{"gene":"CCNK","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2008,"finding":"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.","method":"Overexpression assays in cell lines measuring viral replication; biochemical analysis of P-TEFb complex composition and responsiveness to Tat/HEXIM1","journal":"AIDS (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression with viral replication readout and biochemical characterization, single lab with two orthogonal methods","pmids":["18520353"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Flag-tag affinity purification coupled with mass spectrometry; siRNA knockdown followed by RNA-seq and bulk CTD phosphorylation assays in HCT116 cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal pulldown/MS identification of CCNK-CDK12/13 complexes plus RNA-seq functional characterization, multiple orthogonal methods in one study","pmids":["25561469"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis plus multiple orthogonal sequencing methods and imaging, single lab with rigorous multi-method validation","pmids":["30819820"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution of the ternary complex plus genetic screens and SAR analysis, multiple orthogonal methods establishing the mechanism","pmids":["32804079"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Small-molecule library screen on patient-derived CRC spheroids; ubiquitination assays; CCNK/CDK12 knockout with proliferation and xenograft growth assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — ubiquitination assay, genetic KO with in vitro and in vivo tumor growth readouts, and patient-derived xenograft validation, multiple orthogonal methods","pmids":["34289372"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct AR-CCNK promoter binding, genetic/pharmacological loss-of-function with mechanistic polyadenylation readout, multiple orthogonal methods in one study","pmids":["36129942"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Genome-wide CRISPR/Cas9 loss-of-function screen with a dual-fluorescence polyadenylation readthrough reporter in human cells","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genome-wide CRISPR screen with functional reporter readout, single lab, genetic identification only without biochemical reconstitution of CPA activity","pmids":["38587191"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Patient-derived iPSC/NPC models; NPC-specific Ccnk knockout mice; RNA-seq transcriptomic analysis; rescue experiments with Wnt5a inhibitor measuring NPC proliferation and apoptosis","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular phenotype (proliferation/apoptosis), RNA-seq pathway identification, and pharmacological rescue with orthogonal human and mouse models","pmids":["37597256"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Overexpression of CCNK in mouse oocytes; live imaging and immunofluorescence of CCNB1 nuclear entry; measurement of meiotic resumption timing","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single overexpression study with imaging readout, single lab, no complementary loss-of-function or biochemical reconstitution","pmids":["41355749"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Nanoplatform-delivered CR8 in TNBC cell lines and in vivo; immunoblotting for CDK12, CCNK, and PD-L1; tumor immune microenvironment analysis","journal":"ACS applied materials & interfaces","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological degradation with protein-level readout, single study, no direct mechanistic dissection of how CDK12-CCNK regulates PD-L1","pmids":["41810739"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Cell-based CCNK degradation assays; TMT-based global proteomic profiling for selectivity; xenograft tumor growth assays; pharmacokinetic studies","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteome-wide selectivity profiling by TMT-MS plus in vivo efficacy, single lab, mechanistic basis inferred from prior HQ461/NCT02 work","pmids":["41165741"],"is_preprint":false}],"current_model":"Cyclin K (CCNK) is a transcriptional cyclin that forms stable complexes with CDK12 and CDK13 to regulate RNA Pol II-dependent transcription elongation, co-transcriptional RNA processing, and cleavage/polyadenylation; the CDK12–CCNK complex phosphorylates substrates including the RNA Pol II CTD and 4E-BP1 to control expression of DNA damage response genes and translation of mitotic regulators, while AR directly drives CCNK transcription in prostate cancer and CCNK loss promotes AR splice variant generation via alternative polyadenylation; CCNK is degraded by molecular glue compounds (HQ461, NCT02, CR8) that recruit CDK12 to the DDB1-CUL4-RBX1 E3 ligase, and in neural progenitors CCNK supports proliferation and suppresses apoptosis by restraining Wnt5a signaling."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2008,"claim":"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","pmids":["18520353"],"confidence":"Medium","gaps":["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"]},{"year":2015,"claim":"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","pmids":["25561469"],"confidence":"High","gaps":["Direct kinase substrates beyond CTD not enumerated","Mechanism of gene selectivity unresolved","No structural basis for complex assembly"]},{"year":2019,"claim":"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","pmids":["30819820"],"confidence":"High","gaps":["Relative contribution of translational vs transcriptional roles to mitotic phenotype unclear","Full substrate repertoire of the complex unknown"]},{"year":2020,"claim":"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","pmids":["32804079"],"confidence":"High","gaps":["Determinants of degrader selectivity across cell types not defined","Genotype-specific vulnerability not established here"]},{"year":2021,"claim":"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","pmids":["34289372"],"confidence":"High","gaps":["Molecular basis of TP53-dependent sensitivity not mechanistically dissected","Generalizability beyond CRC unclear"]},{"year":2022,"claim":"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","pmids":["36129942"],"confidence":"High","gaps":["Direct biochemical mechanism coupling CCNK activity to APC/polyadenylation choice not resolved","Clinical relevance of the AR-CCNK loop not established"]},{"year":2023,"claim":"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","pmids":["37597256"],"confidence":"High","gaps":["Mechanism by which CCNK represses WNT5A not defined","Connection to the CDK12/CDK13 kinase function not tested"]},{"year":2024,"claim":"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","pmids":["38587191"],"confidence":"Medium","gaps":["Genetic identification only without biochemical reconstitution of CPA activity","Direct involvement of CCNK in the CPA machinery not shown structurally"]},{"year":2025,"claim":"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","pmids":["41355749"],"confidence":"Medium","gaps":["Single overexpression study without loss-of-function or biochemical confirmation","Mechanism linking CCNK to CCNB1 nuclear import unknown"]},{"year":2025,"claim":"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","pmids":["41165741"],"confidence":"Medium","gaps":["Mechanistic basis inferred from prior glue studies rather than re-derived","Tumor-type and genotype selectivity not fully mapped"]},{"year":2026,"claim":"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","pmids":["41810739"],"confidence":"Low","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,3]}],"complexes":["CCNK-CDK12","CCNK-CDK13","P-TEFb (CCNK-CDK9)"],"partners":["CDK12","CDK13","CDK9","DDB1","CUL4","RBX1","EIF4EBP1","AR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75909","full_name":"Cyclin-K","aliases":[],"length_aa":580,"mass_kda":64.2,"function":"Regulatory subunit of cyclin-dependent kinases that mediates activation of target kinases. Plays a role in transcriptional regulation via its role in regulating the phosphorylation of the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O75909/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCNK","classification":"Common Essential","n_dependent_lines":1195,"n_total_lines":1208,"dependency_fraction":0.9892384105960265},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDK12","stoichiometry":10.0},{"gene":"CDK13","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/CCNK","total_profiled":1310},"omim":[{"mim_id":"618147","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH HYPERTELORISM AND DISTINCTIVE FACIES; IDDHDF","url":"https://www.omim.org/entry/618147"},{"mim_id":"615514","title":"CYCLIN-DEPENDENT KINASE 12; CDK12","url":"https://www.omim.org/entry/615514"},{"mim_id":"612659","title":"REGULATORY FACTOR X, 6; RFX6","url":"https://www.omim.org/entry/612659"},{"mim_id":"611052","title":"SET DOMAIN-CONTAINING PROTEIN 1A; SETD1A","url":"https://www.omim.org/entry/611052"},{"mim_id":"604927","title":"C-TERMINAL DOMAIN OF RNA POLYMERASE II SUBUNIT A, PHOSPHATASE OF, SUBUNIT 1; CTDP1","url":"https://www.omim.org/entry/604927"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":96.4}],"url":"https://www.proteinatlas.org/search/CCNK"},"hgnc":{"alias_symbol":["CPR4"],"prev_symbol":[]},"alphafold":{"accession":"O75909","domains":[{"cath_id":"1.10.472.10","chopping":"29-150","consensus_level":"high","plddt":97.9789,"start":29,"end":150},{"cath_id":"1.10.472.10","chopping":"159-260","consensus_level":"high","plddt":95.0092,"start":159,"end":260}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75909","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75909-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75909-F1-predicted_aligned_error_v6.png","plddt_mean":65.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCNK","jax_strain_url":"https://www.jax.org/strain/search?query=CCNK"},"sequence":{"accession":"O75909","fasta_url":"https://rest.uniprot.org/uniprotkb/O75909.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75909/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75909"}},"corpus_meta":[{"pmid":"9371805","id":"PMC_9371805","title":"All 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Novel Genes Involved in the Interaction Between Caenorhabditis elegans and Stenotrophomonas maltophilia.","date":"2018","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30177956","citation_count":4,"is_preprint":false},{"pmid":"40110997","id":"PMC_40110997","title":"Proximal Deletions of 14q32.2 Result in Severe Neurodevelopmental Outcomes, Congenital Anomalies, and Dysmorphic Features.","date":"2025","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/40110997","citation_count":1,"is_preprint":false},{"pmid":"35886900","id":"PMC_35886900","title":"A Non-Cell-Autonomous Mode of DNA Damage Response in Soma of Caenorhabditis elegans.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35886900","citation_count":1,"is_preprint":false},{"pmid":"41165741","id":"PMC_41165741","title":"Discovery of Highly Potent and Orally Available CCNK Molecular Glue Degraders as Broad-Spectrum Antitumor Agents.","date":"2025","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41165741","citation_count":0,"is_preprint":false},{"pmid":"41355749","id":"PMC_41355749","title":"Overexpression of CCNK Leads to Early Resumption of Meiosis in Mouse Oocytes.","date":"2025","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/41355749","citation_count":0,"is_preprint":false},{"pmid":"41101726","id":"PMC_41101726","title":"A Further Case Supporting CCNK as a Neurodevelopmental Disease Gene.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41101726","citation_count":0,"is_preprint":false},{"pmid":"41928441","id":"PMC_41928441","title":"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.","date":"2026","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/41928441","citation_count":0,"is_preprint":false},{"pmid":"41810739","id":"PMC_41810739","title":"Dual-Stimuli-Responsive Nanoplatform Delivering Molecular Glue CR8 for Synergistic CDK12 Degradation and Immunomodulatory Photothermal Therapy in TNBC.","date":"2026","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/41810739","citation_count":0,"is_preprint":false},{"pmid":"41509278","id":"PMC_41509278","title":"Cysteine protease cathepsin B promotes high population density-induced mutagenesis, driving genome evolution and competitive growth in response to the crowding stress.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41509278","citation_count":0,"is_preprint":false},{"pmid":"42082483","id":"PMC_42082483","title":"Cathepsin B protease mediates high population density-induced mutagenesis to drive genome evolution and competitive growth.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42082483","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19731,"output_tokens":3599,"usd":0.056589,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10761,"output_tokens":3988,"usd":0.076753,"stage2_stop_reason":"end_turn"},"total_usd":0.133342,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully identify which papers are about human CCNK (Cyclin K, also known as CPR4 in mammals). I must exclude:\n- Papers about CPR4 as a yeast cyclophilin (paper [1])\n- Papers about CPR4 as a plant cysteine protease (papers [9], [12], [13])\n- Papers about CPR-4 as C. elegans cathepsin B homolog (papers [8], [27], [29], [35], [36])\n- Papers about CPR4 as a Cryptococcus PCR primer (paper [15])\n- Papers about CPR4 as an insect cuticular protein (papers [18], [33])\n- Papers about chicken progesterone receptor cDNA clones (paper [3])\n- Papers about CPR in cardiopulmonary resuscitation (paper [17])\n- Papers about circRNAs (paper [11])\n- Papers about peptides named CCNK (paper [10])\n- Pure expression/epigenetic correlation studies (papers [7], [22])\n- Pure phenotype/clinical reports with no mechanism (papers [16], [25], [28], [32])\n\nPapers clearly about human CCNK (Cyclin K): [2], [4], [5], [6], [14], [19], [21], [24], [26], [30], [31], [34]\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression assays in cell lines measuring viral replication; biochemical analysis of P-TEFb complex composition and responsiveness to Tat/HEXIM1\",\n      \"journal\": \"AIDS (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression with viral replication readout and biochemical characterization, single lab with two orthogonal methods\",\n      \"pmids\": [\"18520353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Flag-tag affinity purification coupled with mass spectrometry; siRNA knockdown followed by RNA-seq and bulk CTD phosphorylation assays in HCT116 cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal pulldown/MS identification of CCNK-CDK12/13 complexes plus RNA-seq functional characterization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25561469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis plus multiple orthogonal sequencing methods and imaging, single lab with rigorous multi-method validation\",\n      \"pmids\": [\"30819820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution of the ternary complex plus genetic screens and SAR analysis, multiple orthogonal methods establishing the mechanism\",\n      \"pmids\": [\"32804079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Small-molecule library screen on patient-derived CRC spheroids; ubiquitination assays; CCNK/CDK12 knockout with proliferation and xenograft growth assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ubiquitination assay, genetic KO with in vitro and in vivo tumor growth readouts, and patient-derived xenograft validation, multiple orthogonal methods\",\n      \"pmids\": [\"34289372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct AR-CCNK promoter binding, genetic/pharmacological loss-of-function with mechanistic polyadenylation readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"36129942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 loss-of-function screen with a dual-fluorescence polyadenylation readthrough reporter in human cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genome-wide CRISPR screen with functional reporter readout, single lab, genetic identification only without biochemical reconstitution of CPA activity\",\n      \"pmids\": [\"38587191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Patient-derived iPSC/NPC models; NPC-specific Ccnk knockout mice; RNA-seq transcriptomic analysis; rescue experiments with Wnt5a inhibitor measuring NPC proliferation and apoptosis\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular phenotype (proliferation/apoptosis), RNA-seq pathway identification, and pharmacological rescue with orthogonal human and mouse models\",\n      \"pmids\": [\"37597256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression of CCNK in mouse oocytes; live imaging and immunofluorescence of CCNB1 nuclear entry; measurement of meiotic resumption timing\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression study with imaging readout, single lab, no complementary loss-of-function or biochemical reconstitution\",\n      \"pmids\": [\"41355749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Nanoplatform-delivered CR8 in TNBC cell lines and in vivo; immunoblotting for CDK12, CCNK, and PD-L1; tumor immune microenvironment analysis\",\n      \"journal\": \"ACS applied materials & interfaces\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological degradation with protein-level readout, single study, no direct mechanistic dissection of how CDK12-CCNK regulates PD-L1\",\n      \"pmids\": [\"41810739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-based CCNK degradation assays; TMT-based global proteomic profiling for selectivity; xenograft tumor growth assays; pharmacokinetic studies\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteome-wide selectivity profiling by TMT-MS plus in vivo efficacy, single lab, mechanistic basis inferred from prior HQ461/NCT02 work\",\n      \"pmids\": [\"41165741\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Cyclin K (CCNK) is a transcriptional cyclin that forms stable complexes with CDK12 and CDK13 to regulate RNA Pol II-dependent transcription elongation, co-transcriptional RNA processing, and cleavage/polyadenylation; the CDK12–CCNK complex phosphorylates substrates including the RNA Pol II CTD and 4E-BP1 to control expression of DNA damage response genes and translation of mitotic regulators, while AR directly drives CCNK transcription in prostate cancer and CCNK loss promotes AR splice variant generation via alternative polyadenylation; CCNK is degraded by molecular glue compounds (HQ461, NCT02, CR8) that recruit CDK12 to the DDB1-CUL4-RBX1 E3 ligase, and in neural progenitors CCNK supports proliferation and suppresses apoptosis by restraining Wnt5a signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#1, #6]. 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 [#1]. 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 [#2]. 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 [#5]. In neural progenitors, CCNK supports proliferation and suppresses apoptosis by restraining WNT5A expression, a defect rescued by Wnt5a inhibition [#7]. 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 [#3, #4, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Overexpression viral replication assays and biochemical P-TEFb complex analysis in cell lines\",\n      \"pmids\": [\"18520353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Flag affinity purification/MS plus siRNA knockdown with RNA-seq and bulk CTD phosphorylation assays in HCT116 cells\",\n      \"pmids\": [\"25561469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase substrates beyond CTD not enumerated\", \"Mechanism of gene selectivity unresolved\", \"No structural basis for complex assembly\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase assays with S65/T70 site mapping, RIP-seq, Ribo-seq, and confocal imaging of chromosome segregation\",\n      \"pmids\": [\"30819820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of translational vs transcriptional roles to mitotic phenotype unclear\", \"Full substrate repertoire of the complex unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Chemical and genetic screens, biochemical reconstitution of the CDK12-DDB1 interaction, polyubiquitination assays, and SAR analysis in cancer cells\",\n      \"pmids\": [\"32804079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of degrader selectivity across cell types not defined\", \"Genotype-specific vulnerability not established here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Patient-derived CRC spheroid screen, ubiquitination assays, and CCNK/CDK12 knockout with proliferation and xenograft assays\",\n      \"pmids\": [\"34289372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of TP53-dependent sensitivity not mechanistically dissected\", \"Generalizability beyond CRC unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"36129942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism coupling CCNK activity to APC/polyadenylation choice not resolved\", \"Clinical relevance of the AR-CCNK loop not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Patient-derived iPSC/NPC models, NPC-specific Ccnk knockout mice, RNA-seq, and Wnt5a inhibitor rescue\",\n      \"pmids\": [\"37597256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CCNK represses WNT5A not defined\", \"Connection to the CDK12/CDK13 kinase function not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genome-wide CRISPR/Cas9 screen with a dual-fluorescence polyadenylation readthrough reporter in human cells\",\n      \"pmids\": [\"38587191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genetic identification only without biochemical reconstitution of CPA activity\", \"Direct involvement of CCNK in the CPA machinery not shown structurally\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Suggested a meiotic cell cycle role by showing CCNK overexpression accelerates oocyte meiotic resumption via early Cyclin B1 nuclear entry and premature MPF activation.\",\n      \"evidence\": \"CCNK overexpression in mouse oocytes with live imaging and immunofluorescence of CCNB1 entry\",\n      \"pmids\": [\"41355749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single overexpression study without loss-of-function or biochemical confirmation\", \"Mechanism linking CCNK to CCNB1 nuclear import unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cell-based degradation assays, TMT global proteomic selectivity profiling, xenograft efficacy, and PK studies\",\n      \"pmids\": [\"41165741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis inferred from prior glue studies rather than re-derived\", \"Tumor-type and genotype selectivity not fully mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked the CDK12-CCNK axis to immune evasion by showing CR8-mediated complex degradation downregulates PD-L1 in triple-negative breast cancer.\",\n      \"evidence\": \"Nanoplatform-delivered CR8 in TNBC cell lines and in vivo with immunoblotting and tumor immune microenvironment analysis\",\n      \"pmids\": [\"41810739\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [\n      \"CCNK-CDK12\",\n      \"CCNK-CDK13\",\n      \"P-TEFb (CCNK-CDK9)\"\n    ],\n    \"partners\": [\n      \"CDK12\",\n      \"CDK13\",\n      \"CDK9\",\n      \"DDB1\",\n      \"CUL4\",\n      \"RBX1\",\n      \"EIF4EBP1\",\n      \"AR\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}