{"gene":"CCNH","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1997,"finding":"The CDK7-cyclin H (CCNH)-p36 trimeric complex of TFIIH phosphorylates p53 in vitro at C-terminal residues (serines 371, 376, 378, and 392, between residues 311–393), and this phosphorylation enhances p53 sequence-specific DNA binding activity.","method":"In vitro kinase assay with highly purified CDK7-CycH-p36 complex, phosphorylation site mapping, gel mobility shift assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified trimeric complex, phosphorylation site mapping, and functional DNA-binding assay in a single focused study","pmids":["9315650"],"is_preprint":false},{"year":2013,"finding":"The CCNH/CDK7 complex directly interacts with CtBP2 in vivo and in vitro, stabilizes CtBP2 by competing with the tumor repressor HIPK2 for CtBP2 binding, thereby inhibiting HIPK2-mediated phosphorylation and dimerization of CtBP2 and preventing proteasome-dependent CtBP2 degradation; this stabilization promotes breast cancer cell invasion and migration.","method":"Co-immunoprecipitation (in vivo and in vitro), siRNA knockdown of CCNH or CDK7, proteasome inhibitor assays, phosphorylation and dimerization assays, invasion/migration assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP in vivo and in vitro, multiple orthogonal functional assays (degradation, phosphorylation, migration), single lab","pmids":["23393140"],"is_preprint":false},{"year":2011,"finding":"CDK7 and CCNH (cyclin H) form a CDK-activating kinase (CAK) complex that phosphorylates CDC2 at threonine 161 (T161), thereby activating MPF and driving meiotic resumption in porcine oocytes; overexpression of CDK7 or CCNH accelerated meiotic events (GVBD, CCNB synthesis, MPF activation), while knockdown inhibited them.","method":"Overexpression and antisense RNA knockdown in pig oocytes, immunoblot for T161 phosphorylation of CDC2, MPF activity assays, GVBD rate measurement","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments with direct biochemical readouts (T161 phosphorylation, MPF activity), single lab, multiple orthogonal methods","pmids":["21778139"],"is_preprint":false},{"year":2015,"finding":"CCNH/CDK7 directly interacts with CtBP2 in esophageal squamous cell carcinoma (ESCC) cells in vivo and in vitro, and CtBP2-promoted migration of ESCC cells is dependent on CCNH/CDK7.","method":"Co-immunoprecipitation (in vivo and in vitro), cell migration assays with CCNH depletion","journal":"Tumour biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and migration assay, single lab, mechanistic detail largely recapitulates prior study (PMID 23393140)","pmids":["25820824"],"is_preprint":false},{"year":2004,"finding":"CDK7/CycH (CCNH)/MAT1 can be co-expressed and purified as an active trimeric complex from insect cells using His-tag affinity and ion-exchange chromatography, yielding recombinant kinase with properties similar to its natural counterpart.","method":"Recombinant co-expression in Spodoptera frugiperda insect cells, Ni-NTA and Mono S chromatography purification, kinase activity assay","journal":"Biological procedures online","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct reconstitution of active trimeric complex, single lab, biochemical characterization without mutagenesis or structural validation","pmids":["15328539"],"is_preprint":false},{"year":1998,"finding":"The human CCNH gene encoding cyclin H was mapped to chromosome band 5q13.3-q14 by fluorescence in situ hybridization, somatic cell hybrid analyses, and YAC contig mapping.","method":"FISH, somatic cell hybrid analysis, YAC contig mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal mapping methods converge on same chromosomal locus","pmids":["9465303"],"is_preprint":false}],"current_model":"CCNH (cyclin H) functions as the regulatory cyclin subunit of the CDK7-CCNH-MAT1 (CAK) trimeric complex, which phosphorylates CDKs (e.g., CDC2/CDK1 at T161) to drive cell cycle and meiotic progression, phosphorylates p53 at C-terminal serines to enhance its DNA-binding activity as part of TFIIH, and stabilizes CtBP2 by competing with HIPK2 for CtBP2 binding—thereby preventing proteasome-mediated CtBP2 degradation and promoting cancer cell migration."},"narrative":{"mechanistic_narrative":"CCNH (cyclin H) is the regulatory cyclin subunit of the CDK-activating kinase (CAK), forming an active trimeric complex with CDK7 and MAT1 that can be reconstituted from recombinant subunits [PMID:15328539]. Within this complex CCNH/CDK7 phosphorylates CDC2 (CDK1) at threonine 161 to activate MPF and drive meiotic resumption, with gain- and loss-of-function manipulation accelerating or blocking GVBD, cyclin B synthesis, and MPF activation in oocytes [PMID:21778139]. As part of TFIIH, the CDK7-cyclin H-p36 complex also phosphorylates p53 at C-terminal serines (371, 376, 378, 392), enhancing its sequence-specific DNA-binding activity [PMID:9315650]. Beyond its kinase functions, CCNH/CDK7 directly binds the transcriptional corepressor CtBP2 and stabilizes it by competing with HIPK2, blocking HIPK2-mediated phosphorylation, dimerization, and proteasomal degradation of CtBP2, thereby promoting cancer cell invasion and migration [PMID:23393140].","teleology":[{"year":1997,"claim":"Established that the CDK7-cyclin H-p36 complex acts on a substrate beyond CDKs by phosphorylating p53 and modulating its activity, linking CAK/TFIIH to tumor suppressor function.","evidence":"In vitro kinase assay with purified CDK7-CycH-p36, phosphorylation site mapping, and gel mobility shift assay","pmids":["9315650"],"confidence":"High","gaps":["In vitro reconstitution only; cellular relevance of p53 phosphorylation by this complex not tested","Functional consequence limited to DNA binding, not downstream p53 transcriptional output"]},{"year":1998,"claim":"Assigned the human CCNH gene to a defined chromosomal locus, providing a genomic anchor for the cyclin H subunit.","evidence":"FISH, somatic cell hybrid analysis, and YAC contig mapping","pmids":["9465303"],"confidence":"Medium","gaps":["Mapping only; no functional or regulatory information about the locus"]},{"year":2004,"claim":"Demonstrated that CCNH assembles with CDK7 and MAT1 into a catalytically active trimeric complex, enabling biochemical study of the CAK.","evidence":"Recombinant co-expression in insect cells, affinity and ion-exchange purification, kinase activity assay","pmids":["15328539"],"confidence":"Medium","gaps":["No mutagenesis or structural validation of subunit contributions","Substrate specificity of the reconstituted complex not characterized"]},{"year":2011,"claim":"Defined a meiotic role for the CCNH/CDK7 CAK by showing it phosphorylates CDC2 at T161 to activate MPF and drive oocyte meiotic resumption.","evidence":"Overexpression and antisense knockdown in pig oocytes, T161 immunoblot, MPF activity and GVBD assays","pmids":["21778139"],"confidence":"Medium","gaps":["Single-species (porcine oocyte) system","Whether CCNH is rate-limiting versus permissive for CDK1 activation not resolved"]},{"year":2013,"claim":"Identified a non-catalytic role for CCNH/CDK7 in stabilizing the corepressor CtBP2 by competing with HIPK2, connecting CCNH to cancer cell motility.","evidence":"Reciprocal Co-IP, siRNA knockdown, proteasome inhibitor, phosphorylation/dimerization, and invasion/migration assays in breast cancer cells","pmids":["23393140"],"confidence":"Medium","gaps":["Mechanism by which CCNH/CDK7 competes with HIPK2 not structurally defined","Single lab; in vivo tumor relevance not established"]},{"year":2015,"claim":"Extended the CCNH/CDK7-CtBP2 interaction to esophageal squamous cell carcinoma, supporting generality of the migration-promoting axis.","evidence":"Co-IP and migration assays with CCNH depletion in ESCC cells","pmids":["25820824"],"confidence":"Low","gaps":["Single Co-IP and migration assay largely recapitulating the prior breast cancer study","No reciprocal validation or mechanistic depth beyond confirming interaction dependence"]},{"year":null,"claim":"How CCNH's CAK kinase activity, its TFIIH transcriptional role, and its non-catalytic CtBP2-stabilizing function are integrated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the human CCNH-CDK7-MAT1 complex in the corpus","Whether CtBP2 stabilization requires CDK7 catalytic activity is undefined","No in vivo demonstration of CCNH-dependent p53 phosphorylation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1]}],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1]}],"complexes":["CDK7-cyclin H-MAT1 (CAK)","TFIIH"],"partners":["CDK7","MAT1","CDC2","TP53","CTBP2","HIPK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51946","full_name":"Cyclin-H","aliases":["MO15-associated protein","p34","p37"],"length_aa":323,"mass_kda":37.6,"function":"Regulates CDK7, the catalytic subunit of the CDK-activating kinase (CAK) enzymatic complex. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Involved in cell cycle control and in RNA transcription by RNA polymerase II. Its expression and activity are constant throughout the cell cycle","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P51946/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCNH","classification":"Common Essential","n_dependent_lines":1187,"n_total_lines":1208,"dependency_fraction":0.9826158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDC7","stoichiometry":10.0},{"gene":"CDK7","stoichiometry":10.0},{"gene":"CETN2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CCNH","total_profiled":1310},"omim":[{"mim_id":"602659","title":"MENAGE A TROIS 1; MNAT1","url":"https://www.omim.org/entry/602659"},{"mim_id":"601953","title":"CYCLIN H; CCNH","url":"https://www.omim.org/entry/601953"},{"mim_id":"600778","title":"CYCLIN-DEPENDENT KINASE INHIBITOR 1B; CDKN1B","url":"https://www.omim.org/entry/600778"},{"mim_id":"300587","title":"MALIGNANT T-CELL AMPLIFIED SEQUENCE 1; MCTS1","url":"https://www.omim.org/entry/300587"},{"mim_id":"133530","title":"ERCC EXCISION REPAIR 5, ENDONUCLEASE; ERCC5","url":"https://www.omim.org/entry/133530"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCNH"},"hgnc":{"alias_symbol":["p34","p37","CycH"],"prev_symbol":[]},"alphafold":{"accession":"P51946","domains":[{"cath_id":"1.10.472.10","chopping":"1-159_263-268","consensus_level":"medium","plddt":95.3312,"start":1,"end":268},{"cath_id":"1.10.472.10","chopping":"162-260","consensus_level":"medium","plddt":90.347,"start":162,"end":260}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51946","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51946-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51946-F1-predicted_aligned_error_v6.png","plddt_mean":86.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCNH","jax_strain_url":"https://www.jax.org/strain/search?query=CCNH"},"sequence":{"accession":"P51946","fasta_url":"https://rest.uniprot.org/uniprotkb/P51946.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51946/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51946"}},"corpus_meta":[{"pmid":"9315650","id":"PMC_9315650","title":"The CDK7-cycH-p36 complex of transcription factor IIH phosphorylates p53, enhancing its sequence-specific DNA binding activity in vitro.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9315650","citation_count":149,"is_preprint":false},{"pmid":"23393140","id":"PMC_23393140","title":"Interaction with cyclin H/cyclin-dependent kinase 7 (CCNH/CDK7) stabilizes C-terminal binding protein 2 (CtBP2) and promotes cancer cell migration.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23393140","citation_count":68,"is_preprint":false},{"pmid":"7746152","id":"PMC_7746152","title":"Cloning and sequence analysis of cycH gene from Paracoccus denitrificans: the cycH gene product is required for assembly of all c-type cytochromes, including cytochrome c1.","date":"1995","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/7746152","citation_count":47,"is_preprint":false},{"pmid":"8752349","id":"PMC_8752349","title":"Rhodobacter capsulatus CycH: a bipartite gene product with pleiotropic effects on the biogenesis of structurally different c-type cytochromes.","date":"1996","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/8752349","citation_count":46,"is_preprint":false},{"pmid":"21778139","id":"PMC_21778139","title":"CDK7 and CCNH are components of CDK-activating kinase and are required for meiotic progression of pig oocytes.","date":"2011","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/21778139","citation_count":29,"is_preprint":false},{"pmid":"25820824","id":"PMC_25820824","title":"Interaction with CCNH/CDK7 facilitates CtBP2 promoting esophageal squamous cell carcinoma (ESCC) metastasis via upregulating epithelial-mesenchymal transition (EMT) progression.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25820824","citation_count":27,"is_preprint":false},{"pmid":"38356866","id":"PMC_38356866","title":"Lnc-CCNH-8 promotes immune escape by up-regulating PD-L1 in hepatocellular carcinoma.","date":"2024","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/38356866","citation_count":16,"is_preprint":false},{"pmid":"23982724","id":"PMC_23982724","title":"The role of CCNH Val270Ala (rs2230641) and other nucleotide excision repair polymorphisms in individual susceptibility to well-differentiated thyroid cancer.","date":"2013","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23982724","citation_count":15,"is_preprint":false},{"pmid":"12421312","id":"PMC_12421312","title":"Overexpression of ccl1-2 can bypass the need for the putative apocytochrome chaperone CycH during the biogenesis of c-type cytochromes.","date":"2002","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12421312","citation_count":14,"is_preprint":false},{"pmid":"14758542","id":"PMC_14758542","title":"The roles of different regions of the CycH protein in c-type cytochrome biogenesis in Sinorhizobium meliloti.","date":"2004","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/14758542","citation_count":11,"is_preprint":false},{"pmid":"9524269","id":"PMC_9524269","title":"Rhizobium etli cycHJKL gene locus involved in c-type cytochrome biogenesis: sequence analysis and characterization of two cycH mutants.","date":"1998","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9524269","citation_count":11,"is_preprint":false},{"pmid":"15328539","id":"PMC_15328539","title":"A uniform procedure for the purification of CDK7/CycH/MAT1, CDK8/CycC and CDK9/CycT1.","date":"2004","source":"Biological procedures online","url":"https://pubmed.ncbi.nlm.nih.gov/15328539","citation_count":10,"is_preprint":false},{"pmid":"9465303","id":"PMC_9465303","title":"Mapping of the human genes encoding cyclin H (CCNH) and the CDK-activating kinase (CAK) assembly factor MAT1 (MNAT1) to chromosome bands 5q13.3-q14 and 14q23, respectively.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9465303","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8933,"output_tokens":1559,"usd":0.025092,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8279,"output_tokens":2268,"usd":0.049048,"stage2_stop_reason":"end_turn"},"total_usd":0.07414,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"The CDK7-cyclin H (CCNH)-p36 trimeric complex of TFIIH phosphorylates p53 in vitro at C-terminal residues (serines 371, 376, 378, and 392, between residues 311–393), and this phosphorylation enhances p53 sequence-specific DNA binding activity.\",\n      \"method\": \"In vitro kinase assay with highly purified CDK7-CycH-p36 complex, phosphorylation site mapping, gel mobility shift assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified trimeric complex, phosphorylation site mapping, and functional DNA-binding assay in a single focused study\",\n      \"pmids\": [\"9315650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The CCNH/CDK7 complex directly interacts with CtBP2 in vivo and in vitro, stabilizes CtBP2 by competing with the tumor repressor HIPK2 for CtBP2 binding, thereby inhibiting HIPK2-mediated phosphorylation and dimerization of CtBP2 and preventing proteasome-dependent CtBP2 degradation; this stabilization promotes breast cancer cell invasion and migration.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), siRNA knockdown of CCNH or CDK7, proteasome inhibitor assays, phosphorylation and dimerization assays, invasion/migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP in vivo and in vitro, multiple orthogonal functional assays (degradation, phosphorylation, migration), single lab\",\n      \"pmids\": [\"23393140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDK7 and CCNH (cyclin H) form a CDK-activating kinase (CAK) complex that phosphorylates CDC2 at threonine 161 (T161), thereby activating MPF and driving meiotic resumption in porcine oocytes; overexpression of CDK7 or CCNH accelerated meiotic events (GVBD, CCNB synthesis, MPF activation), while knockdown inhibited them.\",\n      \"method\": \"Overexpression and antisense RNA knockdown in pig oocytes, immunoblot for T161 phosphorylation of CDC2, MPF activity assays, GVBD rate measurement\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments with direct biochemical readouts (T161 phosphorylation, MPF activity), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21778139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCNH/CDK7 directly interacts with CtBP2 in esophageal squamous cell carcinoma (ESCC) cells in vivo and in vitro, and CtBP2-promoted migration of ESCC cells is dependent on CCNH/CDK7.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), cell migration assays with CCNH depletion\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and migration assay, single lab, mechanistic detail largely recapitulates prior study (PMID 23393140)\",\n      \"pmids\": [\"25820824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CDK7/CycH (CCNH)/MAT1 can be co-expressed and purified as an active trimeric complex from insect cells using His-tag affinity and ion-exchange chromatography, yielding recombinant kinase with properties similar to its natural counterpart.\",\n      \"method\": \"Recombinant co-expression in Spodoptera frugiperda insect cells, Ni-NTA and Mono S chromatography purification, kinase activity assay\",\n      \"journal\": \"Biological procedures online\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct reconstitution of active trimeric complex, single lab, biochemical characterization without mutagenesis or structural validation\",\n      \"pmids\": [\"15328539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The human CCNH gene encoding cyclin H was mapped to chromosome band 5q13.3-q14 by fluorescence in situ hybridization, somatic cell hybrid analyses, and YAC contig mapping.\",\n      \"method\": \"FISH, somatic cell hybrid analysis, YAC contig mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal mapping methods converge on same chromosomal locus\",\n      \"pmids\": [\"9465303\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCNH (cyclin H) functions as the regulatory cyclin subunit of the CDK7-CCNH-MAT1 (CAK) trimeric complex, which phosphorylates CDKs (e.g., CDC2/CDK1 at T161) to drive cell cycle and meiotic progression, phosphorylates p53 at C-terminal serines to enhance its DNA-binding activity as part of TFIIH, and stabilizes CtBP2 by competing with HIPK2 for CtBP2 binding—thereby preventing proteasome-mediated CtBP2 degradation and promoting cancer cell migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCNH (cyclin H) is the regulatory cyclin subunit of the CDK-activating kinase (CAK), forming an active trimeric complex with CDK7 and MAT1 that can be reconstituted from recombinant subunits [#4]. Within this complex CCNH/CDK7 phosphorylates CDC2 (CDK1) at threonine 161 to activate MPF and drive meiotic resumption, with gain- and loss-of-function manipulation accelerating or blocking GVBD, cyclin B synthesis, and MPF activation in oocytes [#2]. As part of TFIIH, the CDK7-cyclin H-p36 complex also phosphorylates p53 at C-terminal serines (371, 376, 378, 392), enhancing its sequence-specific DNA-binding activity [#0]. Beyond its kinase functions, CCNH/CDK7 directly binds the transcriptional corepressor CtBP2 and stabilizes it by competing with HIPK2, blocking HIPK2-mediated phosphorylation, dimerization, and proteasomal degradation of CtBP2, thereby promoting cancer cell invasion and migration [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that the CDK7-cyclin H-p36 complex acts on a substrate beyond CDKs by phosphorylating p53 and modulating its activity, linking CAK/TFIIH to tumor suppressor function.\",\n      \"evidence\": \"In vitro kinase assay with purified CDK7-CycH-p36, phosphorylation site mapping, and gel mobility shift assay\",\n      \"pmids\": [\"9315650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro reconstitution only; cellular relevance of p53 phosphorylation by this complex not tested\", \"Functional consequence limited to DNA binding, not downstream p53 transcriptional output\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Assigned the human CCNH gene to a defined chromosomal locus, providing a genomic anchor for the cyclin H subunit.\",\n      \"evidence\": \"FISH, somatic cell hybrid analysis, and YAC contig mapping\",\n      \"pmids\": [\"9465303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mapping only; no functional or regulatory information about the locus\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated that CCNH assembles with CDK7 and MAT1 into a catalytically active trimeric complex, enabling biochemical study of the CAK.\",\n      \"evidence\": \"Recombinant co-expression in insect cells, affinity and ion-exchange purification, kinase activity assay\",\n      \"pmids\": [\"15328539\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis or structural validation of subunit contributions\", \"Substrate specificity of the reconstituted complex not characterized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined a meiotic role for the CCNH/CDK7 CAK by showing it phosphorylates CDC2 at T161 to activate MPF and drive oocyte meiotic resumption.\",\n      \"evidence\": \"Overexpression and antisense knockdown in pig oocytes, T161 immunoblot, MPF activity and GVBD assays\",\n      \"pmids\": [\"21778139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-species (porcine oocyte) system\", \"Whether CCNH is rate-limiting versus permissive for CDK1 activation not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a non-catalytic role for CCNH/CDK7 in stabilizing the corepressor CtBP2 by competing with HIPK2, connecting CCNH to cancer cell motility.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, proteasome inhibitor, phosphorylation/dimerization, and invasion/migration assays in breast cancer cells\",\n      \"pmids\": [\"23393140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CCNH/CDK7 competes with HIPK2 not structurally defined\", \"Single lab; in vivo tumor relevance not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the CCNH/CDK7-CtBP2 interaction to esophageal squamous cell carcinoma, supporting generality of the migration-promoting axis.\",\n      \"evidence\": \"Co-IP and migration assays with CCNH depletion in ESCC cells\",\n      \"pmids\": [\"25820824\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP and migration assay largely recapitulating the prior breast cancer study\", \"No reciprocal validation or mechanistic depth beyond confirming interaction dependence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCNH's CAK kinase activity, its TFIIH transcriptional role, and its non-catalytic CtBP2-stabilizing function are integrated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the human CCNH-CDK7-MAT1 complex in the corpus\", \"Whether CtBP2 stabilization requires CDK7 catalytic activity is undefined\", \"No in vivo demonstration of CCNH-dependent p53 phosphorylation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"CDK7-cyclin H-MAT1 (CAK)\", \"TFIIH\"],\n    \"partners\": [\"CDK7\", \"MAT1\", \"CDC2\", \"TP53\", \"CtBP2\", \"HIPK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}