{"gene":"INTS15","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2023,"finding":"INTS15 was identified as an additional subunit of the Integrator complex, assembling primarily with the INTS13/14/10 module and interfacing with the Integrator-PP2A module, as determined by proteomics and AlphaFold2-based structural prediction.","method":"Proteomics (mass spectrometry) and machine-learning structure prediction (AlphaFold2)","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal proteomics identification with structural prediction; single lab, two orthogonal methods","pmids":["36920904"],"is_preprint":false},{"year":2023,"finding":"INTS15 modulates RNA polymerase II pausing at a subset of genes, as revealed by functional genomics analysis following its perturbation.","method":"Functional genomics (CRISPRi/knockdown with genomic occupancy readouts)","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — functional genomics with defined transcriptional phenotype; single lab","pmids":["36920904"],"is_preprint":false},{"year":2023,"finding":"INTS15 stably interacts with the Integrator complex to support small nuclear RNA (snRNA) 3' end processing, and its knockdown causes missplicing of a large number of genes.","method":"Co-immunoprecipitation/stable interaction assay, knockdown with RNA-seq splicing analysis, and snRNA 3' end processing assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — stable interaction demonstrated, snRNA processing assay, and KD with defined molecular phenotype (missplicing); multiple orthogonal methods in a single study","pmids":["36851842"],"is_preprint":false},{"year":2023,"finding":"INTS15 is critical for axonal outgrowth in retinal ganglion cells derived from human iPS cells, as demonstrated by INTS15 knockdown causing defects in this process.","method":"INTS15 knockdown in human iPS cell-derived neural progenitor cells with axonal outgrowth phenotypic readout","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined cellular phenotype in a relevant cell type; single lab","pmids":["36851842"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of the complete Integrator-PP2A complex reveal that INTS15, together with INTS10, INTS13, and INTS14, forms a scorpion-tail-shaped module; the 'sting' of this module may open the DSIF DNA clamp to facilitate Pol II termination.","method":"Cryo-electron microscopy (cryo-EM) structural determination of the Integrator-PP2A complex in pre-termination, post-termination, and free states","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structures in multiple functional states with mechanistic interpretation; single highly cited study with rigorous structural methods","pmids":["38570683"],"is_preprint":false},{"year":2025,"finding":"INTS15 overexpression activates p53 and p21 expression to induce G1 cell cycle arrest, while INTS15 knockdown causes defects in G2/M progression and apoptosis in HeLa and human iPS cells.","method":"Cumate-inducible INTS15 overexpression and siRNA knockdown in HeLa and iPS cells with cell cycle analysis and apoptosis readouts","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with defined cell cycle phenotypes; single lab, multiple cell types","pmids":["40194948"],"is_preprint":false},{"year":2025,"finding":"INTS15 promotes formation of the three germ layers and differentiation into late retinal tissues in iPS cell in vitro differentiation assays.","method":"INTS15 overexpression in human iPS cells with in vitro differentiation assays measuring germ layer and retinal tissue formation","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with defined differentiation phenotype; single lab","pmids":["40194948"],"is_preprint":false}],"current_model":"INTS15 is a bona fide subunit of the Integrator complex that forms a scorpion-tail-shaped module with INTS10/INTS13/INTS14 — visible in cryo-EM structures — where it facilitates RNA Pol II termination by opening the DSIF DNA clamp, while also supporting snRNA 3' end processing, modulating RNAPII pausing, regulating mRNA splicing, and controlling cell cycle progression (G1 arrest via p53/p21 activation and G2/M progression) in human cells."},"narrative":{"teleology":[{"year":2023,"claim":"Establishing that INTS15 is a previously unrecognized Integrator subunit resolved how the INTS10/13/14 module interfaces with the rest of the complex, particularly the PP2A module.","evidence":"Mass spectrometry proteomics and AlphaFold2 structural prediction in human cells","pmids":["36920904"],"confidence":"Medium","gaps":["Interaction topology relied on AlphaFold2 prediction without experimental atomic-resolution confirmation at the time","Stoichiometry of INTS15 within the complex was not determined","No reconstitution of a minimal INTS15-containing subcomplex was performed"]},{"year":2023,"claim":"Demonstrating that INTS15 perturbation alters Pol II pausing and causes snRNA 3ʹ-end processing defects and widespread missplicing established its functional contribution to Integrator-mediated transcriptional and RNA processing activities.","evidence":"CRISPRi/knockdown with genomic occupancy readouts, snRNA processing assays, and RNA-seq splicing analysis in human cells","pmids":["36920904","36851842"],"confidence":"High","gaps":["Whether INTS15 directly contacts nascent RNA or acts solely through structural scaffolding is unknown","Gene-level specificity of pausing effects not fully defined"]},{"year":2023,"claim":"Showing that INTS15 loss impairs axonal outgrowth in iPSC-derived retinal ganglion cells linked its molecular functions to a neurodevelopmental cellular phenotype.","evidence":"siRNA knockdown in human iPSC-derived neural progenitors with morphometric axon readouts","pmids":["36851842"],"confidence":"Medium","gaps":["Mechanism connecting snRNA/splicing defects to axon growth was not dissected","In vivo validation in animal models is lacking"]},{"year":2024,"claim":"High-resolution cryo-EM structures of the full Integrator–PP2A complex in multiple functional states revealed that INTS15/10/13/14 forms a scorpion-tail module whose tip contacts the DSIF DNA clamp, providing a structural mechanism for Pol II termination.","evidence":"Cryo-EM of Integrator–PP2A in pre-termination, post-termination, and free states","pmids":["38570683"],"confidence":"High","gaps":["Functional mutagenesis of the INTS15 'sting' contact with DSIF has not been performed","Whether the clamp-opening mechanism is universal or context-specific is unresolved"]},{"year":2025,"claim":"Gain- and loss-of-function experiments showed INTS15 controls cell cycle progression via the p53/p21 axis and is required for G2/M transition, expanding its role beyond RNA processing to proliferation and differentiation control.","evidence":"Cumate-inducible overexpression and siRNA knockdown in HeLa and iPSCs with cell cycle, apoptosis, and differentiation readouts","pmids":["40194948"],"confidence":"Medium","gaps":["Whether cell cycle effects are direct or secondary to global splicing/transcription defects is not resolved","The transcriptional targets through which INTS15 activates p53/p21 are not identified","Single-lab observation awaiting independent confirmation"]},{"year":null,"claim":"The direct molecular contacts between INTS15 and DSIF/Pol II that drive clamp opening, and the causal chain linking INTS15-dependent RNA processing to cell cycle and differentiation phenotypes, remain to be established.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mutagenesis or reconstitution study has isolated INTS15's specific structural contribution to termination","No separation-of-function alleles distinguish RNA processing versus cell cycle roles","No animal model phenotype has been reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,4]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]}],"complexes":["Integrator complex","Integrator-PP2A complex"],"partners":["INTS10","INTS13","INTS14"],"other_free_text":[]},"mechanistic_narrative":"INTS15 is a subunit of the Integrator complex that functions in RNA polymerase II transcription termination, snRNA 3ʹ-end processing, and cell cycle control. It assembles with INTS10, INTS13, and INTS14 into a scorpion-tail-shaped module that, in cryo-EM structures of the Integrator–PP2A complex, contacts the DSIF DNA clamp to facilitate Pol II termination [PMID:38570683, PMID:36920904]. INTS15 supports snRNA 3ʹ-end maturation, and its depletion causes widespread mRNA missplicing and impaired RNA Pol II pause regulation at a subset of genes [PMID:36851842, PMID:36920904]. Overexpression of INTS15 activates p53/p21 to induce G1 arrest, whereas its knockdown disrupts G2/M progression and promotes apoptosis, and it is required for axonal outgrowth in human iPSC-derived retinal ganglion cells [PMID:40194948, PMID:36851842]."},"prefetch_data":{"uniprot":{"accession":"Q96N11","full_name":"Integrator complex subunit 15","aliases":[],"length_aa":449,"mass_kda":50.0,"function":"Component of the integrator complex, a multiprotein complex that terminates RNA polymerase II (Pol II) transcription in the promoter-proximal region of genes (PubMed:36920904, PubMed:38570683, PubMed:38823386). The integrator complex provides a quality checkpoint during transcription elongation by driving premature transcription termination of transcripts that are unfavorably configured for transcriptional elongation: the complex terminates transcription by (1) catalyzing dephosphorylation of the C-terminal domain (CTD) of Pol II subunit POLR2A/RPB1 and SUPT5H/SPT5, (2) degrading the exiting nascent RNA transcript via endonuclease activity and (3) promoting the release of Pol II from bound DNA (PubMed:38570683). The integrator complex is also involved in terminating the synthesis of non-coding Pol II transcripts, such as enhancer RNAs (eRNAs), small nuclear RNAs (snRNAs), telomerase RNAs and long non-coding RNAs (lncRNAs) (PubMed:38570683). INTS15 is part of the integrator tail module that acts as a platform for the recruitment of transcription factors at promoters (PubMed:38823386). Within the integrator complex, INTS15 is required to bridge different integrator modules (PubMed:36920904)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q96N11/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/INTS15","classification":"Common Essential","n_dependent_lines":701,"n_total_lines":1208,"dependency_fraction":0.5802980132450332},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"POLR2B","stoichiometry":0.2},{"gene":"POLR2F","stoichiometry":0.2},{"gene":"PPP2CA","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"SUPT5H","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/INTS15","total_profiled":1310},"omim":[{"mim_id":"621239","title":"INTEGRATOR COMPLEX SUBUNIT 15; INTS15","url":"https://www.omim.org/entry/621239"},{"mim_id":"620878","title":"INTEGRATOR COMPLEX SUBUNIT 14; INTS14","url":"https://www.omim.org/entry/620878"},{"mim_id":"615079","title":"INTEGRATOR COMPLEX SUBUNIT 13; INTS13","url":"https://www.omim.org/entry/615079"},{"mim_id":"611353","title":"INTEGRATOR COMPLEX SUBUNIT 10; INTS10","url":"https://www.omim.org/entry/611353"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INTS15"},"hgnc":{"alias_symbol":["MGC2718"],"prev_symbol":["C7orf26"]},"alphafold":{"accession":"Q96N11","domains":[{"cath_id":"-","chopping":"205-258_279-392","consensus_level":"medium","plddt":92.3813,"start":205,"end":392},{"cath_id":"1.25.40","chopping":"1-58_65-188","consensus_level":"medium","plddt":92.5047,"start":1,"end":188}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96N11","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96N11-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96N11-F1-predicted_aligned_error_v6.png","plddt_mean":82.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INTS15","jax_strain_url":"https://www.jax.org/strain/search?query=INTS15"},"sequence":{"accession":"Q96N11","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96N11.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96N11/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96N11"}},"corpus_meta":[{"pmid":"35688146","id":"PMC_35688146","title":"Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq.","date":"2022","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/35688146","citation_count":425,"is_preprint":false},{"pmid":"38570683","id":"PMC_38570683","title":"Structural basis of Integrator-dependent RNA polymerase II termination.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/38570683","citation_count":49,"is_preprint":false},{"pmid":"36920904","id":"PMC_36920904","title":"A combinatorial approach to uncover an additional Integrator subunit.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36920904","citation_count":29,"is_preprint":false},{"pmid":"36851842","id":"PMC_36851842","title":"Integrator complex subunit 15 controls mRNA splicing and is critical for eye development.","date":"2023","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36851842","citation_count":10,"is_preprint":false},{"pmid":"38489401","id":"PMC_38489401","title":"Exploring the molecular mechanisms of asthma across multiple datasets.","date":"2024","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38489401","citation_count":3,"is_preprint":false},{"pmid":"40194948","id":"PMC_40194948","title":"INTS15, A Subunit of the Integrator Complex, Plays a Key Regulatory Role in Cell Cycle and Differentiation.","date":"2025","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/40194948","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4044,"output_tokens":1467,"usd":0.017069},"stage2":{"model":"claude-opus-4-6","input_tokens":4728,"output_tokens":1652,"usd":0.09741},"total_usd":0.114479,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"INTS15 was identified as an additional subunit of the Integrator complex, assembling primarily with the INTS13/14/10 module and interfacing with the Integrator-PP2A module, as determined by proteomics and AlphaFold2-based structural prediction.\",\n      \"method\": \"Proteomics (mass spectrometry) and machine-learning structure prediction (AlphaFold2)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal proteomics identification with structural prediction; single lab, two orthogonal methods\",\n      \"pmids\": [\"36920904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"INTS15 modulates RNA polymerase II pausing at a subset of genes, as revealed by functional genomics analysis following its perturbation.\",\n      \"method\": \"Functional genomics (CRISPRi/knockdown with genomic occupancy readouts)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional genomics with defined transcriptional phenotype; single lab\",\n      \"pmids\": [\"36920904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"INTS15 stably interacts with the Integrator complex to support small nuclear RNA (snRNA) 3' end processing, and its knockdown causes missplicing of a large number of genes.\",\n      \"method\": \"Co-immunoprecipitation/stable interaction assay, knockdown with RNA-seq splicing analysis, and snRNA 3' end processing assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — stable interaction demonstrated, snRNA processing assay, and KD with defined molecular phenotype (missplicing); multiple orthogonal methods in a single study\",\n      \"pmids\": [\"36851842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"INTS15 is critical for axonal outgrowth in retinal ganglion cells derived from human iPS cells, as demonstrated by INTS15 knockdown causing defects in this process.\",\n      \"method\": \"INTS15 knockdown in human iPS cell-derived neural progenitor cells with axonal outgrowth phenotypic readout\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular phenotype in a relevant cell type; single lab\",\n      \"pmids\": [\"36851842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of the complete Integrator-PP2A complex reveal that INTS15, together with INTS10, INTS13, and INTS14, forms a scorpion-tail-shaped module; the 'sting' of this module may open the DSIF DNA clamp to facilitate Pol II termination.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) structural determination of the Integrator-PP2A complex in pre-termination, post-termination, and free states\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structures in multiple functional states with mechanistic interpretation; single highly cited study with rigorous structural methods\",\n      \"pmids\": [\"38570683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"INTS15 overexpression activates p53 and p21 expression to induce G1 cell cycle arrest, while INTS15 knockdown causes defects in G2/M progression and apoptosis in HeLa and human iPS cells.\",\n      \"method\": \"Cumate-inducible INTS15 overexpression and siRNA knockdown in HeLa and iPS cells with cell cycle analysis and apoptosis readouts\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with defined cell cycle phenotypes; single lab, multiple cell types\",\n      \"pmids\": [\"40194948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"INTS15 promotes formation of the three germ layers and differentiation into late retinal tissues in iPS cell in vitro differentiation assays.\",\n      \"method\": \"INTS15 overexpression in human iPS cells with in vitro differentiation assays measuring germ layer and retinal tissue formation\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with defined differentiation phenotype; single lab\",\n      \"pmids\": [\"40194948\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTS15 is a bona fide subunit of the Integrator complex that forms a scorpion-tail-shaped module with INTS10/INTS13/INTS14 — visible in cryo-EM structures — where it facilitates RNA Pol II termination by opening the DSIF DNA clamp, while also supporting snRNA 3' end processing, modulating RNAPII pausing, regulating mRNA splicing, and controlling cell cycle progression (G1 arrest via p53/p21 activation and G2/M progression) in human cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"INTS15 is a subunit of the Integrator complex that functions in RNA polymerase II transcription termination, snRNA 3ʹ-end processing, and cell cycle control. It assembles with INTS10, INTS13, and INTS14 into a scorpion-tail-shaped module that, in cryo-EM structures of the Integrator–PP2A complex, contacts the DSIF DNA clamp to facilitate Pol II termination [PMID:38570683, PMID:36920904]. INTS15 supports snRNA 3ʹ-end maturation, and its depletion causes widespread mRNA missplicing and impaired RNA Pol II pause regulation at a subset of genes [PMID:36851842, PMID:36920904]. Overexpression of INTS15 activates p53/p21 to induce G1 arrest, whereas its knockdown disrupts G2/M progression and promotes apoptosis, and it is required for axonal outgrowth in human iPSC-derived retinal ganglion cells [PMID:40194948, PMID:36851842].\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing that INTS15 is a previously unrecognized Integrator subunit resolved how the INTS10/13/14 module interfaces with the rest of the complex, particularly the PP2A module.\",\n      \"evidence\": \"Mass spectrometry proteomics and AlphaFold2 structural prediction in human cells\",\n      \"pmids\": [\"36920904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction topology relied on AlphaFold2 prediction without experimental atomic-resolution confirmation at the time\",\n        \"Stoichiometry of INTS15 within the complex was not determined\",\n        \"No reconstitution of a minimal INTS15-containing subcomplex was performed\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that INTS15 perturbation alters Pol II pausing and causes snRNA 3ʹ-end processing defects and widespread missplicing established its functional contribution to Integrator-mediated transcriptional and RNA processing activities.\",\n      \"evidence\": \"CRISPRi/knockdown with genomic occupancy readouts, snRNA processing assays, and RNA-seq splicing analysis in human cells\",\n      \"pmids\": [\"36920904\", \"36851842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether INTS15 directly contacts nascent RNA or acts solely through structural scaffolding is unknown\",\n        \"Gene-level specificity of pausing effects not fully defined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that INTS15 loss impairs axonal outgrowth in iPSC-derived retinal ganglion cells linked its molecular functions to a neurodevelopmental cellular phenotype.\",\n      \"evidence\": \"siRNA knockdown in human iPSC-derived neural progenitors with morphometric axon readouts\",\n      \"pmids\": [\"36851842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting snRNA/splicing defects to axon growth was not dissected\",\n        \"In vivo validation in animal models is lacking\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"High-resolution cryo-EM structures of the full Integrator–PP2A complex in multiple functional states revealed that INTS15/10/13/14 forms a scorpion-tail module whose tip contacts the DSIF DNA clamp, providing a structural mechanism for Pol II termination.\",\n      \"evidence\": \"Cryo-EM of Integrator–PP2A in pre-termination, post-termination, and free states\",\n      \"pmids\": [\"38570683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional mutagenesis of the INTS15 'sting' contact with DSIF has not been performed\",\n        \"Whether the clamp-opening mechanism is universal or context-specific is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Gain- and loss-of-function experiments showed INTS15 controls cell cycle progression via the p53/p21 axis and is required for G2/M transition, expanding its role beyond RNA processing to proliferation and differentiation control.\",\n      \"evidence\": \"Cumate-inducible overexpression and siRNA knockdown in HeLa and iPSCs with cell cycle, apoptosis, and differentiation readouts\",\n      \"pmids\": [\"40194948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether cell cycle effects are direct or secondary to global splicing/transcription defects is not resolved\",\n        \"The transcriptional targets through which INTS15 activates p53/p21 are not identified\",\n        \"Single-lab observation awaiting independent confirmation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular contacts between INTS15 and DSIF/Pol II that drive clamp opening, and the causal chain linking INTS15-dependent RNA processing to cell cycle and differentiation phenotypes, remain to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No mutagenesis or reconstitution study has isolated INTS15's specific structural contribution to termination\",\n        \"No separation-of-function alleles distinguish RNA processing versus cell cycle roles\",\n        \"No animal model phenotype has been reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"Integrator complex\", \"Integrator-PP2A complex\"],\n    \"partners\": [\"INTS10\", \"INTS13\", \"INTS14\"],\n    \"other_free_text\": []\n  }\n}\n```"}