{"gene":"INTS15","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2023,"finding":"INTS15 (C7orf26) is an additional subunit of the Integrator complex, assembling primarily with the INTS13/14/10 module and interfacing with the Int-PP2A module, as determined by proteomics and AlphaFold2-based structural prediction.","method":"Proteomics (mass spectrometry), AlphaFold2 machine-learning structure prediction, functional genomics","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-based identification combined with structural prediction and functional genomics in a single lab study; no independent replication reported","pmids":["36920904"],"is_preprint":false},{"year":2023,"finding":"INTS15 knockdown causes missplicing of a large number of genes, probably as a secondary consequence of disrupted snRNA 3' end processing, and substantially affects genes associated with eye and brain development; INTS15 stably interacts with the Integrator complex to support small nuclear RNA 3' end processing.","method":"Ints15 knockout/mutant mouse models, siRNA knockdown, iPS cell-derived neural progenitor cells, RNA-seq/splicing analysis, co-immunoprecipitation","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KO mice, knockdown, iPS cells, interaction assays) in a single lab; no independent replication","pmids":["36851842"],"is_preprint":false},{"year":2023,"finding":"INTS15 modulates RNA polymerase II pausing at a subset of genes, as revealed by functional genomics analysis following perturbation of INTS15.","method":"Functional genomics (ChIP-seq/PRO-seq or equivalent RNAPII pausing analysis)","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, functional genomics readout, no independent replication reported","pmids":["36920904"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of the complete Integrator-PP2A complex reveal a scorpion-tail-shaped INTS10-INTS13-INTS14-INTS15 module (the 'sting') that may open the DSIF DNA clamp to facilitate RNA polymerase II termination in the promoter-proximal region.","method":"Cryo-electron microscopy (cryo-EM) of Integrator-PP2A complex in pre-termination, post-termination, and free states","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution cryo-EM structures with multiple functional states resolved in a single rigorous structural study","pmids":["38570683"],"is_preprint":false},{"year":2025,"finding":"Overexpression of INTS15 activates p53 and p21 expression to induce G1 arrest, while INTS15 knockdown results in defects in G2/M progression and apoptosis; INTS15 expression levels vary by cell type and fluctuate during the cell cycle.","method":"Cumate-inducible overexpression in HeLa and human iPS cells, siRNA knockdown, cell cycle analysis, gene expression assays","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both gain- and loss-of-function experiments with defined molecular readouts (p53/p21 activation, cell cycle phase analysis) in a single lab","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":"Human iPS cell differentiation (embryoid body and retinal differentiation assays) with cumate-inducible INTS15 overexpression","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (iPS differentiation assay), no independent replication","pmids":["40194948"],"is_preprint":false},{"year":2023,"finding":"INTS15 is critical for axonal outgrowth in retinal ganglion cells derived from human iPS cells, as shown by INTS15 knockdown experiments.","method":"siRNA knockdown in human iPS cell-derived retinal ganglion cells, axonal outgrowth assay","journal":"Human molecular genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single differentiation-based functional assay, no molecular mechanism pathway placement","pmids":["36851842"],"is_preprint":false}],"current_model":"INTS15 is a bona fide subunit of the Integrator complex that, together with INTS10, INTS13, and INTS14, forms a scorpion-tail-shaped module visible in cryo-EM structures and proposed to open the DSIF DNA clamp during RNA polymerase II termination; it also supports snRNA 3' end processing, modulates RNAPII pausing at a subset of genes, and regulates cell cycle progression by activating p53/p21 to enforce G1 arrest when overexpressed, while its loss causes G2/M defects and apoptosis."},"narrative":{"mechanistic_narrative":"INTS15 (C7orf26) is a bona fide subunit of the Integrator complex that supports RNA polymerase II transcriptional regulation and snRNA 3' end processing [PMID:36920904, PMID:36851842]. It assembles primarily with the INTS13/INTS14/INTS10 module and interfaces with the Integrator-associated PP2A module [PMID:36920904]; cryo-EM of the complete Integrator-PP2A complex resolves these four subunits as a scorpion-tail-shaped 'sting' module positioned to open the DSIF DNA clamp and facilitate promoter-proximal RNAPII termination [PMID:38570683]. Consistent with this structural placement, INTS15 modulates RNAPII pausing at a subset of genes and is required for snRNA 3' end processing, with its loss causing widespread missplicing as a secondary consequence and disrupting genes linked to eye and brain development [PMID:36851842, PMID:36920904]. INTS15 also couples to cell cycle control: overexpression activates p53 and p21 to enforce G1 arrest, while knockdown produces G2/M defects and apoptosis [PMID:40194948]. Functionally, INTS15 is critical for differentiation programs, including retinal ganglion cell axonal outgrowth and retinal tissue formation [PMID:40194948, PMID:36851842].","teleology":[{"year":2023,"claim":"Establishing that the previously uncharacterized C7orf26 is itself an Integrator subunit defined INTS15 as part of the transcription machinery rather than an isolated factor.","evidence":"Proteomics and AlphaFold2 structure prediction with functional genomics placing INTS15 in the INTS13/14/10 module and interfacing with Int-PP2A","pmids":["36920904"],"confidence":"Medium","gaps":["Module assignment rested on prediction plus proteomics without an experimental structure","Stoichiometry and assembly order within the module not resolved"]},{"year":2023,"claim":"Linking INTS15 loss to snRNA 3' end processing defects and downstream missplicing connected the subunit to a concrete biochemical output of the complex and to developmental gene programs.","evidence":"Ints15 KO/mutant mice, siRNA knockdown, iPSC-derived neural progenitors, RNA-seq splicing analysis, and co-immunoprecipitation","pmids":["36851842"],"confidence":"Medium","gaps":["Missplicing inferred as a secondary consequence rather than a direct INTS15 activity","No independent replication of the interaction and processing roles"]},{"year":2023,"claim":"Showing INTS15 modulates RNAPII pausing at a subset of genes extended its role beyond snRNA processing to broader transcriptional regulation.","evidence":"Functional genomics readout of RNAPII pausing after INTS15 perturbation","pmids":["36920904"],"confidence":"Medium","gaps":["Gene selectivity of the pausing effect not mechanistically explained","Single-lab functional genomics without orthogonal validation"]},{"year":2024,"claim":"Cryo-EM resolved how INTS15 contributes structurally, placing it in a scorpion-tail module poised to open the DSIF DNA clamp during promoter-proximal termination.","evidence":"Cryo-EM of the complete Integrator-PP2A complex in pre-termination, post-termination, and free states","pmids":["38570683"],"confidence":"High","gaps":["DSIF clamp-opening function is a structural proposal not yet tested by mutation","Specific residues of INTS15 mediating the activity not defined"]},{"year":2025,"claim":"Coupling INTS15 dosage to p53/p21 activation and cell cycle phase progression revealed a role in cell cycle control beyond transcription.","evidence":"Cumate-inducible overexpression in HeLa and iPS cells, siRNA knockdown, cell cycle and gene expression analyses","pmids":["40194948"],"confidence":"Medium","gaps":["Mechanism linking Integrator function to p53/p21 induction not established","Whether the effect requires Integrator assembly is untested"]},{"year":2025,"claim":"Demonstrating that INTS15 promotes germ-layer formation and retinal differentiation tied the gene to developmental programs in vitro.","evidence":"iPS cell embryoid body and retinal differentiation assays with inducible INTS15 overexpression","pmids":["40194948"],"confidence":"Low","gaps":["Single-lab differentiation assay without independent replication","No molecular pathway connecting INTS15 to differentiation outcomes"]},{"year":null,"claim":"How INTS15's structural role in termination mechanistically produces its gene-selective pausing, snRNA processing, cell cycle, and developmental phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mutational test of the proposed DSIF clamp-opening function","Mechanism linking INTS15 to p53/p21 and developmental programs unknown","No disease-causative variant established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4]}],"complexes":["Integrator complex","Integrator-PP2A complex"],"partners":["INTS10","INTS13","INTS14"],"other_free_text":[]}},"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":454,"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":53,"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":4808,"output_tokens":1560,"usd":0.018912,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8282,"output_tokens":2227,"usd":0.048543,"stage2_stop_reason":"end_turn"},"total_usd":0.067455,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"INTS15 (C7orf26) is an additional subunit of the Integrator complex, assembling primarily with the INTS13/14/10 module and interfacing with the Int-PP2A module, as determined by proteomics and AlphaFold2-based structural prediction.\",\n      \"method\": \"Proteomics (mass spectrometry), AlphaFold2 machine-learning structure prediction, functional genomics\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-based identification combined with structural prediction and functional genomics in a single lab study; no independent replication reported\",\n      \"pmids\": [\"36920904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"INTS15 knockdown causes missplicing of a large number of genes, probably as a secondary consequence of disrupted snRNA 3' end processing, and substantially affects genes associated with eye and brain development; INTS15 stably interacts with the Integrator complex to support small nuclear RNA 3' end processing.\",\n      \"method\": \"Ints15 knockout/mutant mouse models, siRNA knockdown, iPS cell-derived neural progenitor cells, RNA-seq/splicing analysis, co-immunoprecipitation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KO mice, knockdown, iPS cells, interaction assays) in a single lab; no independent replication\",\n      \"pmids\": [\"36851842\"],\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 perturbation of INTS15.\",\n      \"method\": \"Functional genomics (ChIP-seq/PRO-seq or equivalent RNAPII pausing analysis)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, functional genomics readout, no independent replication reported\",\n      \"pmids\": [\"36920904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of the complete Integrator-PP2A complex reveal a scorpion-tail-shaped INTS10-INTS13-INTS14-INTS15 module (the 'sting') that may open the DSIF DNA clamp to facilitate RNA polymerase II termination in the promoter-proximal region.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) of Integrator-PP2A complex in pre-termination, post-termination, and free states\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution cryo-EM structures with multiple functional states resolved in a single rigorous structural study\",\n      \"pmids\": [\"38570683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Overexpression of INTS15 activates p53 and p21 expression to induce G1 arrest, while INTS15 knockdown results in defects in G2/M progression and apoptosis; INTS15 expression levels vary by cell type and fluctuate during the cell cycle.\",\n      \"method\": \"Cumate-inducible overexpression in HeLa and human iPS cells, siRNA knockdown, cell cycle analysis, gene expression assays\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both gain- and loss-of-function experiments with defined molecular readouts (p53/p21 activation, cell cycle phase analysis) in a single lab\",\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\": \"Human iPS cell differentiation (embryoid body and retinal differentiation assays) with cumate-inducible INTS15 overexpression\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (iPS differentiation assay), no independent replication\",\n      \"pmids\": [\"40194948\"],\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 shown by INTS15 knockdown experiments.\",\n      \"method\": \"siRNA knockdown in human iPS cell-derived retinal ganglion cells, axonal outgrowth assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single differentiation-based functional assay, no molecular mechanism pathway placement\",\n      \"pmids\": [\"36851842\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTS15 is a bona fide subunit of the Integrator complex that, together with INTS10, INTS13, and INTS14, forms a scorpion-tail-shaped module visible in cryo-EM structures and proposed to open the DSIF DNA clamp during RNA polymerase II termination; it also supports snRNA 3' end processing, modulates RNAPII pausing at a subset of genes, and regulates cell cycle progression by activating p53/p21 to enforce G1 arrest when overexpressed, while its loss causes G2/M defects and apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INTS15 (C7orf26) is a bona fide subunit of the Integrator complex that supports RNA polymerase II transcriptional regulation and snRNA 3' end processing [#0, #1]. It assembles primarily with the INTS13/INTS14/INTS10 module and interfaces with the Integrator-associated PP2A module [#0]; cryo-EM of the complete Integrator-PP2A complex resolves these four subunits as a scorpion-tail-shaped 'sting' module positioned to open the DSIF DNA clamp and facilitate promoter-proximal RNAPII termination [#3]. Consistent with this structural placement, INTS15 modulates RNAPII pausing at a subset of genes and is required for snRNA 3' end processing, with its loss causing widespread missplicing as a secondary consequence and disrupting genes linked to eye and brain development [#1, #2]. INTS15 also couples to cell cycle control: overexpression activates p53 and p21 to enforce G1 arrest, while knockdown produces G2/M defects and apoptosis [#4]. Functionally, INTS15 is critical for differentiation programs, including retinal ganglion cell axonal outgrowth and retinal tissue formation [#5, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing that the previously uncharacterized C7orf26 is itself an Integrator subunit defined INTS15 as part of the transcription machinery rather than an isolated factor.\",\n      \"evidence\": \"Proteomics and AlphaFold2 structure prediction with functional genomics placing INTS15 in the INTS13/14/10 module and interfacing with Int-PP2A\",\n      \"pmids\": [\"36920904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Module assignment rested on prediction plus proteomics without an experimental structure\", \"Stoichiometry and assembly order within the module not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linking INTS15 loss to snRNA 3' end processing defects and downstream missplicing connected the subunit to a concrete biochemical output of the complex and to developmental gene programs.\",\n      \"evidence\": \"Ints15 KO/mutant mice, siRNA knockdown, iPSC-derived neural progenitors, RNA-seq splicing analysis, and co-immunoprecipitation\",\n      \"pmids\": [\"36851842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Missplicing inferred as a secondary consequence rather than a direct INTS15 activity\", \"No independent replication of the interaction and processing roles\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing INTS15 modulates RNAPII pausing at a subset of genes extended its role beyond snRNA processing to broader transcriptional regulation.\",\n      \"evidence\": \"Functional genomics readout of RNAPII pausing after INTS15 perturbation\",\n      \"pmids\": [\"36920904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Gene selectivity of the pausing effect not mechanistically explained\", \"Single-lab functional genomics without orthogonal validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM resolved how INTS15 contributes structurally, placing it in a scorpion-tail module poised to open the DSIF DNA clamp during promoter-proximal termination.\",\n      \"evidence\": \"Cryo-EM of the complete Integrator-PP2A complex in pre-termination, post-termination, and free states\",\n      \"pmids\": [\"38570683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DSIF clamp-opening function is a structural proposal not yet tested by mutation\", \"Specific residues of INTS15 mediating the activity not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Coupling INTS15 dosage to p53/p21 activation and cell cycle phase progression revealed a role in cell cycle control beyond transcription.\",\n      \"evidence\": \"Cumate-inducible overexpression in HeLa and iPS cells, siRNA knockdown, cell cycle and gene expression analyses\",\n      \"pmids\": [\"40194948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking Integrator function to p53/p21 induction not established\", \"Whether the effect requires Integrator assembly is untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that INTS15 promotes germ-layer formation and retinal differentiation tied the gene to developmental programs in vitro.\",\n      \"evidence\": \"iPS cell embryoid body and retinal differentiation assays with inducible INTS15 overexpression\",\n      \"pmids\": [\"40194948\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab differentiation assay without independent replication\", \"No molecular pathway connecting INTS15 to differentiation outcomes\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How INTS15's structural role in termination mechanistically produces its gene-selective pausing, snRNA processing, cell cycle, and developmental phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mutational test of the proposed DSIF clamp-opening function\", \"Mechanism linking INTS15 to p53/p21 and developmental programs unknown\", \"No disease-causative variant established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"Integrator complex\", \"Integrator-PP2A complex\"],\n    \"partners\": [\"INTS10\", \"INTS13\", \"INTS14\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}