/12/13 and resolved that TFIIH restricts CDK7 to the CTD while free CAK phosphorylates broader targets including splicing factors.

    Evidence Selective inhibitor SY-351, quantitative phosphoproteomics, in vitro kinase assays, RNA-seq splicing analysis; crystal structures of the trimeric CAK

    PMID:33055219 PMID:33060135

    Open questions at the time
    • In vivo signals controlling CAK release from TFIIH not defined
    • Order and hierarchy of CDK9/12/13 activation by CDK7 not fully mapped
  14. 2024 High

    Resolved the two-step T-loop activation (pS164 priming pT170) structurally and mechanistically, and refined CDK7's role in promoter escape via release of initiation factors and Mediator.

    Evidence Crystal structure of dually phosphorylated human CAK with phosphomutant kinase assays; rapid CDK7 inhibition with multi-omics in human cells

    PMID:38821049 PMID:39097586

    Open questions at the time
    • Kinase that deposits pS164 priming mark not identified
    • How initiation-factor release is spatially coordinated downstream not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CDK7's distribution between CAK and TFIIH pools is dynamically controlled in vivo to coordinate cell-cycle progression with transcriptional output remains unresolved.
  • No identified signal or enzyme governing CAK release from TFIIH in cells
  • Upstream kinase priming the S164 T-loop site unknown
  • Relative in vivo importance of each substrate class across cell types undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 4 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1640170 Cell Cycle 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1474165 Reproduction 1 R-HSA-4839726 Chromatin organization 1 R-HSA-73894 DNA Repair 1 R-HSA-8953854 Metabolism of RNA 1
Partners
CCNHCDK1CDK2HINT/HINT1MED1MNAT1XPBXPD
Complex memberships
CDK-activating kinase (CAK: CDK7/cyclin H/MAT1)TFIIH

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 CDK7 (MO15) is the catalytic subunit of the CDK-activating kinase (CAK), which complexes with cyclin H (37 kDa) to form a functional kinase. Reconstitution of CAK in vitro with MO15 and cyclin H demonstrated that MO15 is a cyclin-dependent kinase (CDK7). A conserved threonine in CDK7 is required for full CAK activity; mutation of this residue severely reduces activity. CAK phosphorylates and activates CDK2/cyclin and CDC2/cyclin complexes. Protein purification from mammalian cells, protein sequencing, cDNA cloning, in vitro reconstitution, site-directed mutagenesis Cell High 8069918
1993 MO15 (CDK7) is the catalytic subunit of a CAK that activates cdc2, cdk2, and divergent cdc2-like proteins through phosphorylation of Thr161 (or its homologues) in the T-loop. Immunodepletion of MO15 from Xenopus egg extracts depletes CAK activity, which is recovered in immunoprecipitates, establishing MO15 as the catalytic subunit of CAK in vivo. Protein purification from starfish oocytes, microsequencing, immunodepletion from Xenopus egg extracts, immunoprecipitation kinase assay The EMBO journal High 8344251
1994 CDK7 (MO15) is associated with the TFIIH transcription-DNA repair factor and phosphorylates the C-terminal domain (CTD) of RNA polymerase II. CDK7 is important for nucleotide excision repair through its association with TFIIH, linking cell cycle regulation, transcription, and DNA repair. In vivo and in vitro repair assays, biochemical association studies Cell High 8001135
1994 Cyclin H is a MO15 (CDK7)-associated protein identified by yeast two-hybrid screen and confirmed as a major MO15 partner in vivo; cyclin H binding enhances MO15 kinase activity towards Cdk2/cyclin A, demonstrating that a cyclin/kinase complex can regulate other cyclin/kinase complexes. Yeast two-hybrid screen, co-immunoprecipitation, in vitro kinase assay Nature High 8078587
1994 Mouse CDK7 (p39MO15) assembles with cyclin H to generate a CAK activity capable of phosphorylating and activating both CDK2 and CDK4 in complexes with their respective cyclins (cyclin A and cyclin D). Antisera against p39MO15 completely depletes mammalian cell lysates of CAK activity for both substrates. CAK activity is present in quiescent and cycling cells and is invariant throughout the cell cycle. In vitro reconstitution with insect and mammalian cell proteins, immune complex CAK assay, immunodepletion Molecular and cellular biology High 7935441
1996 MAT1, cyclin H, and CDK7 form a ternary kinase complex (CAK) that exists either free or associated with TFIIH. MAT1 is strongly associated with CDK7 and cyclin H and stimulates the kinase activity of the complex, though it is not strictly required for complex formation or basal activity. The kinase activity of TFIIH-associated CDK7 is reduced after UV light irradiation. Biochemical fractionation, co-immunoprecipitation, in vitro kinase assay, UV irradiation The EMBO journal High 8617234
1997 MAT1 is required for efficient phosphorylation of p53 by CDK7-cyclin H at Ser33 in vitro, while CDK7-cyclin H alone is sufficient to phosphorylate CDK2. MAT1 acts as a substrate specificity-determining factor for CDK7-cyclin H. p53 is phosphorylated at Ser33 in vivo. p36MAT1 and p53 interact both in vitro and in vivo. In vitro phosphorylation assays, site-directed mutagenesis, in vivo phosphorylation, co-immunoprecipitation, pulldown Molecular and cellular biology High 9372954
1997 Addition of MAT1 to recombinant bipartite CDK7-cyclin H switches its substrate preference to favour the RNA pol II CTD over CDK2. TFIIH-associated CDK7 has a strong preference for CTD over CDK2, and acquires specificity for TFIIE and TFIIF not recognized by free CAK. Thus both MAT1 and core TFIIH context govern CDK7 substrate specificity. In vitro kinase assays with recombinant proteins, comparison of free CAK vs. TFIIH-associated kinase, substrate competition assays The EMBO journal High 9130709
1998 Drosophila cdk7 is necessary for CAK activity in vivo in a multicellular organism, as demonstrated by null and temperature-sensitive mutations. cdk7 activity is required for activation of both Cdc2/Cyclin A and Cdc2/Cyclin B complexes, and for cell division, establishing cdk7 as the genuine CAK in metazoans. Genetic: null and temperature-sensitive alleles, in vivo CAK activity assay, genetic complementation Genes & development High 9450931
1998 CDK7/cyclin H kinase activity within TFIIH is inhibited concomitantly with transcriptional repression at mitosis. cdc2/cyclin B phosphorylates p62 and p36 subunits of TFIIH in vitro, and CDK7/cyclin H-mediated CTD phosphorylation is inhibited when cells enter mitosis. This inhibition can be reversed by p21Waf1/Cip1/Sdi1. In vitro transcription with nuclear extracts, mitotic kinase assays, protein phosphorylation labeling, inhibitor rescue experiments Molecular and cellular biology High 9488463
1999 Cyclin H/CDK7/p36 and cyclin C/CDK8 are biochemically distinct CTD kinases that phosphorylate distinct residues in recombinant CTD substrates and differentially phosphorylate endogenous RNA polymerase II in vivo, suggesting unique roles in transcriptional regulation. In vitro kinase assays with recombinant and endogenous substrates, site-specific phosphorylation mapping, small-molecule inhibitor profiling Oncogene Medium 10023686
2001 T-loop phosphorylation of CDK7 (at Ser164 or Thr170) cooperates with MAT1 binding to stabilize the CDK7-cyclin H-MAT1 complex in vivo. Phosphorylation of Thr170 greatly stimulates CTD kinase activity without significantly affecting CDK2 substrate activity, due to accelerated enzyme turnover (increased kcat). This substrate-specific regulation could augment CTD phosphorylation by TFIIH-associated CDK7. Drosophila genetics (temperature-sensitive and phosphosite mutants), co-immunoprecipitation, in vitro kinase assay with enzyme kinetics The EMBO journal High 11447116
2000 The C-terminus of MAT1 binds to the CDK7-cyclin H complex and activates CDK7 kinase activity. The median coiled-coil region of MAT1 anchors CAK to the TFIIH core through interactions with XPD and XPB helicases. The N-terminal RING finger domain of MAT1 is crucial for transcription activation and for CTD phosphorylation by TFIIH. Recombinant TFIIH reconstitution, deletion mutagenesis of MAT1, in vitro kinase and transcription assays The Journal of biological chemistry High 10801852
2000 CDK7 interacts with the histidine triad protein Hint/PKCI-1. This interaction is independent of cyclin H binding or CDK7 kinase activity and is conserved between CDK7/Hint and the yeast Kin28/Hnt1. Overexpression of CDK7 causes partial relocalization of Hint to the nucleus. Genetic interaction between KIN28 and HNT1 in yeast leads to elongated cell morphology and reduced colony formation. Yeast two-hybrid, co-immunoprecipitation, subcellular localization by microscopy, yeast genetics (double mutant) The Journal of biological chemistry Medium 10958787
2004 The crystal structure of human CDK7 in complex with ATP was determined at 3 Å resolution. The kinase is in an inactive conformation similar to inactive CDK2. The activation segment is phosphorylated at Thr170 and is in a defined conformation differing from phospho-CDK2. CDK7 is not a substrate for kinase-associated phosphatase. X-ray crystallography, in vitro kinase assays Structure High 15530371
2007 Mutagenesis studies identified regions in CDK2 responsible for its recognition by CDK7. CDK7 and CDK2 interact in a quasi-symmetric head-to-tail arrangement where the N-terminal lobe of one kinase docks against the C-terminal lobe of the other. Cyclin A hydrophobic pocket is not a recruitment site for CDK7. CDK1 and CDK2 can phosphorylate CDK7, but CDK7 cannot autophosphorylate. Site-directed mutagenesis of CDK2, in vitro kinase assays, structural modeling Proteins Medium 17373709
1997 CDK7, cyclin H, and MAT1 within the CAK complex are localized to coiled bodies (subnuclear structures enriched in snRNPs) in vivo. Cyclin H localization to coiled bodies is predominantly detected during G1 and S phases, with decreased detection in G2. CDK7 and cyclin H do not colocalize with P80 coilin after coiled body disruption, indicating specific targeting to the snRNP-containing domain. Immunofluorescence microscopy, cell cycle synchronization Molecular biology of the cell Medium 9243502
1997 CDK7 immunodepletion from cycling Xenopus egg extracts suppresses CAK activity and arrests extracts before M-phase. Translation of mRNAs encoding Xenopus CDK7 and its associated subunits restores CAK activity in CDK7-immunodepleted extracts, demonstrating that the CDK7 complex is necessary and sufficient for CDK activation in cycling vertebrate extracts. Immunodepletion from Xenopus egg extracts, mRNA injection, in vitro CAK activity assay Oncogene High 9315098
2013 CDK7 is a CDK4- and CDK6-activating kinase in human cells, required to maintain their activity continuously (not just to establish the active state, unlike CDK1/CDK2). Activating phosphorylation of CDK7 rises concurrently with CDK4 phosphorylation as cells exit quiescence, and CDK7 accelerates CDK4 activation in vitro. This reveals a CDK-activation cascade during G1 driven by mitogen signaling. Chemical genetics (analog-sensitive CDK7), in vitro kinase assay, cell synchronization and phosphorylation analysis Molecular cell High 23622515
2015 CDK7 inhibition (by THZ1) causes defects in RNA pol II CTD phosphorylation, co-transcriptional capping, promoter-proximal pausing, and productive elongation in vitro. CDK7 does not affect initiation but blocks essentially all CTD phosphorylation. THZ1 impacts pausing through a capping-independent block of DSIF and NELF loading; P-TEFb-dependent transition to elongation is also inhibited, likely due to loss of DSIF. In vitro transcription with nuclear extract, CDK7 inhibitor THZ1, RNA pol II phosphorylation assays Molecular cell High 26257281
2017 CDK7 inhibition in analog-sensitive cells reduces capping enzyme recruitment, increases RNA pol II promoter-proximal pausing, and causes defective termination at gene 3' ends. CDK7 regulates H3K4me3 spreading at gene 5' ends and H3K36me3 positioning via a CTD code: capping enzymes and H3K4 methyltransferases SETD1A/B selectively bind TFIIH-phosphorylated CTD and TFIIH-phosphorylated CTD stimulates SETD1A/B activity toward nucleosomes. CDK7 analog-sensitive cell system, ChIP-seq, mass spectrometry, in vitro nucleosome methylation assay Cell reports High 28768201
2019 CDK7 phosphorylates MED1 at T1457 in a CDK7-dependent manner; phosphorylated MED1 physically engages androgen receptor (AR) at super-enhancer sites and is essential for AR-mediated transcription. CDK7 inhibition (THZ1) blocks AR/MED1 co-recruitment genome-wide and reverses the hyperphosphorylated MED1-associated enzalutamide-resistant phenotype. ChIP-seq, phosphoproteomic analysis, co-immunoprecipitation, CDK7 inhibitor treatment, CRPC xenograft model Cancer discovery High 31466944
2019 A selective covalent CDK7 inhibitor (YKL-5-124) causes arrest at the G1/S transition and inhibition of E2F-driven gene expression, rescued by a CDK7 mutant unable to covalently engage YKL-5-124, demonstrating on-target specificity. Unlike THZ1, YKL-5-124 did not change RNA pol II CTD phosphorylation, revealing that CDK12/13 (THZ1 off-targets) contribute to CTD phosphorylation effects previously attributed to CDK7. Covalent chemical inhibitor with on-target rescue mutant, cell cycle analysis, gene expression profiling, comparison with selective CDK12/13 inhibitor Cell chemical biology High 30905681
2010 Xpd regulates the subcellular localization of CDK7/CAK and local mitotic kinase activity. Loss of Xpd causes changes in the dynamics of CDK7 distribution to different subcellular compartments, resulting in defects in mitotic spindle dynamics, failure to segregate chromosomes, and chromosomal instability in Drosophila embryos. Drosophila genetics (xpd mutants), immunofluorescence microscopy for CDK7 localization, mitotic kinase activity assays PLoS genetics High 20300654
2020 CDK7 directly activates transcription-associated kinases CDK9, CDK12, and CDK13 (master regulator role). TFIIH restricts CDK7 kinase function to the RNAPII CTD, whereas other substrates (e.g., SPT5, SF3B1) are phosphorylated by the free trimeric CAK (CDK7/CCNH/MAT1). CAK dissociation from TFIIH is essential for broader CDK7 kinase activation. CDK7 also phosphorylates splicing factors SF3B1 and U2AF2, causing widespread splicing defects. Selective CDK7 inhibitor SY-351, quantitative phosphoproteomics, in vitro kinase assays, RNA-seq for splicing analysis Genes & development High 33060135
2020 The crystal structure of the CAK complex (CDK7/Cyclin H/MAT1) was solved at 2.6 Å resolution using Chaetomium thermophilum. The structure reveals an intricate network of interactions between CDK7 and its two binding partners. In vitro activity measurements and functional mutagenesis show that CDK7 activation can occur independent of T-loop phosphorylation and is exclusively MAT1-dependent by positioning the CDK7 T-loop in its active conformation. X-ray crystallography, in vitro kinase assays, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 33055219
2024 The crystal structure of the human CDK7/Cyclin H/MAT1 complex with dual T-loop phosphorylations (pS164 and pT170) was solved. pT170 coordinates conserved basic residues, while pS164 nucleates a unique arginine network involving all three subunits. CAK function (CDK activation) is unaffected by T-loop phosphorylation, whereas activity towards non-CDK substrates (CTD, SPT5) is increased several-fold by T170. Dual phosphorylation stimulates multisite phosphorylation of RNAPII CTD and SPT5. In human cells, CDK7 activation is a two-step process: S164 phosphorylation precedes and may prime T170 phosphorylation. X-ray crystallography, in vitro kinase assays with T-loop phosphomutants, cell-based phosphorylation analysis Nature communications High 39097586
2019 Spironolactone-induced proteasomal degradation of XPB requires CDK7 kinase activity. CDK7 likely phosphorylates XPB at Ser90, which promotes recognition and polyubiquitination by SCFFBXL18 E3 ligase for proteasomal degradation. siRNA library screen, Western blotting, CDK7 kinase inhibition, site-directed mutagenesis of XPB Ser90 Genes to cells Medium 30762924
2003 CDK7 (complexed with cyclin H and Mat1) functions as a CDK5-activating kinase in brain by phosphorylating CDK5 at Ser159, enhancing CDK5/p25 activity. CDK7 or cyclin H immunoprecipitates from mouse brain specifically phosphorylate CDK5 at Ser159; blocked CDK7 immunoprecipitate does not phosphorylate CDK5. Partial purification of brain enzyme, peptide phosphorylation assay, immunoprecipitation kinase assay from mouse brain, mutagenesis (Ser159Ala) Cellular physiology and biochemistry Medium 14586172
2000 p16(INK4A) inhibits CDK7-mediated CTD kinase activity (in addition to CDK4-pRb kinase). The ability of p16(INK4A) to inhibit CDK7-CTD kinase contributes to its capacity to induce cell cycle arrest, representing an alternative pathway for p16-mediated cell cycle regulation. In vitro CTD kinase assay with p16, cell-based G1 arrest experiments Molecular and cellular biology Medium 11003668
2016 CDK7 interacts functionally with MSL1, a component of the Drosophila dosage compensation complex. MSL1 depletion leads to decreased phosphorylation of Ser5 of RNA polymerase II CTD. Genetic and biochemical analyses reveal a functional interaction between MSL1 and CDK7. Genetic interaction analysis, biochemical co-precipitation, in vivo CTD phosphorylation measurement, transgenic flies with phosphomutants Nature structural & molecular biology Medium 27183194
2024 CDK7 kinase activity promotes RNA pol II escape from promoters by facilitating release of initiation factors and Mediator from RNA pol II. CDK7 inhibition causes RNA pol II retention at promoters, decreased initiation, and immediate global downregulation of transcript synthesis, while elongation and termination are not directly affected. RNA pol II can proceed into gene bodies without pausing while retaining initiation factors, which are released further downstream when CDK7-independent phosphorylation occurs. Rapid CDK7 kinase inhibition combined with multi-omics (TT-seq, ChIP-seq, etc.) in human cells Molecular cell High 38821049
2011 CDK7 and CCNH (cyclin H) are required for meiotic progression of porcine oocytes. Overexpression of CDK7 or CCNH accelerates meiotic resumption, Thr161 phosphorylation of CDC2, cyclin B synthesis, and MPF activation; knockdown of CDK7 or CCNH inhibits these meiotic events. MNAT1 overexpression or knockdown had no influence on meiotic resumption. Overexpression and RNA knockdown (antisense RNA injection) in porcine oocytes, kinase activity assay, immunofluorescence Biology of reproduction Medium 21778139
2011 PKC-ι directly associates with and phosphorylates CDK7 at T170 in a cell cycle-dependent manner in glioblastoma cells, leading to downstream CDK2 phosphorylation at T160 and G1-S progression. PKC-ι downregulation reduces CDK7 and CDK2 phosphorylation. Co-immunoprecipitation, in vitro kinase assay with purified PKC-ι, siRNA knockdown, phosphorylation analysis Carcinogenesis Medium 22021906
2019 CDK7 phosphorylates YAP/TAZ at S128/S90 (and Drosophila Yki at S169) to inhibit recruitment of the CRL4DCAF12 E3 ubiquitin ligase complex, preventing ubiquitination and degradation of YAP/TAZ in the nucleus. CDK7 inactivation reduces organ size and inhibits tumor growth, which is reversed by restoring Yki/YAP activity. Drosophila genetics, co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, CRISPR in mammalian cells Genes & development High 31857346
2023 CDK7 phosphorylates nuclear YAP1 at S127 and S397 sites, enhancing its transcriptional function and promoting LDHD protein expression. The CDK7-YAP-LDHD axis enables cancer stem cells to eliminate D-lactate and generate pyruvate, supporting stemness and ferroptosis resistance. In vitro phosphorylation assay, site-directed mutagenesis, ChIP-seq, co-immunoprecipitation, loss-of-function in ESCC cells Signal transduction and targeted therapy Medium 37582812
2016 Triptolide activates CDK7 by phosphorylating Thr170 in parental and MDR tumor cell lines, and CDK7 then phosphorylates RNA pol II large subunit RPB1 at Ser1878, leading to RPB1 degradation and cell killing. Selective CDK7 inhibitor BS-181 partially rescued RPB1 degradation and cell killing by triptolide. In vitro and cell-based kinase assays, CDK7 selective inhibitor rescue experiment, phosphorylation site mapping Molecular cancer therapeutics Medium 27197304
2023 Active mTOR signaling promotes CDK7 inhibitor (samuraciclib)-induced cellular senescence (permanent cell cycle exit). CDK7 inhibition by samuraciclib induces senescence without promoting DNA damage signaling or cell death. mTOR inhibition decreases sensitivity to CDK7 inhibition, and reverting a growth-promoting PIK3CA mutation to wild type decreases CDK7i sensitivity. Genome-wide CRISPR knockout screen, genetic reversion of PIK3CA mutation, senescence assays, cell viability Molecular cell Medium 37977119

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase. Cell 593 8069918
1994 The MO15 cell cycle kinase is associated with the TFIIH transcription-DNA repair factor. Cell 422 8001135
1993 The MO15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (CDKs) through phosphorylation of Thr161 and its homologues. The EMBO journal 380 8344251
2015 CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell 374 26406377
2005 Secrets of a double agent: CDK7 in cell-cycle control and transcription. Journal of cell science 276 16280550
1994 A cyclin associated with the CDK-activating kinase MO15. Nature 252 8078587
1994 Activation of cyclin-dependent kinase 4 (cdk4) by mouse MO15-associated kinase. Molecular and cellular biology 190 7935441
2019 CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer. Cancer cell 180 31883968
1997 p53 is phosphorylated by CDK7-cyclin H in a p36MAT1-dependent manner. Molecular and cellular biology 167 9372954
1997 Regulation of CDK7 substrate specificity by MAT1 and TFIIH. The EMBO journal 162 9130709
1998 Cdk7 is essential for mitosis and for in vivo Cdk-activating kinase activity. Genes & development 158 9450931
2020 CDK7 inhibitors as anticancer drugs. Cancer metastasis reviews 154 32385714
2013 A Cdk7-Cdk4 T-loop phosphorylation cascade promotes G1 progression. Molecular cell 148 23622515
2015 THZ1 Reveals Roles for Cdk7 in Co-transcriptional Capping and Pausing. Molecular cell 141 26257281
2019 Development of a Selective CDK7 Covalent Inhibitor Reveals Predominant Cell-Cycle Phenotype. Cell chemical biology 140 30905681
2017 Human TFIIH Kinase CDK7 Regulates Transcription-Associated Chromatin Modifications. Cell reports 128 28768201
2019 Discovery and Characterization of SY-1365, a Selective, Covalent Inhibitor of CDK7. Cancer research 120 31064851
2004 The crystal structure of human CDK7 and its protein recognition properties. Structure (London, England : 1993) 120 15530371
2001 T-loop phosphorylation stabilizes the CDK7-cyclin H-MAT1 complex in vivo and regulates its CTD kinase activity. The EMBO journal 119 11447116
2018 ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment. Molecular cancer therapeutics 117 29545334
1996 MAT1, cdk7 and cyclin H form a kinase complex which is UV light-sensitive upon association with TFIIH. The EMBO journal 114 8617234
2018 Cdk7: a kinase at the core of transcription and in the crosshairs of cancer drug discovery. Transcription 108 30488763
1999 Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases. Oncogene 104 10023686
2019 CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation. Cancer discovery 100 31466944
2017 SNHG1 lncRNA negatively regulates miR-199a-3p to enhance CDK7 expression and promote cell proliferation in prostate cancer. Biochemical and biophysical research communications 93 28400279
2017 Therapeutic Rationale to Target Highly Expressed CDK7 Conferring Poor Outcomes in Triple-Negative Breast Cancer. Cancer research 85 28455421
1998 Repression of TFIIH transcriptional activity and TFIIH-associated cdk7 kinase activity at mitosis. Molecular and cellular biology 84 9488463
2013 C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway. Circulation research 79 23784961
2017 THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors. Nature communications 78 28134252
2000 Distinct regions of MAT1 regulate cdk7 kinase and TFIIH transcription activities. The Journal of biological chemistry 70 10801852
2020 Selective inhibition of CDK7 reveals high-confidence targets and new models for TFIIH function in transcription. Genes & development 69 33060135
2020 CDK7 Inhibitors in Cancer Therapy: The Sweet Smell of Success? Journal of medicinal chemistry 68 32150405
2023 CDK7-YAP-LDHD axis promotes D-lactate elimination and ferroptosis defense to support cancer stem cell-like properties. Signal transduction and targeted therapy 66 37582812
2021 Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7. Journal of medicinal chemistry 65 34726887
2017 Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors. Cell reports 65 29020632
1996 Pfmrk, a MO15-related protein kinase from Plasmodium falciparum. Gene cloning, sequence, stage-specific expression and chromosome localization. European journal of biochemistry 64 8944769
1994 Two novel human serine/threonine kinases with homologies to the cell cycle regulating Xenopus MO15, and NIMA kinases: cloning and characterization of their expression pattern. Oncogene 62 8208544
2019 CDK7 regulates organ size and tumor growth by safeguarding the Hippo pathway effector Yki/Yap/Taz in the nucleus. Genes & development 58 31857346
2019 Inhibition of the transcriptional kinase CDK7 overcomes therapeutic resistance in HER2-positive breast cancers. Oncogene 56 31462705
2021 Targeting Triple-Negative Breast Cancer with Combination Therapy of EGFR CAR T Cells and CDK7 Inhibition. Cancer immunology research 55 33875483
2019 Targeting Super-Enhancer-Driven Oncogenic Transcription by CDK7 Inhibition in Anaplastic Thyroid Carcinoma. Thyroid : official journal of the American Thyroid Association 55 30924726
2000 Neuronal CDK7 in hippocampus is related to aging and Alzheimer disease. Neurobiology of aging 55 11124424
2019 THZ1 reveals CDK7-dependent transcriptional addictions in pancreatic cancer. Oncogene 54 30692639
1997 The cdk7-cyclin H-MAT1 complex associated with TFIIH is localized in coiled bodies. Molecular biology of the cell 54 9243502
2023 Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib. Nature communications 53 37488191
1996 Expression of CDK7/CAK in normal and tumor cells of diverse histogenesis, cell-cycle position and differentiation. International journal of cancer 53 8647641
2000 Interactions of Cdk7 and Kin28 with Hint/PKCI-1 and Hnt1 histidine triad proteins. The Journal of biological chemistry 52 10958787
2020 Targeting Super-Enhancer-Associated Oncogenes in Osteosarcoma with THZ2, a Covalent CDK7 Inhibitor. Clinical cancer research : an official journal of the American Association for Cancer Research 51 31937612
1995 Molecular cloning of CDK7-associated human MAT1, a cyclin-dependent kinase-activating kinase (CAK) assembly factor. Cancer research 51 8521393
2019 Combinational therapeutic targeting of BRD4 and CDK7 synergistically induces anticancer effects in head and neck squamous cell carcinoma. Cancer letters 50 31765738
1998 A rice homolog of Cdk7/MO15 phosphorylates both cyclin-dependent protein kinases and the carboxy-terminal domain of RNA polymerase II. The Plant journal : for cell and molecular biology 49 10036778
2018 High MITF Expression Is Associated with Super-Enhancers and Suppressed by CDK7 Inhibition in Melanoma. The Journal of investigative dermatology 46 29408204
2016 Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44. Molecular cancer therapeutics 41 27197304
2020 Structural basis for CDK7 activation by MAT1 and Cyclin H. Proceedings of the National Academy of Sciences of the United States of America 39 33055219
2018 Targeting CDK7 increases the stability of Snail to promote the dissemination of colorectal cancer. Cell death and differentiation 39 30451989
2023 Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition. Molecular cell 36 37977119
2016 Selective CDK7 inhibition with BS-181 suppresses cell proliferation and induces cell cycle arrest and apoptosis in gastric cancer. Drug design, development and therapy 36 27042010
2021 Transcriptional control of DNA repair networks by CDK7 regulates sensitivity to radiation in MYC-driven medulloblastoma. Cell reports 35 33910002
2010 Drosophila Xpd regulates Cdk7 localization, mitotic kinase activity, spindle dynamics, and chromosome segregation. PLoS genetics 35 20300654
2023 CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma. Blood 34 36877894
2019 CDK7 inhibitor THZ1 inhibits MCL1 synthesis and drives cholangiocarcinoma apoptosis in combination with BCL2/BCL-XL inhibitor ABT-263. Cell death & disease 33 31399555
2024 Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-resistant Estrogen Receptor-positive Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 32 38381406
2020 Combination therapy with the CDK7 inhibitor and the tyrosine kinase inhibitor exerts synergistic anticancer effects against MYCN-amplified neuroblastoma. International journal of cancer 32 32086952
2019 A high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells. Nature communications 32 31784510
2017 CDK7 inhibition suppresses rheumatoid arthritis inflammation via blockage of NF-κB activation and IL-1β/IL-6 secretion. Journal of cellular and molecular medicine 30 29083085
2024 CDK7 kinase activity promotes RNA polymerase II promoter escape by facilitating initiation factor release. Molecular cell 29 38821049
2011 CDK7 and CCNH are components of CDK-activating kinase and are required for meiotic progression of pig oocytes. Biology of reproduction 29 21778139
1997 Is Cdk7/cyclin H/MAT1 the genuine cdk activating kinase in cycling Xenopus egg extracts? Oncogene 29 9315098
2019 The covalent CDK7 inhibitor THZ1 enhances temsirolimus-induced cytotoxicity via autophagy suppression in human renal cell carcinoma. Cancer letters 28 31812697
2022 Targeting CDK7 in oncology: The avenue forward. Pharmacology & therapeutics 25 35700828
2020 Blockade of CDK7 Reverses Endocrine Therapy Resistance in Breast Cancer. International journal of molecular sciences 25 32340192
2016 CDK7 and miR-210 Co-regulate Cell-Cycle Progression of Neural Progenitors in the Developing Neocortex. Stem cell reports 25 27411104
2009 Combined genetic effect of CDK7 and ESR1 polymorphisms on breast cancer. Breast cancer research and treatment 25 19941161
2007 Recognition of Cdk2 by Cdk7. Proteins 25 17373709
2019 ABC-transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942. Oncogene 24 31530935
2003 The histidine triad protein Hint is not required for murine development or Cdk7 function. Molecular and cellular biology 24 12748294
2000 Regulation of CDK7-carboxyl-terminal domain kinase activity by the tumor suppressor p16(INK4A) contributes to cell cycle regulation. Molecular and cellular biology 24 11003668
2021 Targeting CDK7 suppresses super enhancer-linked inflammatory genes and alleviates CAR T cell-induced cytokine release syndrome. Molecular cancer 23 33397398
2003 Cdk7 functions as a cdk5 activating kinase in brain. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 23 14586172
2023 Super-enhancer-driven lncRNA LIMD1-AS1 activated by CDK7 promotes glioma progression. Cell death & disease 22 37385987
2022 Synergistic Anti-Tumor Effect of Combining Selective CDK7 and BRD4 Inhibition in Neuroblastoma. Frontiers in oncology 22 35198433
2021 Transcriptional inhibition by CDK7/9 inhibitor SNS-032 suppresses tumor growth and metastasis in esophageal squamous cell carcinoma. Cell death & disease 22 34741018
2020 Efficacy of the CDK7 Inhibitor on EMT-Associated Resistance to 3rd Generation EGFR-TKIs in Non-Small Cell Lung Cancer Cell Lines. Cells 22 33287368
2019 Efficacy of the novel CDK7 inhibitor QS1189 in mantle cell lymphoma. Scientific reports 22 31076643
2011 Regulation of Cdk7 activity through a phosphatidylinositol (3)-kinase/PKC-ι-mediated signaling cascade in glioblastoma. Carcinogenesis 22 22021906
2024 Cyclin-dependent kinase 7 (CDK7) inhibitors as a novel therapeutic strategy for different molecular types of breast cancer. British journal of cancer 21 38355840
2021 Discovery of a novel CDK7 inhibitor YPN-005 in small cell lung cancer. European journal of pharmacology 21 34224696
2019 Spironolactone-induced XPB degradation depends on CDK7 kinase and SCFFBXL18 E3 ligase. Genes to cells : devoted to molecular & cellular mechanisms 21 30762924
2019 CDK7 inhibition suppresses aberrant hedgehog pathway and overcomes resistance to smoothened antagonists. Proceedings of the National Academy of Sciences of the United States of America 21 31182587
2023 A patent review of cyclin-dependent kinase 7 (CDK7) inhibitors (2018-2022). Expert opinion on therapeutic patents 20 36975020
2022 CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia. EMBO molecular medicine 20 35253392
2022 CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer. Journal of experimental & clinical cancer research : CR 20 35945614
2019 Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion. The Journal of experimental medicine 20 31506280
2023 The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer. British journal of cancer 19 37076563
2021 Identification of CDK7 Inhibitors from Natural Sources Using Pharmacoinformatics and Molecular Dynamics Simulations. Biomedicines 19 34572383
1995 The regulation and functions of cdk7. Progress in cell cycle research 19 9552366
2016 Functional interplay between MSL1 and CDK7 controls RNA polymerase II Ser5 phosphorylation. Nature structural & molecular biology 18 27183194
2024 Structural basis of Cdk7 activation by dual T-loop phosphorylation. Nature communications 17 39097586
2019 CDK7 inhibition as a promising therapeutic strategy for lung squamous cell carcinomas with a SOX2 amplification. Cellular oncology (Dordrecht, Netherlands) 17 30838525
2007 Developmental expression of cyclin H and Cdk7 in zebrafish: the essential role of cyclin H during early embryo development. Cell research 17 17287831

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