{"gene":"INTS7","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2009,"finding":"Drosophila Ints7 ortholog (deflated/CG18176) is required for normal development; GFP-tagged protein localizes predominantly to the nucleus, and loss-of-function mutants display pleiotropic defects consistent with perturbation of cell signalling or cell proliferation, establishing a developmental role for this Integrator complex subunit.","method":"GFP tagging and fluorescence localization; generation of four mutant alleles with phenotypic analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct nuclear localization by GFP imaging and loss-of-function phenotypic analysis with multiple alleles, single lab","pmids":["19326441"],"is_preprint":false},{"year":2008,"finding":"INTS7 shares a bidirectional intergenic promoter region with CDT2; the transcription factors B-Myb, c-Myb, and p53 down-regulate reporter gene expression in the transcriptional direction of INTS7, while E2F1–E2F4 selectively drive CDT2 but not INTS7, showing asymmetric transcriptional regulation of the two genes from their shared intergenic region.","method":"Luciferase reporter assay in A549 cells; adenoviral overexpression of E2F1; RT-PCR expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay with multiple transcription factors and mRNA validation, single lab","pmids":["18213392"],"is_preprint":false},{"year":2021,"finding":"INTS7 physically interacts with ABCD3 (but not HDLBP) in mouse bone marrow mesenchymal stem cells; suppression of the INTS7–ABCD3 interaction impairs BM-MSC proliferation, induces apoptosis, decreases osteoblastic differentiation, and accelerates adipogenic differentiation, with the mechanism involving increased ROS and γ-H2AX and decreased antioxidant levels.","method":"Co-immunoprecipitation; siRNA knockdown of INTS7, ABCD3, and HDLBP; CCK-8 proliferation assay; Alizarin Red S and Oil Red O staining; ROS and γ-H2AX quantification","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with functional knockdown and multiple orthogonal differentiation assays, single lab","pmids":["34880777"],"is_preprint":false},{"year":2023,"finding":"BAG3 directly interacts with INTS7 in BM-MSCs; BAG3 knockdown decreases INTS7 protein levels and promotes INTS7 ubiquitination, indicating BAG3 stabilizes INTS7 by preventing its proteasomal degradation. Restoration of INTS7 expression rescues the proliferation deficit caused by BAG3 knockdown, placing INTS7 downstream of BAG3 in a pathway that controls BM-MSC expansion via oxidative stress suppression.","method":"Co-immunoprecipitation; protein half-life assay; ubiquitination western blot; siRNA knockdown; CCK-8 and colony formation assays; INTS7 overexpression rescue experiment","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-IP, ubiquitination assay, and epistasis rescue experiment, single lab, multiple orthogonal methods","pmids":["37576499"],"is_preprint":false},{"year":2025,"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 retrovirus loci, and activates the p53–Dux transcriptional axis to drive MERVL expression; this is accompanied by caspase-3 cleavage and anastasis, linking Ints7 to DNA damage response and stem cell fate decisions.","method":"Genome-wide knockout screen; Ints7 depletion; chromatin accessibility assay (ATAC-seq implied); Kap1 phosphorylation western blot; p53 and Dux pathway analysis; caspase-3 cleavage assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen plus mechanistic follow-up with multiple molecular readouts, single lab, single study","pmids":["40842237"],"is_preprint":false},{"year":2025,"finding":"Genetic silencing of INTS7 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.","method":"siRNA/shRNA loss-of-function; CCK-8 proliferation assay; flow cytometry cell cycle analysis","journal":"Briefings in functional genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single study, standard knockdown with proliferation/cell cycle readout but no pathway-level mechanistic resolution","pmids":["40875878"],"is_preprint":false}],"current_model":"INTS7 is a nuclear backbone subunit of the Integrator complex that associates with RNA Polymerase II and participates in snRNA processing; it is stabilized by BAG3 (which prevents its ubiquitination), physically interacts with ABCD3 to suppress oxidative stress and support mesenchymal stem cell proliferation and osteoblastic differentiation, and in embryonic stem cells its loss triggers DNA damage, Kap1 phosphorylation, chromatin remodeling at endogenous retrovirus loci, and p53–Dux-driven MERVL transcription, while in Drosophila its ortholog (deflated) is essential for nuclear-localized functions supporting normal cell signaling and proliferation during development."},"narrative":{"mechanistic_narrative":"INTS7 is a nuclear backbone subunit of the Integrator complex with conserved roles in cell proliferation and signaling during development, established by its Drosophila ortholog deflated whose loss produces pleiotropic developmental defects consistent with perturbed cell signaling and proliferation [PMID:19326441]. In mammalian cells, INTS7 supports proliferation by suppressing oxidative stress: it physically interacts with ABCD3 in bone marrow mesenchymal stem cells, and disruption of this interaction raises ROS and γ-H2AX, induces apoptosis, and shifts the balance from osteoblastic toward adipogenic differentiation [PMID:34880777]. INTS7 stability is governed by BAG3, which binds INTS7 and prevents its proteasomal ubiquitination; restoring INTS7 rescues the proliferation deficit caused by BAG3 loss, placing INTS7 downstream of BAG3 in a pathway controlling stem cell expansion through oxidative stress control [PMID:37576499]. INTS7 also operates at the chromatin/genome-stability interface: its loss in embryonic stem cells elevates DNA damage, drives Kap1 phosphorylation, increases chromatin accessibility at MERVL retrovirus loci, and activates a p53–Dux transcriptional axis to induce MERVL expression alongside caspase-3 cleavage and anastasis [PMID:40842237]. At the transcriptional level, INTS7 is regulated from a bidirectional intergenic promoter shared with CDT2, where B-Myb, c-Myb, and p53 down-regulate INTS7 expression [PMID:18213392].","teleology":[{"year":2008,"claim":"Established how INTS7 itself is transcriptionally controlled, revealing asymmetric regulation from a promoter region shared with a neighboring gene.","evidence":"Luciferase reporter assays with multiple transcription factors and RT-PCR validation in A549 cells","pmids":["18213392"],"confidence":"Medium","gaps":["Does not address INTS7 protein function","Regulation shown on reporters, not at the endogenous locus across cell types"]},{"year":2009,"claim":"Defined a conserved in vivo requirement for the INTS7 ortholog in development, localizing it to the nucleus and linking it to cell signaling and proliferation.","evidence":"GFP localization and loss-of-function phenotypic analysis of four mutant alleles in Drosophila","pmids":["19326441"],"confidence":"Medium","gaps":["Molecular mechanism of the developmental defect not resolved","Integrator-complex biochemical role not directly tested"]},{"year":2021,"claim":"Identified a direct physical partner (ABCD3) and connected INTS7 to oxidative stress suppression governing stem cell proliferation and differentiation fate.","evidence":"Reciprocal co-IP, siRNA knockdown, proliferation, differentiation staining, and ROS/γ-H2AX assays in mouse BM-MSCs","pmids":["34880777"],"confidence":"Medium","gaps":["Mechanism by which the INTS7–ABCD3 interaction controls ROS unknown","Relationship to canonical Integrator function not established"]},{"year":2023,"claim":"Placed INTS7 in a regulatory hierarchy by showing BAG3 stabilizes it against ubiquitin-mediated degradation, with epistasis confirming INTS7 is the functional effector downstream of BAG3.","evidence":"Co-IP, protein half-life and ubiquitination assays, plus INTS7 overexpression rescue in BM-MSCs","pmids":["37576499"],"confidence":"Medium","gaps":["Identity of the ubiquitin ligase acting on INTS7 unknown","Whether BAG3 acts as a direct chaperone or via co-chaperones unresolved"]},{"year":2025,"claim":"Connected INTS7 to genome stability and stem cell fate, showing its loss triggers DNA damage and a chromatin/p53–Dux program driving endogenous retrovirus transcription.","evidence":"Genome-wide knockout screen with chromatin accessibility, Kap1 phosphorylation, p53–Dux pathway and caspase-3 readouts in mouse ESCs","pmids":["40842237"],"confidence":"Medium","gaps":["Whether DNA damage is a direct consequence of lost Integrator activity not dissected","Mechanism of chromatin opening at MERVL loci unresolved"]},{"year":2025,"claim":"Extended the proliferative role of INTS7 to a disease context, showing it promotes cell cycle progression in lung adenocarcinoma.","evidence":"siRNA/shRNA knockdown with proliferation and flow cytometry cell cycle analysis in LUAD lines","pmids":["40875878"],"confidence":"Low","gaps":["No pathway-level mechanism resolved","Single study, standard knockdown without orthogonal validation"]},{"year":null,"claim":"How INTS7's role as an Integrator backbone subunit in snRNA processing/RNA Pol II regulation mechanistically connects to its observed roles in oxidative stress, genome stability, and proliferation remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct biochemical link between Integrator catalytic function and the ROS/DNA-damage phenotypes","Substrate-level role within the Integrator complex not characterized in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[],"complexes":["Integrator complex"],"partners":["ABCD3","BAG3"],"other_free_text":[]}},"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 regulates invasiveness and tumorigenic properties of mammary epithelial cells.","date":"2012","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21732367","citation_count":47,"is_preprint":false},{"pmid":"16014973","id":"PMC_16014973","title":"A new common integration site, Int7, for the mouse mammary tumor virus in mouse mammary tumors identifies a gene whose product has furin-like and thrombospondin-like sequences.","date":"2005","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/16014973","citation_count":43,"is_preprint":false},{"pmid":"34880777","id":"PMC_34880777","title":"INTS7-ABCD3 Interaction Stimulates the Proliferation and Osteoblastic Differentiation of Mouse Bone Marrow Mesenchymal Stem Cells by Suppressing Oxidative Stress.","date":"2021","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34880777","citation_count":26,"is_preprint":false},{"pmid":"19326441","id":"PMC_19326441","title":"Phenotypic analysis of deflated/Ints7 function in Drosophila development.","date":"2009","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/19326441","citation_count":25,"is_preprint":false},{"pmid":"18213392","id":"PMC_18213392","title":"Transcriptional regulation of an evolutionary conserved intergenic region of CDT2-INTS7.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18213392","citation_count":15,"is_preprint":false},{"pmid":"34781123","id":"PMC_34781123","title":"Overexpression and diagnostic significance of INTS7 in lung adenocarcinoma and its effects on tumor microenvironment.","date":"2021","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34781123","citation_count":10,"is_preprint":false},{"pmid":"37576499","id":"PMC_37576499","title":"BAG3 regulates bone marrow mesenchymal stem cell proliferation by targeting INTS7.","date":"2023","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/37576499","citation_count":3,"is_preprint":false},{"pmid":"40842237","id":"PMC_40842237","title":"Ints7 deficiency activates DNA damage response to elicit resurgence of endogenous retrovirus MERVL and anastasis of embryonic stem cells.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/40842237","citation_count":0,"is_preprint":false},{"pmid":"40875878","id":"PMC_40875878","title":"INTS7 modulates cell proliferation and apoptosis via promoting cell cycle progression in lung adenocarcinoma.","date":"2025","source":"Briefings in functional genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40875878","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.06.25327093","title":"Multi-population Genome-Wide Association Study Identifies Multiple Novel Loci associated with Asymptomatic Intracranial Large Artery Stenosis","date":"2025-05-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.06.25327093","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7398,"output_tokens":1692,"usd":0.023787,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8517,"output_tokens":2237,"usd":0.049255,"stage2_stop_reason":"end_turn"},"total_usd":0.073042,"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\": 2009,\n      \"finding\": \"Drosophila Ints7 ortholog (deflated/CG18176) is required for normal development; GFP-tagged protein localizes predominantly to the nucleus, and loss-of-function mutants display pleiotropic defects consistent with perturbation of cell signalling or cell proliferation, establishing a developmental role for this Integrator complex subunit.\",\n      \"method\": \"GFP tagging and fluorescence localization; generation of four mutant alleles with phenotypic analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct nuclear localization by GFP imaging and loss-of-function phenotypic analysis with multiple alleles, single lab\",\n      \"pmids\": [\"19326441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"INTS7 shares a bidirectional intergenic promoter region with CDT2; the transcription factors B-Myb, c-Myb, and p53 down-regulate reporter gene expression in the transcriptional direction of INTS7, while E2F1–E2F4 selectively drive CDT2 but not INTS7, showing asymmetric transcriptional regulation of the two genes from their shared intergenic region.\",\n      \"method\": \"Luciferase reporter assay in A549 cells; adenoviral overexpression of E2F1; RT-PCR expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay with multiple transcription factors and mRNA validation, single lab\",\n      \"pmids\": [\"18213392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"INTS7 physically interacts with ABCD3 (but not HDLBP) in mouse bone marrow mesenchymal stem cells; suppression of the INTS7–ABCD3 interaction impairs BM-MSC proliferation, induces apoptosis, decreases osteoblastic differentiation, and accelerates adipogenic differentiation, with the mechanism involving increased ROS and γ-H2AX and decreased antioxidant levels.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown of INTS7, ABCD3, and HDLBP; CCK-8 proliferation assay; Alizarin Red S and Oil Red O staining; ROS and γ-H2AX quantification\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with functional knockdown and multiple orthogonal differentiation assays, single lab\",\n      \"pmids\": [\"34880777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BAG3 directly interacts with INTS7 in BM-MSCs; BAG3 knockdown decreases INTS7 protein levels and promotes INTS7 ubiquitination, indicating BAG3 stabilizes INTS7 by preventing its proteasomal degradation. Restoration of INTS7 expression rescues the proliferation deficit caused by BAG3 knockdown, placing INTS7 downstream of BAG3 in a pathway that controls BM-MSC expansion via oxidative stress suppression.\",\n      \"method\": \"Co-immunoprecipitation; protein half-life assay; ubiquitination western blot; siRNA knockdown; CCK-8 and colony formation assays; INTS7 overexpression rescue experiment\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-IP, ubiquitination assay, and epistasis rescue experiment, 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 retrovirus loci, and activates the p53–Dux transcriptional axis to drive MERVL expression; this is accompanied by caspase-3 cleavage and anastasis, linking Ints7 to DNA damage response and stem cell fate decisions.\",\n      \"method\": \"Genome-wide knockout screen; Ints7 depletion; chromatin accessibility assay (ATAC-seq implied); Kap1 phosphorylation western blot; p53 and Dux pathway analysis; caspase-3 cleavage assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen plus mechanistic follow-up with multiple molecular readouts, single lab, single study\",\n      \"pmids\": [\"40842237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic silencing of INTS7 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/shRNA loss-of-function; CCK-8 proliferation assay; flow cytometry cell cycle analysis\",\n      \"journal\": \"Briefings in functional genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single study, standard knockdown with proliferation/cell cycle readout but no pathway-level mechanistic resolution\",\n      \"pmids\": [\"40875878\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTS7 is a nuclear backbone subunit of the Integrator complex that associates with RNA Polymerase II and participates in snRNA processing; it is stabilized by BAG3 (which prevents its ubiquitination), physically interacts with ABCD3 to suppress oxidative stress and support mesenchymal stem cell proliferation and osteoblastic differentiation, and in embryonic stem cells its loss triggers DNA damage, Kap1 phosphorylation, chromatin remodeling at endogenous retrovirus loci, and p53–Dux-driven MERVL transcription, while in Drosophila its ortholog (deflated) is essential for nuclear-localized functions supporting normal cell signaling and proliferation during development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INTS7 is a nuclear backbone subunit of the Integrator complex with conserved roles in cell proliferation and signaling during development, established by its Drosophila ortholog deflated whose loss produces pleiotropic developmental defects consistent with perturbed cell signaling and proliferation [#0]. In mammalian cells, INTS7 supports proliferation by suppressing oxidative stress: it physically interacts with ABCD3 in bone marrow mesenchymal stem cells, and disruption of this interaction raises ROS and \\u03b3-H2AX, induces apoptosis, and shifts the balance from osteoblastic toward adipogenic differentiation [#2]. INTS7 stability is governed by BAG3, which binds INTS7 and prevents its proteasomal ubiquitination; restoring INTS7 rescues the proliferation deficit caused by BAG3 loss, placing INTS7 downstream of BAG3 in a pathway controlling stem cell expansion through oxidative stress control [#3]. INTS7 also operates at the chromatin/genome-stability interface: its loss in embryonic stem cells elevates DNA damage, drives Kap1 phosphorylation, increases chromatin accessibility at MERVL retrovirus loci, and activates a p53\\u2013Dux transcriptional axis to induce MERVL expression alongside caspase-3 cleavage and anastasis [#4]. At the transcriptional level, INTS7 is regulated from a bidirectional intergenic promoter shared with CDT2, where B-Myb, c-Myb, and p53 down-regulate INTS7 expression [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established how INTS7 itself is transcriptionally controlled, revealing asymmetric regulation from a promoter region shared with a neighboring gene.\",\n      \"evidence\": \"Luciferase reporter assays with multiple transcription factors and RT-PCR validation in A549 cells\",\n      \"pmids\": [\"18213392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address INTS7 protein function\", \"Regulation shown on reporters, not at the endogenous locus across cell types\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined a conserved in vivo requirement for the INTS7 ortholog in development, localizing it to the nucleus and linking it to cell signaling and proliferation.\",\n      \"evidence\": \"GFP localization and loss-of-function phenotypic analysis of four mutant alleles in Drosophila\",\n      \"pmids\": [\"19326441\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of the developmental defect not resolved\", \"Integrator-complex biochemical role not directly tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a direct physical partner (ABCD3) and connected INTS7 to oxidative stress suppression governing stem cell proliferation and differentiation fate.\",\n      \"evidence\": \"Reciprocal co-IP, siRNA knockdown, proliferation, differentiation staining, and ROS/\\u03b3-H2AX assays in mouse BM-MSCs\",\n      \"pmids\": [\"34880777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the INTS7\\u2013ABCD3 interaction controls ROS unknown\", \"Relationship to canonical Integrator function not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed INTS7 in a regulatory hierarchy by showing BAG3 stabilizes it against ubiquitin-mediated degradation, with epistasis confirming INTS7 is the functional effector downstream of BAG3.\",\n      \"evidence\": \"Co-IP, protein half-life and ubiquitination assays, plus INTS7 overexpression rescue in BM-MSCs\",\n      \"pmids\": [\"37576499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the ubiquitin ligase acting on INTS7 unknown\", \"Whether BAG3 acts as a direct chaperone or via co-chaperones unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected INTS7 to genome stability and stem cell fate, showing its loss triggers DNA damage and a chromatin/p53\\u2013Dux program driving endogenous retrovirus transcription.\",\n      \"evidence\": \"Genome-wide knockout screen with chromatin accessibility, Kap1 phosphorylation, p53\\u2013Dux pathway and caspase-3 readouts in mouse ESCs\",\n      \"pmids\": [\"40842237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DNA damage is a direct consequence of lost Integrator activity not dissected\", \"Mechanism of chromatin opening at MERVL loci unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the proliferative role of INTS7 to a disease context, showing it promotes cell cycle progression in lung adenocarcinoma.\",\n      \"evidence\": \"siRNA/shRNA knockdown with proliferation and flow cytometry cell cycle analysis in LUAD lines\",\n      \"pmids\": [\"40875878\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No pathway-level mechanism resolved\", \"Single study, standard knockdown without orthogonal validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How INTS7's role as an Integrator backbone subunit in snRNA processing/RNA Pol II regulation mechanistically connects to its observed roles in oxidative stress, genome stability, and proliferation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical link between Integrator catalytic function and the ROS/DNA-damage phenotypes\", \"Substrate-level role within the Integrator complex not characterized in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [\"Integrator complex\"],\n    \"partners\": [\"ABCD3\", \"BAG3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}