{"gene":"INTS2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2019,"finding":"Drosophila Integrator subunit IntS2 (ortholog of human INTS2) prevents dedifferentiation of intermediate neural progenitors (INPs) back into neural stem cells (type II neuroblasts); INP-specific knockdown of intS2 resulted in formation of excess type II neuroblasts, placing IntS2 as a component of the Integrator complex required to maintain INP identity during neural lineage development.","method":"Drosophila INP-specific RNAi knockdown of intS2 with quantification of ectopic type II neuroblast formation; genetic interaction and cell-type-specific DamID analysis of other Integrator subunits","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype (ectopic neuroblast formation) in Drosophila ortholog; single lab but supported by parallel knockdown of multiple Integrator subunits and DamID","pmids":["31018143"],"is_preprint":false}],"current_model":"INTS2 functions as a subunit of the Integrator complex where, as demonstrated by its Drosophila ortholog intS2, it is required to prevent dedifferentiation of intermediate neural progenitors back into neural stem cells, likely by supporting Integrator-mediated transcriptional regulation of key differentiation factors."},"narrative":{"mechanistic_narrative":"INTS2 is a subunit of the Integrator complex implicated in the transcriptional control of neural lineage progression, as established through its Drosophila ortholog intS2 [PMID:31018143]. INP-specific knockdown of intS2 causes intermediate neural progenitors to dedifferentiate back into type II neuroblasts, producing ectopic neural stem cells and identifying INTS2 as required to maintain intermediate progenitor identity during neural development [PMID:31018143]. Beyond this ortholog-based role in safeguarding progenitor identity through Integrator function, no further mechanistic detail—biochemical activity, direct partners, or human-specific function—has been characterized in the available corpus.","teleology":[{"year":2019,"claim":"Established that an Integrator subunit is required not just for general transcription but specifically to lock in intermediate progenitor identity and prevent reversion to a stem-cell state.","evidence":"INP-specific RNAi knockdown of the Drosophila ortholog intS2 with quantification of ectopic type II neuroblast formation, alongside genetic interaction and DamID analysis of Integrator subunits","pmids":["31018143"],"confidence":"Medium","gaps":["The direct transcriptional targets through which INTS2 maintains INP identity were not defined","Evidence rests on the Drosophila ortholog; the human INTS2 function was not directly tested","The biochemical activity of INTS2 within the Integrator complex was not resolved"]},{"year":null,"claim":"How INTS2 contributes biochemically to Integrator function and whether its progenitor-maintenance role is conserved in mammalian neurogenesis remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No human or mammalian functional data in the corpus","No molecular activity, substrate, or structural assignment for INTS2","Direct physical partners within the Integrator complex not mapped in these findings"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Integrator complex"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H0H0","full_name":"Integrator complex subunit 2","aliases":[],"length_aa":1196,"mass_kda":133.4,"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:33243860, PubMed:38570683). 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:33243860, 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:16239144). Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the integrator complex (PubMed:23904267)","subcellular_location":"Nucleus; Nucleus membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9H0H0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/INTS2","classification":"Common Essential","n_dependent_lines":1125,"n_total_lines":1208,"dependency_fraction":0.9312913907284768},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"INTS14","stoichiometry":4.0},{"gene":"POLR2B","stoichiometry":0.2},{"gene":"POLR2E","stoichiometry":0.2},{"gene":"POLR2F","stoichiometry":0.2},{"gene":"POLR2K","stoichiometry":0.2},{"gene":"PPP2CA","stoichiometry":0.2},{"gene":"SEM1","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"SUPT5H","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/INTS2","total_profiled":1310},"omim":[{"mim_id":"611346","title":"INTEGRATOR COMPLEX SUBUNIT 2; INTS2","url":"https://www.omim.org/entry/611346"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INTS2"},"hgnc":{"alias_symbol":["INT2"],"prev_symbol":["KIAA1287"]},"alphafold":{"accession":"Q9H0H0","domains":[{"cath_id":"-","chopping":"21-85","consensus_level":"high","plddt":86.3208,"start":21,"end":85},{"cath_id":"-","chopping":"536-723","consensus_level":"medium","plddt":79.7155,"start":536,"end":723},{"cath_id":"-","chopping":"827-900_925-951_989-1009","consensus_level":"medium","plddt":87.2977,"start":827,"end":1009},{"cath_id":"-","chopping":"1073-1160_1179-1204","consensus_level":"medium","plddt":77.8671,"start":1073,"end":1204},{"cath_id":"1.25.40","chopping":"92-288","consensus_level":"medium","plddt":86.4069,"start":92,"end":288},{"cath_id":"1.10.220","chopping":"739-824","consensus_level":"medium","plddt":81.0938,"start":739,"end":824}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0H0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0H0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0H0-F1-predicted_aligned_error_v6.png","plddt_mean":78.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INTS2","jax_strain_url":"https://www.jax.org/strain/search?query=INTS2"},"sequence":{"accession":"Q9H0H0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H0H0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H0H0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0H0"}},"corpus_meta":[{"pmid":"26811494","id":"PMC_26811494","title":"Genetic alterations and their clinical implications in gastric cancer peritoneal carcinomatosis revealed by whole-exome sequencing of malignant ascites.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26811494","citation_count":39,"is_preprint":false},{"pmid":"31018143","id":"PMC_31018143","title":"The Integrator Complex Prevents Dedifferentiation of Intermediate Neural Progenitors back into Neural Stem Cells.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31018143","citation_count":25,"is_preprint":false},{"pmid":"40959972","id":"PMC_40959972","title":"Expanding the Autosomal Recessive Gene Spectrum of Parkinson's Disease: A Study within the CPD10KGP.","date":"2025","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/40959972","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3867,"output_tokens":387,"usd":0.008703,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6631,"output_tokens":817,"usd":0.02679,"stage2_stop_reason":"end_turn"},"total_usd":0.035493,"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\": 2019,\n      \"finding\": \"Drosophila Integrator subunit IntS2 (ortholog of human INTS2) prevents dedifferentiation of intermediate neural progenitors (INPs) back into neural stem cells (type II neuroblasts); INP-specific knockdown of intS2 resulted in formation of excess type II neuroblasts, placing IntS2 as a component of the Integrator complex required to maintain INP identity during neural lineage development.\",\n      \"method\": \"Drosophila INP-specific RNAi knockdown of intS2 with quantification of ectopic type II neuroblast formation; genetic interaction and cell-type-specific DamID analysis of other Integrator subunits\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype (ectopic neuroblast formation) in Drosophila ortholog; single lab but supported by parallel knockdown of multiple Integrator subunits and DamID\",\n      \"pmids\": [\"31018143\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTS2 functions as a subunit of the Integrator complex where, as demonstrated by its Drosophila ortholog intS2, it is required to prevent dedifferentiation of intermediate neural progenitors back into neural stem cells, likely by supporting Integrator-mediated transcriptional regulation of key differentiation factors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INTS2 is a subunit of the Integrator complex implicated in the transcriptional control of neural lineage progression, as established through its Drosophila ortholog intS2 [#0]. INP-specific knockdown of intS2 causes intermediate neural progenitors to dedifferentiate back into type II neuroblasts, producing ectopic neural stem cells and identifying INTS2 as required to maintain intermediate progenitor identity during neural development [#0]. Beyond this ortholog-based role in safeguarding progenitor identity through Integrator function, no further mechanistic detail—biochemical activity, direct partners, or human-specific function—has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that an Integrator subunit is required not just for general transcription but specifically to lock in intermediate progenitor identity and prevent reversion to a stem-cell state.\",\n      \"evidence\": \"INP-specific RNAi knockdown of the Drosophila ortholog intS2 with quantification of ectopic type II neuroblast formation, alongside genetic interaction and DamID analysis of Integrator subunits\",\n      \"pmids\": [\"31018143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The direct transcriptional targets through which INTS2 maintains INP identity were not defined\",\n        \"Evidence rests on the Drosophila ortholog; the human INTS2 function was not directly tested\",\n        \"The biochemical activity of INTS2 within the Integrator complex was not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How INTS2 contributes biochemically to Integrator function and whether its progenitor-maintenance role is conserved in mammalian neurogenesis remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No human or mammalian functional data in the corpus\",\n        \"No molecular activity, substrate, or structural assignment for INTS2\",\n        \"Direct physical partners within the Integrator complex not mapped in these findings\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [\"Integrator complex\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":2,"faith_total":2,"faith_pct":100.0}}