{"gene":"INTS7","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2005,"finding":"INTS7 (named KIAA0999/INT7) was identified as one of at least 12 novel subunits of the Integrator complex, a large multiprotein assembly that associates with the C-terminal domain (CTD) of RNA polymerase II and mediates 3'-end processing of small nuclear RNAs (snRNAs). The Integrator complex was purified by affinity purification and its subunits identified by mass spectrometry; Integrator was shown to be recruited to U1 and U2 snRNA genes and required for their 3' end processing.","method":"Affinity purification and mass spectrometry; ChIP at snRNA genes; in vitro and cell-based snRNA processing assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — original complex purification with functional validation of snRNA processing, foundational paper with >400 citations","pmids":["16239144"],"is_preprint":false},{"year":2007,"finding":"INTS7 was identified as a component of the human Integrator complex in a systematic affinity purification/mass spectrometry survey of the transcription and RNA processing machinery, confirming its membership in the complex associated with RNA polymerase II.","method":"Protein affinity purification coupled to mass spectrometry","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 — AP-MS in systematic transcription machinery survey, replicates Integrator complex membership","pmids":["17643375"],"is_preprint":false},{"year":2008,"finding":"The CDT2-INTS7 intergenic region (246 bp in human) was shown to function as a bidirectional promoter. Transcription factors E2F1–E2F4 up-regulated expression from this promoter in the CDT2 direction only, while B-Myb, c-Myb, and p53 down-regulated expression in the INTS7 direction. Overexpressed E2F1 increased CDT2 but not INTS7 mRNA, demonstrating asymmetric regulation of the two genes from the shared promoter.","method":"Luciferase reporter assays, adenoviral-mediated E2F1 overexpression, RT-PCR in human and mouse tissues","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional reporter assays with transcription factor overexpression, single lab","pmids":["18213392"],"is_preprint":false},{"year":2009,"finding":"The Drosophila ortholog of INTS7, encoded by the gene deflated (CG18176), is essential for normal development. Loss-of-function mutations caused pleiotropic developmental defects including a pupal lethal abdominal phenotype, consistent with perturbation of cell signaling or cell proliferation. GFP-tagged Deflated protein was found to be predominantly nuclear, and deflated mRNA was detected at low levels in proliferating cells, establishing a requirement for this Ints7 homolog in normal cell signaling and proliferation.","method":"Generation and analysis of four loss-of-function alleles; GFP-tagging and imaging; in situ hybridization","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple alleles, GFP localization, developmental phenotyping in ortholog model organism","pmids":["19326441"],"is_preprint":false},{"year":2010,"finding":"Novel components of the endogenous human Integrator complex, including INTS7, were consistently purified and identified by immunoprecipitation/mass spectrometry from nuclear extracts, further establishing INTS7 as a stable core component of the Integrator complex.","method":"IP/MS with spectral count-based specificity filters targeting endogenous complexes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — endogenous complex purification with quantitative MS, semi-quantitative specificity controls","pmids":["20133760"],"is_preprint":false},{"year":2011,"finding":"INTS7 (the RNA processing protein) was identified in a genome-wide DNA damage response screen and found to be recruited to sites of DNA damage, implicating INTS7 in the DNA damage response pathway alongside factors such as CLOCK and RHINO.","method":"Functional genomic screen for damage-induced cell cycle arrest; recruitment to DNA damage sites by imaging","journal":"Science (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide functional screen with direct localization to damage sites, single study","pmids":["21659603"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structural analysis identified the INTAC complex — Integrator bound to the PP2A core enzyme (PP2A-AC). INTS7 is part of the backbone module of the nine-subunit Integrator scaffold that, together with the shoulder module, forms a cruciform central scaffold. The INTAC complex dephosphorylates the RNA Pol II CTD at Ser-2, -5, and -7, integrating dual enzymatic activities (RNA cleavage via the endonuclease module and CTD dephosphorylation via PP2A) into a single structural assembly.","method":"Cryo-EM at 3.5 Å resolution; biochemical dephosphorylation assays of Pol II CTD","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — near-atomic cryo-EM structure plus functional phosphatase assay, >150 citations","pmids":["33243860"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of the Integrator-PP2A pretermination complex bound to paused RNA Pol II revealed the structural basis of Integrator-mediated transcription regulation. INTS7 is part of the backbone module. Integrator engages Pol II and pausing factors DSIF and NELF to exclude elongation factors SPT6 and PAF1C. PP2A is positioned to counteract Pol II CTD phosphorylation, and the Integrator endonuclease docks at the RNA exit site to cleave nascent RNA ~20 nt from the active site, enabling transcription termination.","method":"Cryo-EM structure of pretermination complex; structural analysis of subunit interfaces","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structure of functional complex with mechanistic interpretation, >100 citations","pmids":["34762484"],"is_preprint":false},{"year":2021,"finding":"INTS7 directly interacts with ABCD3 (also known as PMP70) in mouse bone marrow mesenchymal stem cells (BM-MSCs), and this INTS7-ABCD3 interaction is required for BM-MSC proliferation and osteoblastic differentiation. Knockdown of either INTS7 or ABCD3 (but not HDLBP) impaired proliferation, induced apoptosis, decreased osteoblastic differentiation, and accelerated adipogenic differentiation. Mechanistically, INTS7 and ABCD3 suppression elevated reactive oxygen species (ROS) and γ-H2AX levels while reducing antioxidants, indicating that the INTS7-ABCD3 complex promotes BM-MSC expansion and osteoblastic fate partly by suppressing oxidative stress.","method":"siRNA knockdown; co-immunoprecipitation; CCK-8 proliferation assay; Alizarin Red S and Oil Red O differentiation staining; ROS and γ-H2AX quantification","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP plus multiple orthogonal functional readouts, single lab","pmids":["34880777"],"is_preprint":false},{"year":2022,"finding":"OpenCell systematic endogenous tagging of human proteins confirmed nuclear localization of INTS7 and identified its interaction partners by mass spectrometry, consistent with its role as a nuclear component of the Integrator complex.","method":"CRISPR-based endogenous GFP tagging; confocal live-cell imaging; affinity purification mass spectrometry","journal":"Science (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 — endogenous tagging with live imaging and AP-MS, proteome-scale study","pmids":["35271311"],"is_preprint":false},{"year":2023,"finding":"BAG3 directly interacts with INTS7 in BM-MSCs, as demonstrated by co-immunoprecipitation. BAG3 knockdown decreased INTS7 protein levels and promoted its ubiquitination, indicating that BAG3 stabilizes INTS7 by protecting it from proteasomal degradation. The resulting decrease in INTS7 upon BAG3 loss increased ROS and DNA damage in BM-MSCs, and re-expression of INTS7 or addition of an antioxidant rescued the proliferation defect caused by BAG3 depletion, placing INTS7 downstream of BAG3 in a pathway controlling oxidative stress and cell expansion.","method":"Co-immunoprecipitation; protein half-life assay; western blotting for ubiquitination; CCK-8 and colony formation assays; flow cytometry; TUNEL assay; INTS7 rescue experiment","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 — direct co-IP, ubiquitination assay, and rescue experiment with multiple orthogonal readouts, single lab","pmids":["37576499"],"is_preprint":false},{"year":2025,"finding":"Loss of Ints7 (a backbone subunit of the Integrator complex) in mouse embryonic stem cells (mESCs) increased DNA damage and triggered expression of the endogenous retrovirus MERVL. Mechanistically, Ints7 depletion induced phosphorylation of Kap1 (a heterochromatin maintenance factor), increased chromatin accessibility at MERVL loci, and activated the p53-Dux transcriptional axis to drive MERVL transcription. Furthermore, DNA damage-induced MERVL resurgence was accompanied by caspase-3 cleavage and a process of anastasis (cell survival after transient apoptotic signaling), linking Ints7 to a cellular circuit integrating DNA damage response and developmental potential of stem cells.","method":"Genome-wide CRISPR knockout screen; Ints7 knockout mESCs; chromatin accessibility assays (ATAC-seq); Kap1 phosphorylation analysis; p53-Dux axis transcriptional analysis; caspase-3 activation assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen, genetic knockout, multiple mechanistic readouts (chromatin accessibility, phosphorylation, transcription factor axis), orthogonal methods in single study","pmids":["40842237"],"is_preprint":false},{"year":2025,"finding":"siRNA-mediated knockdown of INTS7 in lung adenocarcinoma cell lines significantly inhibited cell proliferation and induced cell cycle arrest, as measured by CCK-8 assay and flow cytometry, establishing a functional role for INTS7 in promoting cell cycle progression in LUAD cells.","method":"siRNA knockdown; CCK-8 proliferation assay; flow cytometry cell cycle analysis","journal":"Briefings in functional genomics","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single knockdown approach with phenotypic readout but limited pathway placement","pmids":["40875878"],"is_preprint":false}],"current_model":"INTS7 is a backbone structural subunit of the metazoan Integrator complex, which associates with the CTD of RNA polymerase II to mediate snRNA 3'-end processing, promote transcription termination by cleaving nascent RNA and dephosphorylating the Pol II CTD (via the associated PP2A), and is recruited to sites of DNA damage where its loss triggers Kap1 phosphorylation, increased chromatin accessibility at retroviral loci, and p53-Dux-driven transcription; outside the Integrator complex, INTS7 is stabilized by BAG3 (which prevents its ubiquitination) and interacts with ABCD3 to suppress oxidative stress and promote bone marrow mesenchymal stem cell proliferation and osteoblastic differentiation."},"narrative":{"teleology":[{"year":2005,"claim":"Identification of INTS7 as a subunit of the Integrator complex resolved the molecular machinery responsible for snRNA 3′-end processing associated with the Pol II CTD, establishing its fundamental functional context.","evidence":"Affinity purification/mass spectrometry of the Integrator complex with ChIP and snRNA processing assays in human cells","pmids":["16239144"],"confidence":"High","gaps":["Precise structural position of INTS7 within the complex unknown","Direct contribution of INTS7 versus other subunits to snRNA processing not delineated"]},{"year":2007,"claim":"Independent AP-MS surveys replicated INTS7 as a stable component of the endogenous Integrator complex, solidifying its assignment as a constitutive subunit rather than a transient interactor.","evidence":"Systematic AP-MS of transcription and RNA processing machinery in human nuclear extracts","pmids":["17643375","20133760"],"confidence":"Medium","gaps":["Stoichiometry within the complex not determined","Functional consequence of INTS7 depletion alone not tested"]},{"year":2009,"claim":"Genetic loss-of-function studies of the Drosophila ortholog deflated demonstrated that INTS7 is essential for metazoan development and cell proliferation, extending the gene's significance beyond snRNA processing.","evidence":"Four loss-of-function alleles in Drosophila with developmental phenotyping and GFP localization","pmids":["19326441"],"confidence":"Medium","gaps":["Whether developmental defects arise from snRNA processing failure or other Integrator functions was unclear","No mammalian knockout phenotype yet reported"]},{"year":2011,"claim":"A genome-wide DNA damage response screen revealed that INTS7 is recruited to sites of DNA damage, implicating the Integrator backbone in genome maintenance beyond transcription.","evidence":"Functional genomic screen for damage-induced cell cycle arrest with imaging of recruitment to damage foci","pmids":["21659603"],"confidence":"Medium","gaps":["Mechanism of recruitment to damage sites unknown","Whether INTS7 acts at damage sites as part of Integrator or independently was unresolved"]},{"year":2020,"claim":"Near-atomic cryo-EM structures placed INTS7 within the backbone module of the INTAC complex and revealed how Integrator integrates RNA endonuclease and PP2A-mediated CTD phosphatase activities into a single structural assembly for transcription regulation.","evidence":"Cryo-EM at 3.5 Å resolution with biochemical CTD dephosphorylation assays","pmids":["33243860"],"confidence":"High","gaps":["INTS7-specific contacts within the backbone not fully resolved at side-chain level","No reconstitution of INTAC lacking INTS7 to test its structural necessity"]},{"year":2021,"claim":"Structural determination of the Integrator–PP2A–Pol II pretermination complex showed how the backbone module containing INTS7 scaffolds the endonuclease and phosphatase near paused Pol II to exclude elongation factors and enable transcription termination.","evidence":"Cryo-EM of the pretermination complex with structural analysis of subunit interfaces","pmids":["34762484"],"confidence":"High","gaps":["Direct mutagenesis of INTS7 interface residues not performed","Dynamics of INTS7 engagement during the transition from pausing to termination unknown"]},{"year":2021,"claim":"Discovery that INTS7 directly interacts with the peroxisomal ABC transporter ABCD3 to suppress oxidative stress and promote osteoblastic differentiation in BM-MSCs revealed a functional role outside canonical Integrator-mediated transcription termination.","evidence":"Reciprocal co-immunoprecipitation, siRNA knockdown, ROS quantification, and differentiation assays in mouse BM-MSCs","pmids":["34880777"],"confidence":"Medium","gaps":["Whether the INTS7–ABCD3 interaction occurs independently of the Integrator complex is untested","Structural basis and binding interface unknown","Mechanism by which oxidative stress is suppressed not molecularly defined"]},{"year":2023,"claim":"BAG3 was shown to stabilize INTS7 by preventing its ubiquitin-dependent degradation, placing INTS7 protein turnover downstream of a co-chaperone pathway and linking it to oxidative stress resistance in BM-MSCs.","evidence":"Co-immunoprecipitation, ubiquitination assay, protein half-life measurement, and INTS7 rescue experiment in BM-MSCs","pmids":["37576499"],"confidence":"Medium","gaps":["E3 ligase responsible for INTS7 ubiquitination not identified","Whether BAG3 regulation of INTS7 affects Integrator complex assembly or only non-Integrator functions is unknown"]},{"year":2025,"claim":"Knockout of Ints7 in mouse ESCs established a mechanistic circuit in which Integrator backbone loss triggers Kap1 phosphorylation, chromatin opening at endogenous retroviruses, and p53–Dux-driven MERVL derepression coupled with caspase-3-mediated anastasis, connecting Integrator to heterochromatin maintenance and developmental potency.","evidence":"CRISPR knockout in mESCs with ATAC-seq, Kap1 phosphorylation analysis, p53–Dux transcriptional profiling, and caspase-3 activation assays","pmids":["40842237"],"confidence":"High","gaps":["Whether INTS7-specific loss versus general Integrator disruption is responsible for MERVL derepression is not resolved","Upstream kinase phosphorylating Kap1 upon INTS7 loss not identified","Relevance to human ESCs or in vivo embryonic development untested"]},{"year":null,"claim":"The specific structural contacts of INTS7 within the Integrator backbone, its individual contribution to complex assembly and enzymatic functions (versus other backbone subunits), and whether its non-Integrator activities (ABCD3, BAG3 axis) operate through independent protein pools remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted INTAC lacking only INTS7 to define its unique structural contribution","No separation-of-function mutant distinguishing Integrator-dependent from -independent roles","E3 ligase and degron motif for INTS7 ubiquitination unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,6,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,9]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,6,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,7,11]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5,11]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[11]}],"complexes":["Integrator complex","Integrator-PP2A (INTAC)"],"partners":["INTS1","INTS4","INTS11","PP2A","ABCD3","BAG3"],"other_free_text":[]},"mechanistic_narrative":"INTS7 is a backbone structural subunit of the metazoan Integrator complex, a multiprotein assembly that associates with the RNA polymerase II C-terminal domain to mediate 3′-end processing of small nuclear RNAs and promote transcription termination [PMID:16239144, PMID:33243860]. Cryo-EM structures show that INTS7 resides in the backbone module of the Integrator–PP2A (INTAC) complex, which couples nascent RNA cleavage by the endonuclease module with CTD dephosphorylation by PP2A, engaging paused Pol II together with DSIF and NELF to exclude elongation factors and enforce premature termination [PMID:33243860, PMID:34762484]. Loss of INTS7 in mouse embryonic stem cells increases DNA damage, triggers Kap1 phosphorylation and chromatin opening at endogenous retrovirus loci, and activates the p53–Dux transcriptional axis to derepress MERVL, linking Integrator backbone integrity to heterochromatin maintenance and developmental potency [PMID:40842237]. Outside its Integrator role, INTS7 is stabilized by BAG3 (which prevents its ubiquitin-dependent degradation) and interacts with the peroxisomal transporter ABCD3 to suppress reactive oxygen species and promote osteoblastic differentiation of bone marrow mesenchymal stem cells [PMID:37576499, PMID:34880777]."},"prefetch_data":{"uniprot":{"accession":"Q9NVH2","full_name":"Integrator complex subunit 7","aliases":[],"length_aa":962,"mass_kda":106.8,"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). May be not involved in the recruitment of cytoplasmic dynein to the nuclear envelope by different components of the INT complex (PubMed:23904267). Plays a role in DNA damage response (DDR) signaling during the S phase (PubMed:21659603)","subcellular_location":"Nucleus; Chromosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9NVH2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/INTS7","classification":"Common Essential","n_dependent_lines":1197,"n_total_lines":1208,"dependency_fraction":0.9908940397350994},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"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}],"url":"https://opencell.sf.czbiohub.org/search/INTS7","total_profiled":1310},"omim":[{"mim_id":"611350","title":"INTEGRATOR COMPLEX SUBUNIT 7; INTS7","url":"https://www.omim.org/entry/611350"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INTS7"},"hgnc":{"alias_symbol":["DKFZP434B168","INT7"],"prev_symbol":["C1orf73"]},"alphafold":{"accession":"Q9NVH2","domains":[{"cath_id":"-","chopping":"356-459","consensus_level":"medium","plddt":91.6367,"start":356,"end":459},{"cath_id":"-","chopping":"466-552","consensus_level":"medium","plddt":89.9536,"start":466,"end":552},{"cath_id":"-","chopping":"553-794","consensus_level":"high","plddt":88.2204,"start":553,"end":794},{"cath_id":"2.60.40.2550","chopping":"801-931","consensus_level":"high","plddt":84.9355,"start":801,"end":931},{"cath_id":"1.20.5","chopping":"935-962","consensus_level":"medium","plddt":59.3546,"start":935,"end":962}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVH2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVH2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVH2-F1-predicted_aligned_error_v6.png","plddt_mean":88.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INTS7","jax_strain_url":"https://www.jax.org/strain/search?query=INTS7"},"sequence":{"accession":"Q9NVH2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NVH2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NVH2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVH2"}},"corpus_meta":[{"pmid":"21732367","id":"PMC_21732367","title":"Rspo2/Int7 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complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17643375","id":"PMC_17643375","title":"Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme.","date":"2007","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/17643375","citation_count":367,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26949251","id":"PMC_26949251","title":"The cell proliferation antigen Ki-67 organises heterochromatin.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26949251","citation_count":265,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21659603","id":"PMC_21659603","title":"A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling.","date":"2011","source":"Science (New York, 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/29117863","citation_count":135,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25187353","id":"PMC_25187353","title":"Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25187353","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34762484","id":"PMC_34762484","title":"Structural basis of Integrator-mediated transcription regulation.","date":"2021","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/34762484","citation_count":112,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20379614","id":"PMC_20379614","title":"Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.","date":"2010","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/20379614","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20133760","id":"PMC_20133760","title":"Streamlined analysis schema for high-throughput identification of endogenous protein complexes.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20133760","citation_count":102,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6626,"output_tokens":1503,"usd":0.021212},"stage2":{"model":"claude-opus-4-6","input_tokens":4747,"output_tokens":1906,"usd":0.107078},"total_usd":0.339736,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of 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\"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"INTS7 is identified as a subunit of the Integrator complex that associates with the largest subunit of RNA Polymerase II; its gene is arranged head-to-head with CDT2 and driven by a bidirectional promoter regulated by E2F, B-Myb, c-Myb, and p53 transcription factors.\",\n      \"method\": \"Luciferase reporter assay, adenoviral E2F1 overexpression, RT-PCR expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional promoter assays with multiple transcription factors; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18213392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"INTS7 directly interacts with ABCD3 (but not HDLBP) in mouse bone marrow mesenchymal stem cells; this interaction is required for BM-MSC proliferation and osteoblastic differentiation, and suppression of the INTS7-ABCD3 interaction increases reactive oxygen species and γ-H2AX levels while reducing antioxidant levels.\",\n      \"method\": \"siRNA knockdown of INTS7 and ABCD3, co-immunoprecipitation, Alizarin Red S and Oil Red O staining, ROS quantification, flow cytometry (apoptosis)\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP plus functional KD with multiple readouts; single lab\",\n      \"pmids\": [\"34880777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BAG3 directly interacts with INTS7 and stabilizes it by reducing its ubiquitination; BAG3 knockdown decreases INTS7 protein levels, promotes INTS7 ubiquitination, increases ROS and DNA damage, and impairs BM-MSC proliferation — phenotypes rescued by INTS7 overexpression or antioxidant treatment.\",\n      \"method\": \"Co-immunoprecipitation, protein half-life assay, siRNA knockdown, ubiquitination assay, CCK-8 proliferation assay, flow cytometry, TUNEL assay, rescue experiments\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ubiquitination assay plus rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37576499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of Ints7 (a backbone subunit of the Integrator complex) in mouse embryonic stem cells increases DNA damage, induces phosphorylation of Kap1, increases chromatin accessibility at MERVL loci, and activates the p53-Dux axis to drive MERVL transcription; this is accompanied by caspase-3 cleavage and anastasis.\",\n      \"method\": \"Genome-wide knockout screen, Ints7 deletion/depletion in mESCs, ATAC-seq (chromatin accessibility), western blotting (p-Kap1, p53, Dux), caspase-3 assay, MERVL reporter\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genome-wide screen followed by mechanistic dissection with multiple orthogonal methods (chromatin accessibility, phospho-signaling, p53-Dux axis) in single rigorous study\",\n      \"pmids\": [\"40842237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"INTS7 depletion in lung adenocarcinoma cell lines significantly inhibits cell proliferation and induces cell cycle arrest, establishing a functional role for INTS7 in promoting cell cycle progression in LUAD cells.\",\n      \"method\": \"siRNA-mediated INTS7 knockdown, CCK-8 proliferation assay, flow cytometry cell cycle analysis\",\n      \"journal\": \"Briefings in functional genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined proliferation/cell cycle phenotype; single lab\",\n      \"pmids\": [\"40875878\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTS7 is a backbone subunit of the Integrator complex that associates with RNA Polymerase II and is required for snRNA 3'-end processing; mechanistically, it suppresses DNA damage responses (in part by preventing Kap1 phosphorylation and maintaining chromatin compaction at retroviral loci), interacts with ABCD3 and is stabilized against ubiquitination by BAG3 to suppress oxidative stress and support stem cell proliferation/osteoblastic differentiation, and promotes cell cycle progression in multiple cell types.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\nRetrieved papers:\n1. PMID:21732367 — Rspo2/Int7: This is about RSPO2 (R-spondin 2), identified at a mouse mammary tumor virus integration site called \"Int7\" — NOT INTS7 the Integrator complex subunit. EXCLUDE (alias collision)\n2. PMID:16014973 — Int7 as MMTV integration site, identifies gene \"2610028F08RIK\" with furin/thrombospondin domains — NOT INTS7 Integrator subunit. EXCLUDE (alias collision)\n3. PMID:34880777 — INTS7-ABCD3 interaction in BM-MSCs. KEEP\n4. PMID:19326441 — Drosophila deflated/Ints7 functional analysis. KEEP (ortholog)\n5. PMID:18213392 — CDT2-INTS7 intergenic region transcriptional regulation. KEEP (mentions INTS7 as Integrator subunit interacting with RNAPII)\n6. PMID:34781123 — INTS7 in lung adenocarcinoma, expression/biomarker study. EXCLUDE (no mechanistic findings)\n7. PMID:37576499 — BAG3 regulates BMMSCs by targeting INTS7. KEEP\n8. PMID:40842237 — Ints7 deficiency activates DNA damage response, MERVL. KEEP\n9. PMID:40875878 — INTS7 in LUAD, mostly expression/survival with some functional KD. KEEP (has loss-of-function with phenotype)\n10. bio_10.1101_2025.05.06.25327093 — GWAS for intracranial stenosis, INTS7 mentioned in gene-set. EXCLUDE (no mechanistic finding)\n\nGene2pubmed curated papers:\n- PMID:12477932, 11076863, 14702039, 15489334, 16344560: cDNA/genome projects. EXCLUDE (no mechanistic findings about INTS7)\n- PMID:26186194, 28514442, 33961781: BioPlex interactome — INTS7 appears as interactor. These are proteome-scale, not INTS7-specific. EXCLUDE (no specific mechanistic finding)\n- PMID:26496610: HeLa interactome. EXCLUDE\n- PMID:21873635: GO annotation. EXCLUDE\n- PMID:33060197: COVID/coronavirus host factors. EXCLUDE\n- PMID:25910212: Disease mutations/interactome. EXCLUDE\n- PMID:16239144: Integrator complex original discovery paper — KEEP (INTS7 is one of the 12 novel subunits)\n- PMID:14702039: cDNA sequencing. EXCLUDE\n- PMID:35271311: OpenCell localization. KEEP (endogenous tagging/localization)\n- PMID:26949251: Ki-67/heterochromatin. EXCLUDE\n- PMID:21659603: DNA damage response screen — INTS7 recruited to DNA damage sites. KEEP\n- PMID:30804502: BRCA1-BARD1. EXCLUDE\n- PMID:34004147: PP2A-Integrator-CDK9 axis — involves Integrator but focuses on INTS6. EXCLUDE (INTS7 not specifically studied)\n- PMID:33243860: INTAC structure — Integrator+PP2A. KEEP (INTS7 is a backbone subunit)\n- PMID:30554943: BET bromodomain interactomes. EXCLUDE\n- PMID:29117863: TRIM25. EXCLUDE\n- PMID:25187353: Clozapine agranulocytosis. EXCLUDE\n- PMID:20379614: Smoking cessation. EXCLUDE\n- PMID:20133760: IP/MS Integrator complex — KEEP (novel components of Integrator including INTS7)\n- PMID:17643375: 7SK capping enzyme/transcription machinery — KEEP (Integrator complex identified)\n- PMID:11230166: cDNA sequencing. EXCLUDE\n- PMID:26344197: Metazoan complexes. EXCLUDE\n- PMID:34762484: Integrator structure. KEEP (INTS7 as backbone subunit, structural)\n- PMID:18187620: HIV host factors screen. EXCLUDE (INTS7 listed as HDF but no mechanistic detail)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"INTS7 (named KIAA0999/INT7) was identified as one of at least 12 novel subunits of the Integrator complex, a large multiprotein assembly that associates with the C-terminal domain (CTD) of RNA polymerase II and mediates 3'-end processing of small nuclear RNAs (snRNAs). The Integrator complex was purified by affinity purification and its subunits identified by mass spectrometry; Integrator was shown to be recruited to U1 and U2 snRNA genes and required for their 3' end processing.\",\n      \"method\": \"Affinity purification and mass spectrometry; ChIP at snRNA genes; in vitro and cell-based snRNA processing assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original complex purification with functional validation of snRNA processing, foundational paper with >400 citations\",\n      \"pmids\": [\"16239144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"INTS7 was identified as a component of the human Integrator complex in a systematic affinity purification/mass spectrometry survey of the transcription and RNA processing machinery, confirming its membership in the complex associated with RNA polymerase II.\",\n      \"method\": \"Protein affinity purification coupled to mass spectrometry\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — AP-MS in systematic transcription machinery survey, replicates Integrator complex membership\",\n      \"pmids\": [\"17643375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The CDT2-INTS7 intergenic region (246 bp in human) was shown to function as a bidirectional promoter. Transcription factors E2F1–E2F4 up-regulated expression from this promoter in the CDT2 direction only, while B-Myb, c-Myb, and p53 down-regulated expression in the INTS7 direction. Overexpressed E2F1 increased CDT2 but not INTS7 mRNA, demonstrating asymmetric regulation of the two genes from the shared promoter.\",\n      \"method\": \"Luciferase reporter assays, adenoviral-mediated E2F1 overexpression, RT-PCR in human and mouse tissues\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional reporter assays with transcription factor overexpression, single lab\",\n      \"pmids\": [\"18213392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The Drosophila ortholog of INTS7, encoded by the gene deflated (CG18176), is essential for normal development. Loss-of-function mutations caused pleiotropic developmental defects including a pupal lethal abdominal phenotype, consistent with perturbation of cell signaling or cell proliferation. GFP-tagged Deflated protein was found to be predominantly nuclear, and deflated mRNA was detected at low levels in proliferating cells, establishing a requirement for this Ints7 homolog in normal cell signaling and proliferation.\",\n      \"method\": \"Generation and analysis of four loss-of-function alleles; GFP-tagging and imaging; in situ hybridization\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple alleles, GFP localization, developmental phenotyping in ortholog model organism\",\n      \"pmids\": [\"19326441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Novel components of the endogenous human Integrator complex, including INTS7, were consistently purified and identified by immunoprecipitation/mass spectrometry from nuclear extracts, further establishing INTS7 as a stable core component of the Integrator complex.\",\n      \"method\": \"IP/MS with spectral count-based specificity filters targeting endogenous complexes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — endogenous complex purification with quantitative MS, semi-quantitative specificity controls\",\n      \"pmids\": [\"20133760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"INTS7 (the RNA processing protein) was identified in a genome-wide DNA damage response screen and found to be recruited to sites of DNA damage, implicating INTS7 in the DNA damage response pathway alongside factors such as CLOCK and RHINO.\",\n      \"method\": \"Functional genomic screen for damage-induced cell cycle arrest; recruitment to DNA damage sites by imaging\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide functional screen with direct localization to damage sites, single study\",\n      \"pmids\": [\"21659603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structural analysis identified the INTAC complex — Integrator bound to the PP2A core enzyme (PP2A-AC). INTS7 is part of the backbone module of the nine-subunit Integrator scaffold that, together with the shoulder module, forms a cruciform central scaffold. The INTAC complex dephosphorylates the RNA Pol II CTD at Ser-2, -5, and -7, integrating dual enzymatic activities (RNA cleavage via the endonuclease module and CTD dephosphorylation via PP2A) into a single structural assembly.\",\n      \"method\": \"Cryo-EM at 3.5 Å resolution; biochemical dephosphorylation assays of Pol II CTD\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — near-atomic cryo-EM structure plus functional phosphatase assay, >150 citations\",\n      \"pmids\": [\"33243860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of the Integrator-PP2A pretermination complex bound to paused RNA Pol II revealed the structural basis of Integrator-mediated transcription regulation. INTS7 is part of the backbone module. Integrator engages Pol II and pausing factors DSIF and NELF to exclude elongation factors SPT6 and PAF1C. PP2A is positioned to counteract Pol II CTD phosphorylation, and the Integrator endonuclease docks at the RNA exit site to cleave nascent RNA ~20 nt from the active site, enabling transcription termination.\",\n      \"method\": \"Cryo-EM structure of pretermination complex; structural analysis of subunit interfaces\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure of functional complex with mechanistic interpretation, >100 citations\",\n      \"pmids\": [\"34762484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"INTS7 directly interacts with ABCD3 (also known as PMP70) in mouse bone marrow mesenchymal stem cells (BM-MSCs), and this INTS7-ABCD3 interaction is required for BM-MSC proliferation and osteoblastic differentiation. Knockdown of either INTS7 or ABCD3 (but not HDLBP) impaired proliferation, induced apoptosis, decreased osteoblastic differentiation, and accelerated adipogenic differentiation. Mechanistically, INTS7 and ABCD3 suppression elevated reactive oxygen species (ROS) and γ-H2AX levels while reducing antioxidants, indicating that the INTS7-ABCD3 complex promotes BM-MSC expansion and osteoblastic fate partly by suppressing oxidative stress.\",\n      \"method\": \"siRNA knockdown; co-immunoprecipitation; CCK-8 proliferation assay; Alizarin Red S and Oil Red O differentiation staining; ROS and γ-H2AX quantification\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus multiple orthogonal functional readouts, single lab\",\n      \"pmids\": [\"34880777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OpenCell systematic endogenous tagging of human proteins confirmed nuclear localization of INTS7 and identified its interaction partners by mass spectrometry, consistent with its role as a nuclear component of the Integrator complex.\",\n      \"method\": \"CRISPR-based endogenous GFP tagging; confocal live-cell imaging; affinity purification mass spectrometry\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — endogenous tagging with live imaging and AP-MS, proteome-scale study\",\n      \"pmids\": [\"35271311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BAG3 directly interacts with INTS7 in BM-MSCs, as demonstrated by co-immunoprecipitation. BAG3 knockdown decreased INTS7 protein levels and promoted its ubiquitination, indicating that BAG3 stabilizes INTS7 by protecting it from proteasomal degradation. The resulting decrease in INTS7 upon BAG3 loss increased ROS and DNA damage in BM-MSCs, and re-expression of INTS7 or addition of an antioxidant rescued the proliferation defect caused by BAG3 depletion, placing INTS7 downstream of BAG3 in a pathway controlling oxidative stress and cell expansion.\",\n      \"method\": \"Co-immunoprecipitation; protein half-life assay; western blotting for ubiquitination; CCK-8 and colony formation assays; flow cytometry; TUNEL assay; INTS7 rescue experiment\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct co-IP, ubiquitination assay, and rescue experiment with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"37576499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of Ints7 (a backbone subunit of the Integrator complex) in mouse embryonic stem cells (mESCs) increased DNA damage and triggered expression of the endogenous retrovirus MERVL. Mechanistically, Ints7 depletion induced phosphorylation of Kap1 (a heterochromatin maintenance factor), increased chromatin accessibility at MERVL loci, and activated the p53-Dux transcriptional axis to drive MERVL transcription. Furthermore, DNA damage-induced MERVL resurgence was accompanied by caspase-3 cleavage and a process of anastasis (cell survival after transient apoptotic signaling), linking Ints7 to a cellular circuit integrating DNA damage response and developmental potential of stem cells.\",\n      \"method\": \"Genome-wide CRISPR knockout screen; Ints7 knockout mESCs; chromatin accessibility assays (ATAC-seq); Kap1 phosphorylation analysis; p53-Dux axis transcriptional analysis; caspase-3 activation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen, genetic knockout, multiple mechanistic readouts (chromatin accessibility, phosphorylation, transcription factor axis), orthogonal methods in single study\",\n      \"pmids\": [\"40842237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"siRNA-mediated knockdown of INTS7 in lung adenocarcinoma cell lines significantly inhibited cell proliferation and induced cell cycle arrest, as measured by CCK-8 assay and flow cytometry, establishing a functional role for INTS7 in promoting cell cycle progression in LUAD cells.\",\n      \"method\": \"siRNA knockdown; CCK-8 proliferation assay; flow cytometry cell cycle analysis\",\n      \"journal\": \"Briefings in functional genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single knockdown approach with phenotypic readout but limited pathway placement\",\n      \"pmids\": [\"40875878\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTS7 is a backbone structural subunit of the metazoan Integrator complex, which associates with the CTD of RNA polymerase II to mediate snRNA 3'-end processing, promote transcription termination by cleaving nascent RNA and dephosphorylating the Pol II CTD (via the associated PP2A), and is recruited to sites of DNA damage where its loss triggers Kap1 phosphorylation, increased chromatin accessibility at retroviral loci, and p53-Dux-driven transcription; outside the Integrator complex, INTS7 is stabilized by BAG3 (which prevents its ubiquitination) and interacts with ABCD3 to suppress oxidative stress and promote bone marrow mesenchymal stem cell proliferation and osteoblastic differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"INTS7 is a backbone subunit of the Integrator complex that associates with RNA Polymerase II and functions in genome integrity maintenance, chromatin regulation, and cell proliferation. Loss of INTS7 in mouse embryonic stem cells induces DNA damage, triggers Kap1 phosphorylation, increases chromatin accessibility at MERVL retroviral loci, and activates a p53–Dux axis driving endogenous retrovirus transcription and caspase-3-dependent anastasis [PMID:40842237]. INTS7 interacts with ABCD3 to support bone marrow mesenchymal stem cell proliferation and osteoblastic differentiation while suppressing reactive oxygen species accumulation, and its protein stability is maintained by BAG3, which shields INTS7 from ubiquitin-mediated degradation [PMID:34880777, PMID:37576499]. INTS7 depletion also arrests the cell cycle in lung adenocarcinoma cells, indicating a general requirement for cell cycle progression across cell types [PMID:40875878].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that INTS7 is a bona fide Integrator subunit whose transcription is coordinately regulated with CDT2 via a bidirectional promoter responsive to E2F, B-Myb, c-Myb, and p53 placed INTS7 within the RNA Pol II–associated snRNA processing machinery and linked its expression to cell cycle control.\",\n      \"evidence\": \"Luciferase reporter assays with transcription factor overexpression and RT-PCR in human cells\",\n      \"pmids\": [\"18213392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct evidence that INTS7 is required for snRNA 3'-end processing in this study\",\n        \"Bidirectional promoter regulation characterized only via overexpression; endogenous factor requirements not tested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that the Drosophila INTS7 ortholog (deflated) is essential for normal development and localizes to the nucleus established that the gene has a conserved, non-redundant role in metazoan biology.\",\n      \"evidence\": \"Loss-of-function mutant alleles and GFP-tagged protein localization in Drosophila\",\n      \"pmids\": [\"19326441\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Pleiotropic phenotype does not distinguish Integrator-dependent from Integrator-independent functions\",\n        \"No mammalian validation in this study\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying ABCD3 as a direct INTS7 interaction partner that cooperates with INTS7 to suppress ROS and DNA damage in bone marrow mesenchymal stem cells revealed a non-canonical role for INTS7 in oxidative stress control and osteoblastic differentiation.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown of INTS7/ABCD3, ROS quantification, and differentiation staining in mouse BM-MSCs\",\n      \"pmids\": [\"34880777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the INTS7–ABCD3 interaction occurs within or outside the Integrator complex is unknown\",\n        \"Mechanism by which INTS7–ABCD3 suppresses ROS not defined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that BAG3 stabilizes INTS7 by reducing its ubiquitination, and that BAG3-knockdown phenotypes (elevated ROS, DNA damage, impaired proliferation) are rescued by INTS7 overexpression, placed INTS7 protein turnover as a regulated node controlling stem cell fitness.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, protein half-life measurement, siRNA knockdown with INTS7 rescue in BM-MSCs\",\n      \"pmids\": [\"37576499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The E3 ubiquitin ligase responsible for INTS7 degradation is unidentified\",\n        \"Whether BAG3-mediated stabilization affects Integrator complex assembly is untested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mechanistic dissection in mouse ESCs showed that INTS7 loss causes DNA damage, Kap1 phosphorylation, chromatin decompaction at MERVL loci, and activation of the p53–Dux transcriptional axis, thereby establishing INTS7 as a guardian of chromatin compaction at endogenous retroviruses and linking Integrator function to retroviral silencing and anastasis.\",\n      \"evidence\": \"Genome-wide CRISPR screen, Ints7 deletion in mESCs, ATAC-seq, western blotting for p-Kap1/p53/Dux, caspase-3 assay, MERVL reporter\",\n      \"pmids\": [\"40842237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether INTS7 maintains chromatin compaction through its Integrator-associated RNA processing activity or through a separate mechanism is unresolved\",\n        \"Generalizability of the MERVL derepression phenotype beyond mESCs is untested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"INTS7 depletion in lung adenocarcinoma cells causes cell cycle arrest, extending the proliferation requirement observed in stem cells to a cancer context and supporting a general role in cell cycle progression.\",\n      \"evidence\": \"siRNA knockdown, CCK-8 proliferation assay, flow cytometry cell cycle analysis in LUAD cell lines\",\n      \"pmids\": [\"40875878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether cell cycle arrest is a direct consequence of Integrator dysfunction or secondary to DNA damage is unclear\",\n        \"No in vivo tumor model validation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A key unresolved question is whether INTS7's roles in DNA damage suppression, ROS control, and retroviral silencing are all mechanistically downstream of its Integrator complex snRNA processing function or reflect additional, complex-independent activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No separation-of-function mutants distinguishing Integrator-dependent from Integrator-independent roles\",\n        \"No structural model of INTS7 within the Integrator complex at atomic resolution\",\n        \"The direct enzymatic or scaffolding contribution of INTS7 to Integrator catalytic activity is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"Integrator complex\"],\n    \"partners\": [\"ABCD3\", \"BAG3\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"INTS7 is a backbone structural subunit of the metazoan Integrator complex, a multiprotein assembly that associates with the RNA polymerase II C-terminal domain to mediate 3′-end processing of small nuclear RNAs and promote transcription termination [PMID:16239144, PMID:33243860]. Cryo-EM structures show that INTS7 resides in the backbone module of the Integrator–PP2A (INTAC) complex, which couples nascent RNA cleavage by the endonuclease module with CTD dephosphorylation by PP2A, engaging paused Pol II together with DSIF and NELF to exclude elongation factors and enforce premature termination [PMID:33243860, PMID:34762484]. Loss of INTS7 in mouse embryonic stem cells increases DNA damage, triggers Kap1 phosphorylation and chromatin opening at endogenous retrovirus loci, and activates the p53–Dux transcriptional axis to derepress MERVL, linking Integrator backbone integrity to heterochromatin maintenance and developmental potency [PMID:40842237]. Outside its Integrator role, INTS7 is stabilized by BAG3 (which prevents its ubiquitin-dependent degradation) and interacts with the peroxisomal transporter ABCD3 to suppress reactive oxygen species and promote osteoblastic differentiation of bone marrow mesenchymal stem cells [PMID:37576499, PMID:34880777].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of INTS7 as a subunit of the Integrator complex resolved the molecular machinery responsible for snRNA 3′-end processing associated with the Pol II CTD, establishing its fundamental functional context.\",\n      \"evidence\": \"Affinity purification/mass spectrometry of the Integrator complex with ChIP and snRNA processing assays in human cells\",\n      \"pmids\": [\"16239144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise structural position of INTS7 within the complex unknown\", \"Direct contribution of INTS7 versus other subunits to snRNA processing not delineated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Independent AP-MS surveys replicated INTS7 as a stable component of the endogenous Integrator complex, solidifying its assignment as a constitutive subunit rather than a transient interactor.\",\n      \"evidence\": \"Systematic AP-MS of transcription and RNA processing machinery in human nuclear extracts\",\n      \"pmids\": [\"17643375\", \"20133760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry within the complex not determined\", \"Functional consequence of INTS7 depletion alone not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic loss-of-function studies of the Drosophila ortholog deflated demonstrated that INTS7 is essential for metazoan development and cell proliferation, extending the gene's significance beyond snRNA processing.\",\n      \"evidence\": \"Four loss-of-function alleles in Drosophila with developmental phenotyping and GFP localization\",\n      \"pmids\": [\"19326441\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether developmental defects arise from snRNA processing failure or other Integrator functions was unclear\", \"No mammalian knockout phenotype yet reported\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A genome-wide DNA damage response screen revealed that INTS7 is recruited to sites of DNA damage, implicating the Integrator backbone in genome maintenance beyond transcription.\",\n      \"evidence\": \"Functional genomic screen for damage-induced cell cycle arrest with imaging of recruitment to damage foci\",\n      \"pmids\": [\"21659603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of recruitment to damage sites unknown\", \"Whether INTS7 acts at damage sites as part of Integrator or independently was unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Near-atomic cryo-EM structures placed INTS7 within the backbone module of the INTAC complex and revealed how Integrator integrates RNA endonuclease and PP2A-mediated CTD phosphatase activities into a single structural assembly for transcription regulation.\",\n      \"evidence\": \"Cryo-EM at 3.5 Å resolution with biochemical CTD dephosphorylation assays\",\n      \"pmids\": [\"33243860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"INTS7-specific contacts within the backbone not fully resolved at side-chain level\", \"No reconstitution of INTAC lacking INTS7 to test its structural necessity\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural determination of the Integrator–PP2A–Pol II pretermination complex showed how the backbone module containing INTS7 scaffolds the endonuclease and phosphatase near paused Pol II to exclude elongation factors and enable transcription termination.\",\n      \"evidence\": \"Cryo-EM of the pretermination complex with structural analysis of subunit interfaces\",\n      \"pmids\": [\"34762484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mutagenesis of INTS7 interface residues not performed\", \"Dynamics of INTS7 engagement during the transition from pausing to termination unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that INTS7 directly interacts with the peroxisomal ABC transporter ABCD3 to suppress oxidative stress and promote osteoblastic differentiation in BM-MSCs revealed a functional role outside canonical Integrator-mediated transcription termination.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, siRNA knockdown, ROS quantification, and differentiation assays in mouse BM-MSCs\",\n      \"pmids\": [\"34880777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the INTS7–ABCD3 interaction occurs independently of the Integrator complex is untested\", \"Structural basis and binding interface unknown\", \"Mechanism by which oxidative stress is suppressed not molecularly defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"BAG3 was shown to stabilize INTS7 by preventing its ubiquitin-dependent degradation, placing INTS7 protein turnover downstream of a co-chaperone pathway and linking it to oxidative stress resistance in BM-MSCs.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, protein half-life measurement, and INTS7 rescue experiment in BM-MSCs\",\n      \"pmids\": [\"37576499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase responsible for INTS7 ubiquitination not identified\", \"Whether BAG3 regulation of INTS7 affects Integrator complex assembly or only non-Integrator functions is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Knockout of Ints7 in mouse ESCs established a mechanistic circuit in which Integrator backbone loss triggers Kap1 phosphorylation, chromatin opening at endogenous retroviruses, and p53–Dux-driven MERVL derepression coupled with caspase-3-mediated anastasis, connecting Integrator to heterochromatin maintenance and developmental potency.\",\n      \"evidence\": \"CRISPR knockout in mESCs with ATAC-seq, Kap1 phosphorylation analysis, p53–Dux transcriptional profiling, and caspase-3 activation assays\",\n      \"pmids\": [\"40842237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether INTS7-specific loss versus general Integrator disruption is responsible for MERVL derepression is not resolved\", \"Upstream kinase phosphorylating Kap1 upon INTS7 loss not identified\", \"Relevance to human ESCs or in vivo embryonic development untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific structural contacts of INTS7 within the Integrator backbone, its individual contribution to complex assembly and enzymatic functions (versus other backbone subunits), and whether its non-Integrator activities (ABCD3, BAG3 axis) operate through independent protein pools remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted INTAC lacking only INTS7 to define its unique structural contribution\", \"No separation-of-function mutant distinguishing Integrator-dependent from -independent roles\", \"E3 ligase and degron motif for INTS7 ubiquitination unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 7, 11]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\n      \"Integrator complex\",\n      \"Integrator-PP2A (INTAC)\"\n    ],\n    \"partners\": [\n      \"INTS1\",\n      \"INTS4\",\n      \"INTS11\",\n      \"PP2A\",\n      \"ABCD3\",\n      \"BAG3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}