Affinage

CCNK

Cyclin-K · UniProt O75909

Length
580 aa
Mass
64.2 kDa
Annotated
2026-06-09
36 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Cyclin K (CCNK) is a transcriptional cyclin that functions as the activating partner of the cyclin-dependent kinases CDK12 and CDK13, with these complexes governing RNA Pol II-dependent transcription, co-transcriptional RNA processing, and 3'-end cleavage/polyadenylation (PMID:25561469, PMID:38587191). CCNK-CDK12/13 complexes co-purify with numerous RNA processing factors, and CCNK depletion preferentially reduces expression of DNA damage response and snoRNA genes and causes RNA processing defects without globally altering CTD phosphorylation (PMID:25561469). Beyond transcription, the CDK12-CCNK complex phosphorylates the translational repressor 4E-BP1 at S65/T70 to promote 4E-BP1/eIF4G exchange on CHK1 and other mTORC1 target mRNAs, and its loss produces chromosome misalignment and segregation defects, linking CCNK to translational control of mitotic genome stability (PMID:30819820). In prostate cancer, androgen receptor binds the CCNK promoter to drive Cyclin K expression, and loss of CDK12/CCNK activity shifts AR pre-mRNA toward intron 3 polyadenylation, generating AR splice variants that promote castration resistance (PMID:36129942). In neural progenitors, CCNK supports proliferation and suppresses apoptosis by restraining WNT5A expression, a defect rescued by Wnt5a inhibition (PMID:37597256). CCNK is a tractable target of molecular glue degraders (HQ461, NCT02, CR8, ZLY025) that recruit CDK12 to the DDB1-CUL4-RBX1 E3 ligase, triggering CCNK polyubiquitination and proteasomal degradation, loss of CDK12 substrate phosphorylation, and tumor cell killing, with TP53 deficiency associated with sensitivity (PMID:32804079, PMID:34289372, PMID:41165741).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2008 Medium

    Established that Cyclin K can assemble into P-TEFb-type complexes distinct from Cyclin T, addressing whether CCNK participates in transcriptional kinase complexes and revealing a virological consequence.

    Evidence Overexpression viral replication assays and biochemical P-TEFb complex analysis in cell lines

    PMID:18520353

    Open questions at the time
    • The physiological CDK partner of CCNK was not yet resolved
    • Mechanism of lentiviral inhibition not dissected
    • Later work assigned CCNK primarily to CDK12/CDK13 rather than CDK9
  2. 2015 High

    Defined CCNK as the dedicated cyclin partner of CDK12 and CDK13 and showed these complexes selectively control DNA damage response and snoRNA gene expression and RNA processing, answering which kinases CCNK activates and what genes it regulates.

    Evidence Flag affinity purification/MS plus siRNA knockdown with RNA-seq and bulk CTD phosphorylation assays in HCT116 cells

    PMID:25561469

    Open questions at the time
    • Direct kinase substrates beyond CTD not enumerated
    • Mechanism of gene selectivity unresolved
    • No structural basis for complex assembly
  3. 2019 High

    Extended CCNK function beyond transcription by showing the CDK12-CCNK complex phosphorylates 4E-BP1 to control translation of mitotic mRNAs, explaining how CCNK loss compromises genome stability.

    Evidence In vitro kinase assays with S65/T70 site mapping, RIP-seq, Ribo-seq, and confocal imaging of chromosome segregation

    PMID:30819820

    Open questions at the time
    • Relative contribution of translational vs transcriptional roles to mitotic phenotype unclear
    • Full substrate repertoire of the complex unknown
  4. 2020 High

    Revealed that CCNK is degradable by a molecular glue that reprograms CDK12 into a DDB1-CUL4-RBX1 substrate receptor, opening a therapeutic strategy and confirming CCNK's role in supporting CDK12 kinase output.

    Evidence Chemical and genetic screens, biochemical reconstitution of the CDK12-DDB1 interaction, polyubiquitination assays, and SAR analysis in cancer cells

    PMID:32804079

    Open questions at the time
    • Determinants of degrader selectivity across cell types not defined
    • Genotype-specific vulnerability not established here
  5. 2021 High

    Showed a second molecular glue (NCT02) co-degrades CCNK and CDK12 and that TP53 deficiency marks sensitivity, addressing which tumors are vulnerable to CCNK loss.

    Evidence Patient-derived CRC spheroid screen, ubiquitination assays, and CCNK/CDK12 knockout with proliferation and xenograft assays

    PMID:34289372

    Open questions at the time
    • Molecular basis of TP53-dependent sensitivity not mechanistically dissected
    • Generalizability beyond CRC unclear
  6. 2022 High

    Placed CCNK in an androgen receptor regulatory loop and linked its activity to AR mRNA polyadenylation, explaining how CDK12/CCNK loss drives AR splice variants and castration resistance.

    Evidence ChIP of AR at the CCNK promoter, CDK12 inhibitor/CCNK degrader treatment, genetic inactivation, RT-PCR of AR splice variants, and PARP inhibitor rescue in prostate cancer

    PMID:36129942

    Open questions at the time
    • Direct biochemical mechanism coupling CCNK activity to APC/polyadenylation choice not resolved
    • Clinical relevance of the AR-CCNK loop not established
  7. 2023 High

    Identified a developmental role for CCNK in neural progenitors, showing it sustains proliferation and suppresses apoptosis by restraining WNT5A, framing CCNK as upstream of Wnt5a signaling.

    Evidence Patient-derived iPSC/NPC models, NPC-specific Ccnk knockout mice, RNA-seq, and Wnt5a inhibitor rescue

    PMID:37597256

    Open questions at the time
    • Mechanism by which CCNK represses WNT5A not defined
    • Connection to the CDK12/CDK13 kinase function not tested
  8. 2024 Medium

    Implicated the CCNK/CDK12 complex as a core cleavage and polyadenylation factor through unbiased functional screening, sharpening CCNK's role in 3'-end RNA processing.

    Evidence Genome-wide CRISPR/Cas9 screen with a dual-fluorescence polyadenylation readthrough reporter in human cells

    PMID:38587191

    Open questions at the time
    • Genetic identification only without biochemical reconstitution of CPA activity
    • Direct involvement of CCNK in the CPA machinery not shown structurally
  9. 2025 Medium

    Suggested a meiotic cell cycle role by showing CCNK overexpression accelerates oocyte meiotic resumption via early Cyclin B1 nuclear entry and premature MPF activation.

    Evidence CCNK overexpression in mouse oocytes with live imaging and immunofluorescence of CCNB1 entry

    PMID:41355749

    Open questions at the time
    • Single overexpression study without loss-of-function or biochemical confirmation
    • Mechanism linking CCNK to CCNB1 nuclear import unknown
  10. 2025 Medium

    Advanced CCNK degradation toward in vivo therapeutics with a metabolically optimized, highly selective degrader, validating CCNK as a druggable target via the DDB1-CUL4 mechanism.

    Evidence Cell-based degradation assays, TMT global proteomic selectivity profiling, xenograft efficacy, and PK studies

    PMID:41165741

    Open questions at the time
    • Mechanistic basis inferred from prior glue studies rather than re-derived
    • Tumor-type and genotype selectivity not fully mapped
  11. 2026 Low

    Linked the CDK12-CCNK axis to immune evasion by showing CR8-mediated complex degradation downregulates PD-L1 in triple-negative breast cancer.

    Evidence Nanoplatform-delivered CR8 in TNBC cell lines and in vivo with immunoblotting and tumor immune microenvironment analysis

    PMID:41810739

    Open questions at the time
    • No direct mechanistic dissection of how CDK12-CCNK regulates PD-L1
    • Single study, delivery-platform dependent
    • Causality between CCNK loss and PD-L1 not separated from CDK12 loss

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCNK-CDK12/13 achieves gene- and substrate-selective output, and how this single kinase module is wired into distinct developmental, meiotic, and immune programs, remains unresolved.
  • No structural model coupling CCNK assembly to substrate selection
  • Mechanism by which CCNK loss reprograms polyadenylation choice undefined
  • Whether developmental, meiotic, and immune roles depend on the canonical CDK12/13 kinase activity untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-73894 DNA Repair 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-8953854 Metabolism of RNA 2
Partners
ARCDK12CDK13CDK9CUL4DDB1EIF4EBP1RBX1
Complex memberships
CCNK-CDK12CCNK-CDK13P-TEFb (CCNK-CDK9)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Cyclin K (CCNK/CPR4) forms P-TEFb complexes with CDK9 that are unresponsive to Tat-mediated activation and HEXIM1-mediated inactivation, in contrast to Cyclin T-containing P-TEFb; overexpression of Cyclin K inhibits HIV and SIV replication, identifying it as a natural inhibitor of primate lentiviruses. Overexpression assays in cell lines measuring viral replication; biochemical analysis of P-TEFb complex composition and responsiveness to Tat/HEXIM1 AIDS (London, England) Medium 18520353
2015 CDK12 and CDK13 each associate with Cyclin K (CCNK) as their cyclin partner; these complexes co-purify with numerous RNA processing factors. Knockdown of CCNK (or CDK12/CDK13) preferentially reduces expression of DNA damage response genes and snoRNA genes without globally affecting RNA Pol II CTD phosphorylation levels, and leads to defects in RNA processing. Flag-tag affinity purification coupled with mass spectrometry; siRNA knockdown followed by RNA-seq and bulk CTD phosphorylation assays in HCT116 cells Molecular and cellular biology High 25561469
2019 CDK12, in complex with Cyclin K (CCNK), phosphorylates the translational repressor 4E-BP1 at S65 and T70 (two Ser-Pro sites), facilitating exchange of 4E-BP1 with eIF4G at the 5' cap of CHK1 and other mTORC1 target mRNAs. Depletion of CCNK causes severe chromosome misalignment, bridging, and segregation defects, establishing a role for the CDK12–CCNK complex in translational control of mitotic genome stability. In vitro kinase assays with site-specific phosphorylation mapping (S65/T70); RIP-seq; ribosome profiling (Ribo-seq); confocal imaging of chromosome segregation after CCNK depletion Genes & development High 30819820
2020 The molecular glue HQ461 promotes a direct interaction between CDK12 and the DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of the CDK12-binding partner Cyclin K (CCNK). Degradation of CCNK by HQ461 reduces CDK12 kinase function (decreased phosphorylation of CDK12 substrates), downregulates DNA damage response genes, and kills cancer cells. High-throughput chemical screening; loss-of-function and gain-of-function genetic screens in human cancer cells; biochemical reconstitution of the CDK12–DDB1 interaction; polyubiquitination assays; structure-activity relationship analysis eLife High 32804079
2021 The small molecule NCT02 acts as a molecular glue that induces ubiquitination and proteasomal degradation of Cyclin K (CCNK) and co-degradation of its complex partner CDK12. Knockout of CCNK or CDK12 decreases proliferation of colorectal cancer (CRC) cells in vitro and tumor growth in vivo, and sensitivity to CCNK/CDK12 degradation is associated with TP53 deficiency. Small-molecule library screen on patient-derived CRC spheroids; ubiquitination assays; CCNK/CDK12 knockout with proliferation and xenograft growth assays Cell reports High 34289372
2022 Androgen receptor (AR) binds to the CCNK gene promoter and upregulates Cyclin K expression. Conversely, the antiandrogen enzalutamide decreases AR occupancy at the CCNK promoter and suppresses CCNK expression. Pharmacological inhibition or genetic inactivation of CDK12, or CCNK degrader treatment, induces AR gene intron 3 polyadenylation usage and AR splice variant expression, driving castration resistance in prostate cancer. ChIP assay of AR at CCNK promoter; CDK12 inhibitor and CCNK degrader treatment; genetic inactivation of CDK12/CCNK; RT-PCR for AR splice variants; enzalutamide resistance assays; PARP inhibitor rescue experiments Proceedings of the National Academy of Sciences of the United States of America High 36129942
2024 Genome-wide CRISPR/Cas9 screening using a dual-fluorescence 3'-end processing reporter identified the CCNK/CDK12 complex as a potential core cleavage and polyadenylation (CPA) factor in human cells. Genome-wide CRISPR/Cas9 loss-of-function screen with a dual-fluorescence polyadenylation readthrough reporter in human cells Nucleic acids research Medium 38587191
2023 Loss of CCNK (Cyclin K) in patient-derived neural progenitor cells (NPCs) and in NPC-specific Ccnk knockout mice causes deficient NPC proliferation and enhanced apoptosis. RNA sequencing revealed significant upregulation of WNT5A in CCNK-deficient NPCs. A Wnt5a inhibitor rescued NPC proliferation defects and reduced apoptosis in both patient-derived NPCs and developing cortex of Ccnk KO mice, placing CCNK upstream of Wnt5a signaling in neural progenitor biology. Patient-derived iPSC/NPC models; NPC-specific Ccnk knockout mice; RNA-seq transcriptomic analysis; rescue experiments with Wnt5a inhibitor measuring NPC proliferation and apoptosis Annals of neurology High 37597256
2025 CCNK overexpression in mouse oocytes accelerates resumption of meiosis (germinal vesicle breakdown), attributed to early nuclear entry of Cyclin B1 (CCNB1) and premature activation of maturation promoting factor (MPF/CDK1-CyclinB1), establishing a role for CCNK in regulating meiotic cell cycle progression. Overexpression of CCNK in mouse oocytes; live imaging and immunofluorescence of CCNB1 nuclear entry; measurement of meiotic resumption timing Molecular reproduction and development Medium 41355749
2026 The molecular glue CR8 induces CDK12–CCNK complex degradation; precise delivery in triple-negative breast cancer leads to PD-L1 downregulation and reversal of immunosuppression. Photothermal therapy-induced PD-L1 upregulation is counteracted by CR8-mediated CDK12 degradation, demonstrating that the CDK12–CCNK axis regulates PD-L1 expression. Nanoplatform-delivered CR8 in TNBC cell lines and in vivo; immunoblotting for CDK12, CCNK, and PD-L1; tumor immune microenvironment analysis ACS applied materials & interfaces Low 41810739
2025 A metabolically optimized CCNK molecular glue degrader (ZLY025) potently degrades CCNK (DC50 = 42.7 nM, Dmax >93%) via the DDB1-CUL4 E3 ubiquitin ligase mechanism, with high selectivity confirmed by TMT-based global proteomics showing minimal off-target degradation, and demonstrates antitumor activity in xenograft models. Cell-based CCNK degradation assays; TMT-based global proteomic profiling for selectivity; xenograft tumor growth assays; pharmacokinetic studies Journal of medicinal chemistry Medium 41165741

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America 233 9371805
2020 Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation. eLife 166 32804079
2015 Characterization of human cyclin-dependent kinase 12 (CDK12) and CDK13 complexes in C-terminal domain phosphorylation, gene transcription, and RNA processing. Molecular and cellular biology 165 25561469
1986 Cloning of the chicken progesterone receptor. Proceedings of the National Academy of Sciences of the United States of America 165 2426697
2021 Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer. Cell reports 70 34289372
2019 CDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stability. Genes & development 69 30819820
2016 Aflatoxin B1 induces persistent epigenomic effects in primary human hepatocytes associated with hepatocellular carcinoma. Toxicology 68 27153756
2017 Cysteine protease cathepsin B mediates radiation-induced bystander effects. Nature 66 28723894
2000 Comparison of globulin mobilization and cysteine proteinases in embryonic axes and cotyledons during germination and seedling growth of vetch (Vicia sativa L.). Journal of experimental botany 56 10944156
2020 Angiotensin I-Converting Enzyme (ACE) Inhibitory and Antioxidant Activity of Umami Peptides after In Vitro Gastrointestinal Digestion. Journal of agricultural and food chemistry 55 32662986
2018 Crosstalk in competing endogenous RNA networks reveals new circular RNAs involved in the pathogenesis of early HIV infection. Journal of translational medicine 50 30486834
2001 Stored cysteine proteinases start globulin mobilization in protein bodies of embryonic axes and cotyledons during vetch (Vicia sativa L.) seed germination. Planta 43 11346945
2000 The families of papain- and legumain-like cysteine proteinases from embryonic axes and cotyledons of Vicia seeds: developmental patterns, intracellular localization and functions in globulin proteolysis. Plant molecular biology 39 10949376
2022 CYCLIN K down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and PARP inhibitor vulnerability in castration-resistant prostate cancer. Proceedings of the National Academy of Sciences of the United States of America 23 36129942
1996 Assessment of a PCR technique for the detection and identification of Cryptococcus neoformans. Journal of medical and veterinary mycology : bi-monthly publication of the International Society for Human and Animal Mycology 23 8873884
2018 De Novo Mutations of CCNK Cause a Syndromic Neurodevelopmental Disorder with Distinctive Facial Dysmorphism. American journal of human genetics 20 30122539
2012 Effect of cardiopulmonary resuscitation on restoration of myocardial ATP in prolonged ventricular fibrillation. Resuscitation 18 22727945
2021 Antifungal roles of adult-specific cuticular protein genes of the red flour beetle, Tribolium castaneum. Journal of invertebrate pathology 17 34606828
2022 CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature. Genetics in medicine : official journal of the American College of Medical Genetics 16 35063350
2013 Identification of Target Genes Involved in the Antiproliferative Effect of Enzyme-Modified Ginseng Extract in HepG2 Hepatocarcinoma Cell. Evidence-based complementary and alternative medicine : eCAM 15 24174975
2024 Identifying human pre-mRNA cleavage and polyadenylation factors by genome-wide CRISPR screens using a dual fluorescence readthrough reporter. Nucleic acids research 13 38587191
2023 Transcriptome Profiling of Cardiac Glycoside Treatment Reveals EGR1 and Downstream Proteins of MAPK/ERK Signaling Pathway in Human Breast Cancer Cells. International journal of molecular sciences 9 37958905
2012 Identification and characterization of novel microRNA candidates from deep sequencing. Clinica chimica acta; international journal of clinical chemistry 9 23153516
2021 A Recurrent De Novo Terminal Duplication of 14q32 in Korean Siblings Associated with Developmental Delay and Intellectual Disability, Growth Retardation, Facial Dysmorphism, and Cerebral Infarction: A Case Report and Literature Review. Genes 5 34573370
2008 Cyclin K/CPR4 inhibits primate lentiviral replication by inactivating Tat/positive transcription elongation factor b-dependent long terminal repeat transcription. AIDS (London, England) 5 18520353
2023 CCNK Gene Deficiency Influences Neural Progenitor Cells Via Wnt5a Signaling in CCNK-Related Syndrome. Annals of neurology 4 37597256
2018 Transcriptomic, Functional, and Network Analyses Reveal Novel Genes Involved in the Interaction Between Caenorhabditis elegans and Stenotrophomonas maltophilia. Frontiers in cellular and infection microbiology 4 30177956
2025 Proximal Deletions of 14q32.2 Result in Severe Neurodevelopmental Outcomes, Congenital Anomalies, and Dysmorphic Features. American journal of medical genetics. Part A 1 40110997
2022 A Non-Cell-Autonomous Mode of DNA Damage Response in Soma of Caenorhabditis elegans. International journal of molecular sciences 1 35886900
2026 Dual-Stimuli-Responsive Nanoplatform Delivering Molecular Glue CR8 for Synergistic CDK12 Degradation and Immunomodulatory Photothermal Therapy in TNBC. ACS applied materials & interfaces 0 41810739
2026 Ectopic Wnt6 expression induces twin-spot markings in the epidermis of the silkworm Bombyx mori - Potential molecular target to discover evolutionary mechanisms of adaptive body coloration in insects. The FEBS journal 0 41928441
2026 Cathepsin B protease mediates high population density-induced mutagenesis to drive genome evolution and competitive growth. Nature communications 0 42082483
2025 A Further Case Supporting CCNK as a Neurodevelopmental Disease Gene. Clinical genetics 0 41101726
2025 Discovery of Highly Potent and Orally Available CCNK Molecular Glue Degraders as Broad-Spectrum Antitumor Agents. Journal of medicinal chemistry 0 41165741
2025 Overexpression of CCNK Leads to Early Resumption of Meiosis in Mouse Oocytes. Molecular reproduction and development 0 41355749
2025 Cysteine protease cathepsin B promotes high population density-induced mutagenesis, driving genome evolution and competitive growth in response to the crowding stress. bioRxiv : the preprint server for biology 0 41509278

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