{"gene":"INTS14","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2020,"finding":"INTS10, INTS13 (Asunder), and INTS14 form a separable, functional module of the Integrator complex. The crystal structure of INTS13-INTS14 reveals a strongly entwined heterodimer with a unique chain interlink and unexpected structural homology to the Ku70-Ku80 DNA repair complex. This module displays nucleic acid-binding affinity, preferring RNA hairpins over DNA. The module plays an accessory role in snRNA 3'-end maturation but has a stronger influence on transcription termination after pausing. INTS13 directly contacts the Integrator cleavage module via a conserved C-terminal motif, suggesting that the INTS10-INTS13-INTS14 module brings the cleavage module and target transcripts into proximity.","method":"Structural determination (X-ray crystallography of INTS13-INTS14), biochemical reconstitution, nucleic acid binding assays, mass spectrometry (cross-linking), functional snRNA processing and termination assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with in vitro binding assays, mutagenesis of conserved motifs, and functional assays across two biological processes (snRNA processing and transcription termination) in a single rigorous study","pmids":["32647223"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of the complete Integrator-PP2A complex reveal that INTS10-INTS13-INTS14-INTS15 form a scorpion-tail-shaped module. In the pre-termination complex, this module's 'sting' region is positioned to open the DSIF DNA clamp on the paused Pol II elongation complex, facilitating Pol II removal from the DNA template and transcription termination.","method":"Cryo-electron microscopy (cryo-EM) of pre-termination, post-termination, and free Integrator-PP2A complexes","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structures of multiple functional states of the complete complex, directly resolving the INTS14-containing module and its spatial relationship to DSIF and Pol II","pmids":["38570683"],"is_preprint":false},{"year":2022,"finding":"Knockdown of INTS14 in prostate cell lines decreased MYC mRNA and protein expression and induced G0/G1 cell cycle arrest, indicating that INTS14 positively regulates MYC promoter activity.","method":"CRISPR library screen for MYC promoter regulators, siRNA knockdown of INTS14, qRT-PCR and western blot for MYC expression, cell cycle analysis","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional knockdown with defined molecular and cell-cycle phenotypes, but single lab, limited mechanistic detail on how INTS14 activates the MYC promoter","pmids":["35887071"],"is_preprint":false}],"current_model":"INTS14 is a core subunit of the Integrator complex that, together with INTS10 and INTS13, forms a discrete nucleic acid-binding module (preferring RNA hairpins) structurally homologous to Ku70-Ku80; within the fully assembled Integrator-PP2A complex this 'scorpion-tail' module is positioned to open the DSIF DNA clamp on paused RNA Pol II, facilitating promoter-proximal transcription termination, while INTS13's direct contact with the Integrator cleavage module links this module to both snRNA 3'-end processing and protein-coding gene regulation including control of MYC expression."},"narrative":{"mechanistic_narrative":"INTS14 is a core subunit of the Integrator complex that functions within a discrete nucleic acid-binding submodule controlling RNA Polymerase II promoter-proximal transcription termination [PMID:32647223, PMID:38570683]. Together with INTS10 and INTS13, INTS14 forms a separable functional module; the INTS13-INTS14 heterodimer is a strongly entwined, chain-interlinked pair structurally homologous to the Ku70-Ku80 DNA repair complex, and the assembled module binds nucleic acids with a preference for RNA hairpins over DNA [PMID:32647223]. Within the complete Integrator-PP2A complex, INTS10-INTS13-INTS14 (with INTS15) form a scorpion-tail-shaped module whose 'sting' region opens the DSIF DNA clamp on paused Pol II, facilitating polymerase removal from the template and transcription termination [PMID:38570683]. INTS13's conserved C-terminal motif contacts the Integrator cleavage module, positioning this submodule to bring the cleavage machinery and target transcripts into proximity, and the module additionally plays an accessory role in snRNA 3'-end maturation [PMID:32647223]. Beyond its role in transcription termination, INTS14 positively regulates MYC promoter activity, with its depletion reducing MYC expression and inducing G0/G1 arrest [PMID:35887071].","teleology":[{"year":2020,"claim":"Established that INTS14 is not a standalone factor but part of a separable, structurally distinct Integrator submodule, defining its molecular architecture and nucleic-acid-binding character.","evidence":"X-ray crystallography of the INTS13-INTS14 heterodimer with biochemical reconstitution, nucleic acid binding assays, cross-linking mass spectrometry, and functional snRNA/termination assays","pmids":["32647223"],"confidence":"High","gaps":["The functional significance of the Ku-like fold for transcription is not mechanistically resolved","How RNA hairpin recognition is coupled to cleavage module activity is not directly demonstrated"]},{"year":2022,"claim":"Connected INTS14 to protein-coding gene regulation by showing it positively controls MYC expression and cell cycle progression, extending its role beyond snRNA processing.","evidence":"CRISPR screen for MYC promoter regulators, siRNA knockdown of INTS14, qRT-PCR/western blot for MYC, and cell cycle analysis in prostate cell lines","pmids":["35887071"],"confidence":"Medium","gaps":["Single lab with limited mechanistic detail on how INTS14 activates the MYC promoter","Whether MYC regulation requires the INTS14 termination function or a separate activity is unknown"]},{"year":2024,"claim":"Resolved how the INTS14-containing module physically executes termination by visualizing its spatial relationship to the paused Pol II machinery in defined functional states.","evidence":"Cryo-EM structures of pre-termination, post-termination, and free Integrator-PP2A complexes","pmids":["38570683"],"confidence":"High","gaps":["Dynamics and timing of DSIF clamp opening are inferred from static states","Determinants selecting which paused transcripts are terminated are not defined"]},{"year":null,"claim":"How INTS14's submodule integrates RNA hairpin recognition, cleavage module recruitment, and MYC promoter activation into a unified regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct link established between hairpin binding and gene-specific selectivity","Mechanism connecting termination function to positive MYC regulation is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]}],"complexes":["Integrator complex","Integrator-PP2A complex"],"partners":["INTS13","INTS10","INTS15"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96SY0","full_name":"Integrator complex subunit 14","aliases":["von Willebrand factor A domain-containing protein 9"],"length_aa":518,"mass_kda":57.5,"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: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:32647223). Within the integrator complex, INTS14 is part of the integrator tail module that acts as a platform for the recruitment of transcription factors at promoters (PubMed:38823386, PubMed:38906142)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96SY0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/INTS14","classification":"Common Essential","n_dependent_lines":732,"n_total_lines":1208,"dependency_fraction":0.6059602649006622},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000138614","cell_line_id":"CID001829","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":1}],"interactors":[{"gene":"VWA9","stoichiometry":10.0},{"gene":"POLR2K","stoichiometry":10.0},{"gene":"POLR2A","stoichiometry":4.0},{"gene":"INTS2","stoichiometry":4.0},{"gene":"INIP","stoichiometry":4.0},{"gene":"INTS9","stoichiometry":4.0},{"gene":"INTS8","stoichiometry":4.0},{"gene":"ZNF655","stoichiometry":4.0},{"gene":"INTS1","stoichiometry":4.0},{"gene":"INTS3","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001829","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":"Nuclear bodies","reliability":"Approved"},{"location":"Mitochondria","reliability":"Approved"},{"location":"Nuclear membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INTS14"},"hgnc":{"alias_symbol":["DKFZP564O1664"],"prev_symbol":["C15orf44","VWA9"]},"alphafold":{"accession":"Q96SY0","domains":[{"cath_id":"3.40.50.410","chopping":"2-208","consensus_level":"high","plddt":92.4544,"start":2,"end":208},{"cath_id":"2.40.290.10","chopping":"211-280_305-373","consensus_level":"high","plddt":87.7999,"start":211,"end":373},{"cath_id":"1.10.220","chopping":"408-496","consensus_level":"high","plddt":89.4654,"start":408,"end":496}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96SY0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96SY0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96SY0-F1-predicted_aligned_error_v6.png","plddt_mean":86.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INTS14","jax_strain_url":"https://www.jax.org/strain/search?query=INTS14"},"sequence":{"accession":"Q96SY0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96SY0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96SY0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96SY0"}},"corpus_meta":[{"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":"32647223","id":"PMC_32647223","title":"INTS10-INTS13-INTS14 form a functional module of Integrator that binds nucleic acids and the cleavage module.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32647223","citation_count":52,"is_preprint":false},{"pmid":"38200816","id":"PMC_38200816","title":"Genome-Wide Association Studies Reveal Candidate Genes Associated with Pigmentation Patterns of Single Feathers of Tianfu Nonghua Ducks.","date":"2023","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/38200816","citation_count":8,"is_preprint":false},{"pmid":"35887071","id":"PMC_35887071","title":"Efficient Identification of the MYC Regulator with the Use of the CRISPR Library and Context-Matched Database Screenings.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35887071","citation_count":7,"is_preprint":false},{"pmid":"38292235","id":"PMC_38292235","title":"Generation of ints14 Knockout Zebrafish using CRISPR/Cas9 for the Study of Development and Disease Mechanisms.","date":"2023","source":"Development & reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/38292235","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4468,"output_tokens":1041,"usd":0.014509,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7518,"output_tokens":1618,"usd":0.03902,"stage2_stop_reason":"end_turn"},"total_usd":0.053529,"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\": 2020,\n      \"finding\": \"INTS10, INTS13 (Asunder), and INTS14 form a separable, functional module of the Integrator complex. The crystal structure of INTS13-INTS14 reveals a strongly entwined heterodimer with a unique chain interlink and unexpected structural homology to the Ku70-Ku80 DNA repair complex. This module displays nucleic acid-binding affinity, preferring RNA hairpins over DNA. The module plays an accessory role in snRNA 3'-end maturation but has a stronger influence on transcription termination after pausing. INTS13 directly contacts the Integrator cleavage module via a conserved C-terminal motif, suggesting that the INTS10-INTS13-INTS14 module brings the cleavage module and target transcripts into proximity.\",\n      \"method\": \"Structural determination (X-ray crystallography of INTS13-INTS14), biochemical reconstitution, nucleic acid binding assays, mass spectrometry (cross-linking), functional snRNA processing and termination assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with in vitro binding assays, mutagenesis of conserved motifs, and functional assays across two biological processes (snRNA processing and transcription termination) in a single rigorous study\",\n      \"pmids\": [\"32647223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of the complete Integrator-PP2A complex reveal that INTS10-INTS13-INTS14-INTS15 form a scorpion-tail-shaped module. In the pre-termination complex, this module's 'sting' region is positioned to open the DSIF DNA clamp on the paused Pol II elongation complex, facilitating Pol II removal from the DNA template and transcription termination.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) of pre-termination, post-termination, and free Integrator-PP2A complexes\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structures of multiple functional states of the complete complex, directly resolving the INTS14-containing module and its spatial relationship to DSIF and Pol II\",\n      \"pmids\": [\"38570683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of INTS14 in prostate cell lines decreased MYC mRNA and protein expression and induced G0/G1 cell cycle arrest, indicating that INTS14 positively regulates MYC promoter activity.\",\n      \"method\": \"CRISPR library screen for MYC promoter regulators, siRNA knockdown of INTS14, qRT-PCR and western blot for MYC expression, cell cycle analysis\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional knockdown with defined molecular and cell-cycle phenotypes, but single lab, limited mechanistic detail on how INTS14 activates the MYC promoter\",\n      \"pmids\": [\"35887071\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTS14 is a core subunit of the Integrator complex that, together with INTS10 and INTS13, forms a discrete nucleic acid-binding module (preferring RNA hairpins) structurally homologous to Ku70-Ku80; within the fully assembled Integrator-PP2A complex this 'scorpion-tail' module is positioned to open the DSIF DNA clamp on paused RNA Pol II, facilitating promoter-proximal transcription termination, while INTS13's direct contact with the Integrator cleavage module links this module to both snRNA 3'-end processing and protein-coding gene regulation including control of MYC expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INTS14 is a core subunit of the Integrator complex that functions within a discrete nucleic acid-binding submodule controlling RNA Polymerase II promoter-proximal transcription termination [#0, #1]. Together with INTS10 and INTS13, INTS14 forms a separable functional module; the INTS13-INTS14 heterodimer is a strongly entwined, chain-interlinked pair structurally homologous to the Ku70-Ku80 DNA repair complex, and the assembled module binds nucleic acids with a preference for RNA hairpins over DNA [#0]. Within the complete Integrator-PP2A complex, INTS10-INTS13-INTS14 (with INTS15) form a scorpion-tail-shaped module whose 'sting' region opens the DSIF DNA clamp on paused Pol II, facilitating polymerase removal from the template and transcription termination [#1]. INTS13's conserved C-terminal motif contacts the Integrator cleavage module, positioning this submodule to bring the cleavage machinery and target transcripts into proximity, and the module additionally plays an accessory role in snRNA 3'-end maturation [#0]. Beyond its role in transcription termination, INTS14 positively regulates MYC promoter activity, with its depletion reducing MYC expression and inducing G0/G1 arrest [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that INTS14 is not a standalone factor but part of a separable, structurally distinct Integrator submodule, defining its molecular architecture and nucleic-acid-binding character.\",\n      \"evidence\": \"X-ray crystallography of the INTS13-INTS14 heterodimer with biochemical reconstitution, nucleic acid binding assays, cross-linking mass spectrometry, and functional snRNA/termination assays\",\n      \"pmids\": [\"32647223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The functional significance of the Ku-like fold for transcription is not mechanistically resolved\",\n        \"How RNA hairpin recognition is coupled to cleavage module activity is not directly demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected INTS14 to protein-coding gene regulation by showing it positively controls MYC expression and cell cycle progression, extending its role beyond snRNA processing.\",\n      \"evidence\": \"CRISPR screen for MYC promoter regulators, siRNA knockdown of INTS14, qRT-PCR/western blot for MYC, and cell cycle analysis in prostate cell lines\",\n      \"pmids\": [\"35887071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab with limited mechanistic detail on how INTS14 activates the MYC promoter\",\n        \"Whether MYC regulation requires the INTS14 termination function or a separate activity is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved how the INTS14-containing module physically executes termination by visualizing its spatial relationship to the paused Pol II machinery in defined functional states.\",\n      \"evidence\": \"Cryo-EM structures of pre-termination, post-termination, and free Integrator-PP2A complexes\",\n      \"pmids\": [\"38570683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Dynamics and timing of DSIF clamp opening are inferred from static states\",\n        \"Determinants selecting which paused transcripts are terminated are not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How INTS14's submodule integrates RNA hairpin recognition, cleavage module recruitment, and MYC promoter activation into a unified regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct link established between hairpin binding and gene-specific selectivity\",\n        \"Mechanism connecting termination function to positive MYC regulation is uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"Integrator complex\", \"Integrator-PP2A complex\"],\n    \"partners\": [\"INTS13\", \"INTS10\", \"INTS15\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}