{"gene":"INTS10","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2020,"finding":"INTS10, INTS13 (Asunder), and INTS14 form a separable, functional module of the Integrator complex. The INTS13-INTS14 sub-complex adopts a strongly entwined structure with a unique chain interlink and structural homology to the Ku70-Ku80 DNA repair complex. The INTS10-INTS13-INTS14 module displays affinity for DNA and RNA, preferring RNA hairpins. INTS13 directly binds Integrator's cleavage module via a conserved C-terminal motif, suggesting the module bridges cleavage module and target transcripts. The module plays an accessory role in snRNA maturation but has a stronger influence on transcription termination after pausing.","method":"Biochemical reconstitution, X-ray crystallography, mass spectrometry cross-linking, RNA/DNA binding assays, functional snRNA processing and transcription termination assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure resolved, reconstituted module biochemically, multiple orthogonal methods (structure, binding assays, functional assays) in a single rigorous study","pmids":["32647223"],"is_preprint":false},{"year":2021,"finding":"The INTS10/13/14 sub-complex is one of the biochemically characterized modules of the Integrator complex, distinct from the catalytic core INTS4/9/11 ternary complex. Cryo-EM structure of the catalytic core reveals how INTS11 nuclease is stabilized by INTS9 and INTS4, forming a composite electropositive groove for putative RNA binding.","method":"Biochemical fractionation, cryo-EM (3.5 Å resolution structure of INTS4/9/11)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure at 3.5 Å with biochemical validation; INTS10/13/14 module identity established by biochemical characterization","pmids":["33548203"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of complete Integrator-PP2A complex reveal that INTS10-INTS13-INTS14-INTS15 form a scorpion-tail-shaped module. In the pre-termination complex, this module's 'sting' may open the DSIF DNA clamp to facilitate Pol II termination. This provides structural evidence for the module's role in the termination mechanism.","method":"Cryo-EM (multiple functional state structures of Integrator-PP2A complex)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple cryo-EM structures in different functional states, revealing structural basis for INTS10-containing module in termination","pmids":["38570683"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of human Integrator sub-complexes INTS10/13/14/15 and INTS5/8/10/15 were determined. INTS13 within the fully assembled Integrator was identified as a direct binding platform for transcription factor ZNF655, which modulates Integrator stability at specific genomic loci and regulates transcription attenuation.","method":"Cryo-EM structure determination, in silico protein-protein interaction screen of >1,500 TFs, biochemical validation of ZNF655-INTS13 interaction","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures of two sub-complexes plus biochemical interaction validation of ZNF655 binding via INTS13","pmids":["38823386"],"is_preprint":false},{"year":2016,"finding":"INTS10 suppresses HBV replication via IRF3 in liver cells. Clinical plasma INTS10 levels are significantly decreased in persistent HBV-infected individuals compared to spontaneously recovered subjects and negatively correlate with HBV load.","method":"Cell-based HBV replication assays in liver cells, expression quantitative trait locus analysis, clinical plasma sample measurements","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assay with IRF3 pathway placement, supported by eQTL and clinical correlation, single lab","pmids":["27244555"],"is_preprint":false},{"year":2024,"finding":"Depletion of Integrator's INTS10 subunit disrupts neural cell identity, causing cells to shift towards mesenchymal identity. INTS10 is part of an enhancer module of Integrator that stabilizes SOX2 binding at chromatin upon exit from pluripotency, promoting epigenetic changes and transcription factor binding at neural enhancers.","method":"INTS10 knockdown/depletion, chromatin immunoprecipitation, cell fate assays (neural vs. mesenchymal identity markers), SOX2 chromatin binding assays","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype (cell fate switch) with molecular mechanism (SOX2 stabilization at enhancers), single lab","pmids":["39592860"],"is_preprint":false},{"year":2023,"finding":"RNU4ATAC mutations in patient-derived cells cause splicing defects of INTS7 and INTS10 minor introns, leading to reduced levels of INTS7 and INTS10 proteins, and subsequent alterations in the assembly of Integrator subunits, demonstrating that INTS10 protein homeostasis depends on proper minor spliceosome function.","method":"Analysis of lymphoblastoid cells from RNU4ATAC compound heterozygous patients; RT-PCR splicing assays, western blot protein quantification, Integrator assembly analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cell analysis with splicing and protein-level readouts; single study with two orthogonal methods","pmids":["36537210"],"is_preprint":false},{"year":2026,"finding":"INTS10 is a substrate of Coxsackievirus B3 (CVB3) 3C protease (3Cpro), which cleaves INTS10 at residue Q221. This cleavage disrupts U snRNA (U1 and U2) processing. Knockdown of INTS10 enhances CVB3 replication; overexpression of U1 snRNA inhibits CVB3 infection while knockdown promotes it, indicating that 3Cpro-mediated INTS10 cleavage subverts host defenses by impairing snRNA biogenesis.","method":"Protease cleavage assay with CVB3 3Cpro, site-directed mutagenesis identifying Q221 cleavage site, INTS10 knockdown/overexpression with viral replication readout, U1/U2 snRNA overexpression/knockdown assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro protease assay with mutagenesis identifying cleavage site, plus functional knockdown assays; single lab","pmids":["41596640"],"is_preprint":false},{"year":2026,"finding":"ZBTB26 interacts with the Integrator auxiliary module via INTS10 and INTS13, binds specific DNA motifs, and co-occupies select promoters and enhancers with Integrator. ZBTB26 is required for recruitment of Integrator to target loci, and the ZBTB26-Integrator axis sustains active transcriptional states at specific promoters and enhancers, extending Integrator's function to transcriptional activation.","method":"Co-immunoprecipitation, ChIP-seq, ZBTB26 knockdown with transcriptional readouts, genome-wide occupancy analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction data combined with ChIP-seq and loss-of-function transcriptional assays; single lab","pmids":["42219880"],"is_preprint":false}],"current_model":"INTS10 is a core subunit of the metazoan Integrator complex that forms a distinct INTS10-INTS13-INTS14(-INTS15) auxiliary/arm module with nucleic acid-binding activity (preferring RNA hairpins); this module, whose structure has been resolved by cryo-EM, uses INTS13 as a platform to recruit transcription factors (e.g., ZNF655, SOX2) and connect target transcripts to Integrator's catalytic core, thereby facilitating Pol II promoter-proximal termination, snRNA 3′-end processing, and enhancer-driven cell fate decisions, while also functioning as an antiviral factor that suppresses HBV replication via IRF3 and is targeted for cleavage by enteroviral 3C protease to subvert host snRNA biogenesis."},"narrative":{"mechanistic_narrative":"INTS10 is a core subunit of the metazoan Integrator complex that, together with INTS13 and INTS14 (and INTS15), forms a separable, structurally defined auxiliary module distinct from the catalytic INTS4/9/11 core [PMID:32647223, PMID:33548203]. The INTS10-INTS13-INTS14 module binds DNA and RNA with a preference for RNA hairpins and connects to Integrator's cleavage module through a conserved C-terminal motif in INTS13, positioning it to bridge target transcripts to the catalytic core; functionally this module plays an accessory role in snRNA maturation but exerts a stronger influence on transcription termination after Pol II pausing [PMID:32647223]. Cryo-EM of the complete Integrator-PP2A assembly shows INTS10-INTS13-INTS14-INTS15 forming a scorpion-tail-shaped module whose 'sting' can open the DSIF DNA clamp in the pre-termination complex, providing a structural basis for its role in promoter-proximal termination [PMID:38570683]. Within this module INTS13 acts as a recruitment platform for sequence-specific transcription factors including ZNF655 and ZBTB26, which target Integrator to specific promoters and enhancers and modulate transcriptional attenuation and activation [PMID:38823386, PMID:42219880]. Beyond transcription regulation, INTS10 governs cell-fate decisions, stabilizing SOX2 binding at neural enhancers upon exit from pluripotency such that its depletion shifts cells toward mesenchymal identity [PMID:39592860], and it acts as an antiviral factor: it suppresses HBV replication via IRF3 [PMID:27244555] and its 3'-end snRNA-processing function is subverted by enteroviral 3C protease, which cleaves INTS10 at Q221 to impair U1/U2 snRNA biogenesis [PMID:41596640].","teleology":[{"year":2020,"claim":"Established that INTS10 is not merely a peripheral Integrator subunit but the anchor of a distinct, biochemically separable module with intrinsic nucleic-acid-binding activity that physically bridges the catalytic cleavage module to target transcripts.","evidence":"Biochemical reconstitution, X-ray crystallography of INTS13-INTS14, cross-linking MS, and RNA/DNA binding plus functional snRNA and termination assays","pmids":["32647223"],"confidence":"High","gaps":["Did not resolve full-length INTS10 structure within assembled Integrator","Mechanism by which RNA-hairpin preference selects substrates not defined"]},{"year":2021,"claim":"Defined the INTS10/13/14 module as architecturally separate from the catalytic INTS4/9/11 ternary core, clarifying division of labor within Integrator.","evidence":"Biochemical fractionation and 3.5 Å cryo-EM of the INTS4/9/11 catalytic core","pmids":["33548203"],"confidence":"High","gaps":["Structure of the INTS10-containing module itself not resolved here","Physical coupling geometry between module and catalytic core unresolved"]},{"year":2024,"claim":"Placed INTS10 within the complete Integrator-PP2A holoenzyme and provided a mechanical model for how the module drives Pol II termination by opening the DSIF clamp.","evidence":"Cryo-EM structures of the Integrator-PP2A complex in multiple functional states","pmids":["38570683"],"confidence":"High","gaps":["Direct demonstration that the 'sting' opens DSIF in cells not shown","Dynamics of the conformational transition not captured"]},{"year":2024,"claim":"Showed INTS10 (via INTS13) serves as a transcription-factor docking platform, explaining how Integrator is targeted to specific genomic loci for attenuation.","evidence":"Cryo-EM of INTS10/13/14/15 and INTS5/8/10/15 sub-complexes plus in silico TF screen and biochemical validation of ZNF655-INTS13 binding","pmids":["38823386"],"confidence":"High","gaps":["Generality of TF recruitment beyond ZNF655 not established here","Direct contribution of INTS10 versus INTS13 to TF binding not separated"]},{"year":2016,"claim":"First functional role for INTS10 outside transcription machinery: an antiviral factor restricting HBV through the IRF3 pathway, with clinical correlation to viral persistence.","evidence":"Cell-based HBV replication assays, eQTL analysis, and clinical plasma INTS10 measurements","pmids":["27244555"],"confidence":"Medium","gaps":["Molecular link between INTS10 and IRF3 not mechanistically resolved","Single lab; whether antiviral activity requires Integrator assembly unknown"]},{"year":2023,"claim":"Demonstrated that INTS10 protein abundance depends on minor-spliceosome processing of its own minor intron, linking RNU4ATAC dysfunction to Integrator assembly defects.","evidence":"RT-PCR splicing and western blot in RNU4ATAC compound-heterozygous patient lymphoblastoid cells","pmids":["36537210"],"confidence":"Medium","gaps":["Direct causal contribution of INTS10 loss to patient phenotype not isolated","Single patient-cell study"]},{"year":2024,"claim":"Connected INTS10 to cell-fate determination, showing it stabilizes SOX2 at neural enhancers to enforce neural over mesenchymal identity during exit from pluripotency.","evidence":"INTS10 depletion, ChIP and SOX2 chromatin-binding assays, and cell-fate marker analysis","pmids":["39592860"],"confidence":"Medium","gaps":["Mechanism of SOX2 stabilization by the module not defined","Single lab"]},{"year":2026,"claim":"Identified INTS10 as a direct target of viral subversion, with CVB3 3C protease cleaving it at Q221 to disable host U snRNA biogenesis and promote viral replication.","evidence":"3Cpro cleavage assay with Q221 mutagenesis, INTS10 knockdown/overexpression with viral readouts, and U1/U2 snRNA manipulation","pmids":["41596640"],"confidence":"Medium","gaps":["Whether cleavage disrupts module assembly versus catalytic coupling not resolved","Single lab"]},{"year":2026,"claim":"Extended INTS10's regulatory repertoire to transcriptional activation by showing ZBTB26 recruits Integrator via INTS10/INTS13 to sustain active states at promoters and enhancers.","evidence":"Co-IP, ChIP-seq, and ZBTB26 knockdown with transcriptional and occupancy readouts","pmids":["42219880"],"confidence":"Medium","gaps":["Relative contribution of INTS10 versus INTS13 to ZBTB26 binding not separated","Single lab"]},{"year":null,"claim":"How the INTS10 module's nucleic-acid preferences and TF-docking activity are integrated to choose between termination, snRNA processing, and enhancer activation at individual loci remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking RNA-hairpin recognition to locus selection","Determinants partitioning attenuation versus activation outcomes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,3,8]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,7]}],"complexes":["Integrator complex","INTS10-INTS13-INTS14(-INTS15) auxiliary module"],"partners":["INTS13","INTS14","INTS15","ZNF655","ZBTB26","SOX2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NVR2","full_name":"Integrator complex subunit 10","aliases":[],"length_aa":710,"mass_kda":82.2,"function":"Component of the integrator complex, a multiprotein complex that terminates RNA polymerase II (Pol II) transcription in the promoter-proximal region of genes (PubMed:38570683, PubMed:38823386). The integrator complex provides a quality checkpoint during transcription elongation by driving premature transcription termination of transcripts that are unfavorably configured for transcriptional elongation: the complex terminates transcription by (1) catalyzing dephosphorylation of the C-terminal domain (CTD) of Pol II subunit POLR2A/RPB1 and SUPT5H/SPT5, (2) degrading the exiting nascent RNA transcript via endonuclease activity and (3) promoting the release of Pol II from bound DNA (PubMed:38570683). The integrator complex is also involved in terminating the synthesis of non-coding Pol II transcripts, such as enhancer RNAs (eRNAs), small nuclear RNAs (snRNAs), telomerase RNAs and long non-coding RNAs (lncRNAs) (PubMed:16239144, PubMed:32647223). Within the integrator complex, INTS10 is part of the integrator tail module that acts as a platform for the recruitment of transcription factors at promoters (PubMed:38823386). May be not involved in the recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the integrator complex (PubMed:23904267)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NVR2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INTS10","classification":"Not Classified","n_dependent_lines":503,"n_total_lines":1208,"dependency_fraction":0.4163907284768212},"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/INTS10","total_profiled":1310},"omim":[{"mim_id":"621239","title":"INTEGRATOR COMPLEX SUBUNIT 15; INTS15","url":"https://www.omim.org/entry/621239"},{"mim_id":"620878","title":"INTEGRATOR COMPLEX SUBUNIT 14; INTS14","url":"https://www.omim.org/entry/620878"},{"mim_id":"615079","title":"INTEGRATOR COMPLEX SUBUNIT 13; INTS13","url":"https://www.omim.org/entry/615079"},{"mim_id":"611353","title":"INTEGRATOR COMPLEX SUBUNIT 10; INTS10","url":"https://www.omim.org/entry/611353"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INTS10"},"hgnc":{"alias_symbol":["FLJ10569","INT10"],"prev_symbol":["C8orf35"]},"alphafold":{"accession":"Q9NVR2","domains":[{"cath_id":"-","chopping":"612-710","consensus_level":"medium","plddt":83.6762,"start":612,"end":710}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVR2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVR2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVR2-F1-predicted_aligned_error_v6.png","plddt_mean":82.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INTS10","jax_strain_url":"https://www.jax.org/strain/search?query=INTS10"},"sequence":{"accession":"Q9NVR2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NVR2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NVR2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVR2"}},"corpus_meta":[{"pmid":"22076464","id":"PMC_22076464","title":"Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia.","date":"2011","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/22076464","citation_count":94,"is_preprint":false},{"pmid":"25555482","id":"PMC_25555482","title":"Genome-wide association study of nicotine dependence in American populations: identification of novel risk loci in both African-Americans and European-Americans.","date":"2014","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/25555482","citation_count":72,"is_preprint":false},{"pmid":"27244555","id":"PMC_27244555","title":"Genome-wide association study identifies 8p21.3 associated with persistent hepatitis B virus infection among Chinese.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27244555","citation_count":60,"is_preprint":false},{"pmid":"33548203","id":"PMC_33548203","title":"Structure of the catalytic core of the Integrator complex.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/33548203","citation_count":55,"is_preprint":false},{"pmid":"38570683","id":"PMC_38570683","title":"Structural basis of Integrator-dependent RNA polymerase II termination.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/38570683","citation_count":53,"is_preprint":false},{"pmid":"32647223","id":"PMC_32647223","title":"INTS10-INTS13-INTS14 form a functional module of Integrator that binds nucleic acids and the cleavage module.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32647223","citation_count":52,"is_preprint":false},{"pmid":"39719507","id":"PMC_39719507","title":"In vivo hyperphosphorylation of tau is associated with synaptic loss and behavioral abnormalities in the absence of tau seeds.","date":"2024","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39719507","citation_count":35,"is_preprint":false},{"pmid":"38823386","id":"PMC_38823386","title":"Structural basis of the Integrator complex assembly and association with transcription factors.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/38823386","citation_count":27,"is_preprint":false},{"pmid":"28027311","id":"PMC_28027311","title":"Somatic Mutation Patterns in Hemizygous Genomic Regions Unveil Purifying Selection during Tumor Evolution.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28027311","citation_count":22,"is_preprint":false},{"pmid":"16507104","id":"PMC_16507104","title":"A detailed Hapmap of the Sitosterolemia locus spanning 69 kb; differences between Caucasians and African-Americans.","date":"2006","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16507104","citation_count":19,"is_preprint":false},{"pmid":"32902719","id":"PMC_32902719","title":"Genome-wide landscape establishes novel association signals for metabolic traits in the Arab population.","date":"2020","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32902719","citation_count":19,"is_preprint":false},{"pmid":"34417287","id":"PMC_34417287","title":"Dupilumab for STAT3-Hyper-IgE Syndrome With Refractory Intestinal Complication.","date":"2021","source":"Pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/34417287","citation_count":11,"is_preprint":false},{"pmid":"24202059","id":"PMC_24202059","title":"Targeted exome capture and sequencing identifies novel PRPF31 mutations in autosomal dominant retinitis pigmentosa in Chinese families.","date":"2013","source":"BMJ open","url":"https://pubmed.ncbi.nlm.nih.gov/24202059","citation_count":11,"is_preprint":false},{"pmid":"36537210","id":"PMC_36537210","title":"Mutations in the non-coding RNU4ATAC gene affect the homeostasis and function of the Integrator complex.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36537210","citation_count":9,"is_preprint":false},{"pmid":"39592860","id":"PMC_39592860","title":"The enhancer module of Integrator controls cell identity and early neural fate commitment.","date":"2024","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39592860","citation_count":7,"is_preprint":false},{"pmid":"34133796","id":"PMC_34133796","title":"Effects of genetic polymorphisms in INTS10 and their interaction with environmental factors on progression from persistent HBV infection to hepatocellular carcinoma.","date":"2021","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/34133796","citation_count":5,"is_preprint":false},{"pmid":"28978030","id":"PMC_28978030","title":"Genetic profile and biological implication of PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) in human cancers: an analysis using The Cancer Genome Atlas.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28978030","citation_count":5,"is_preprint":false},{"pmid":"37064118","id":"PMC_37064118","title":"Case report: Complete pathological admission in N3 unresectable locally advanced lung adenocarcinoma with a novel INTS10-ALK and EML4-ALK fusion after neoadjuvant crizotinib.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37064118","citation_count":1,"is_preprint":false},{"pmid":"41383743","id":"PMC_41383743","title":"Expression and significance of INTS10 and IRF3 in chronic hepatitis B patients.","date":"2025","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41383743","citation_count":0,"is_preprint":false},{"pmid":"41596640","id":"PMC_41596640","title":"Coxsackievirus B3 Cleaves INTS10 Through 3C Protease to Facilitate Its Replication.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41596640","citation_count":0,"is_preprint":false},{"pmid":"42219880","id":"PMC_42219880","title":"A ZBTB26-Integrator Axis Mediates Targeted Transcriptional Activation.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/42219880","citation_count":0,"is_preprint":false},{"pmid":"41373569","id":"PMC_41373569","title":"Genome-Wide Association Studies of Growth and Carcass Traits in Charolais Cattle Based on High-Coverage Whole-Genome Resequencing.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41373569","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.15.623736","title":"Single  <i>MAPT</i>  knock-in mouse models of frontotemporal dementia for sharing with the neurodegenerative research community","date":"2024-11-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.15.623736","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13051,"output_tokens":2531,"usd":0.038559,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9619,"output_tokens":3181,"usd":0.06381,"stage2_stop_reason":"end_turn"},"total_usd":0.102369,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"INTS10, INTS13 (Asunder), and INTS14 form a separable, functional module of the Integrator complex. The INTS13-INTS14 sub-complex adopts a strongly entwined structure with a unique chain interlink and structural homology to the Ku70-Ku80 DNA repair complex. The INTS10-INTS13-INTS14 module displays affinity for DNA and RNA, preferring RNA hairpins. INTS13 directly binds Integrator's cleavage module via a conserved C-terminal motif, suggesting the module bridges cleavage module and target transcripts. The module plays an accessory role in snRNA maturation but has a stronger influence on transcription termination after pausing.\",\n      \"method\": \"Biochemical reconstitution, X-ray crystallography, mass spectrometry cross-linking, RNA/DNA binding assays, functional snRNA processing and transcription termination assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure resolved, reconstituted module biochemically, multiple orthogonal methods (structure, binding assays, functional assays) in a single rigorous study\",\n      \"pmids\": [\"32647223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The INTS10/13/14 sub-complex is one of the biochemically characterized modules of the Integrator complex, distinct from the catalytic core INTS4/9/11 ternary complex. Cryo-EM structure of the catalytic core reveals how INTS11 nuclease is stabilized by INTS9 and INTS4, forming a composite electropositive groove for putative RNA binding.\",\n      \"method\": \"Biochemical fractionation, cryo-EM (3.5 Å resolution structure of INTS4/9/11)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure at 3.5 Å with biochemical validation; INTS10/13/14 module identity established by biochemical characterization\",\n      \"pmids\": [\"33548203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of complete Integrator-PP2A complex reveal that INTS10-INTS13-INTS14-INTS15 form a scorpion-tail-shaped module. In the pre-termination complex, this module's 'sting' may open the DSIF DNA clamp to facilitate Pol II termination. This provides structural evidence for the module's role in the termination mechanism.\",\n      \"method\": \"Cryo-EM (multiple functional state structures of Integrator-PP2A complex)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple cryo-EM structures in different functional states, revealing structural basis for INTS10-containing module in termination\",\n      \"pmids\": [\"38570683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of human Integrator sub-complexes INTS10/13/14/15 and INTS5/8/10/15 were determined. INTS13 within the fully assembled Integrator was identified as a direct binding platform for transcription factor ZNF655, which modulates Integrator stability at specific genomic loci and regulates transcription attenuation.\",\n      \"method\": \"Cryo-EM structure determination, in silico protein-protein interaction screen of >1,500 TFs, biochemical validation of ZNF655-INTS13 interaction\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures of two sub-complexes plus biochemical interaction validation of ZNF655 binding via INTS13\",\n      \"pmids\": [\"38823386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"INTS10 suppresses HBV replication via IRF3 in liver cells. Clinical plasma INTS10 levels are significantly decreased in persistent HBV-infected individuals compared to spontaneously recovered subjects and negatively correlate with HBV load.\",\n      \"method\": \"Cell-based HBV replication assays in liver cells, expression quantitative trait locus analysis, clinical plasma sample measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assay with IRF3 pathway placement, supported by eQTL and clinical correlation, single lab\",\n      \"pmids\": [\"27244555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Depletion of Integrator's INTS10 subunit disrupts neural cell identity, causing cells to shift towards mesenchymal identity. INTS10 is part of an enhancer module of Integrator that stabilizes SOX2 binding at chromatin upon exit from pluripotency, promoting epigenetic changes and transcription factor binding at neural enhancers.\",\n      \"method\": \"INTS10 knockdown/depletion, chromatin immunoprecipitation, cell fate assays (neural vs. mesenchymal identity markers), SOX2 chromatin binding assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype (cell fate switch) with molecular mechanism (SOX2 stabilization at enhancers), single lab\",\n      \"pmids\": [\"39592860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNU4ATAC mutations in patient-derived cells cause splicing defects of INTS7 and INTS10 minor introns, leading to reduced levels of INTS7 and INTS10 proteins, and subsequent alterations in the assembly of Integrator subunits, demonstrating that INTS10 protein homeostasis depends on proper minor spliceosome function.\",\n      \"method\": \"Analysis of lymphoblastoid cells from RNU4ATAC compound heterozygous patients; RT-PCR splicing assays, western blot protein quantification, Integrator assembly analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cell analysis with splicing and protein-level readouts; single study with two orthogonal methods\",\n      \"pmids\": [\"36537210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"INTS10 is a substrate of Coxsackievirus B3 (CVB3) 3C protease (3Cpro), which cleaves INTS10 at residue Q221. This cleavage disrupts U snRNA (U1 and U2) processing. Knockdown of INTS10 enhances CVB3 replication; overexpression of U1 snRNA inhibits CVB3 infection while knockdown promotes it, indicating that 3Cpro-mediated INTS10 cleavage subverts host defenses by impairing snRNA biogenesis.\",\n      \"method\": \"Protease cleavage assay with CVB3 3Cpro, site-directed mutagenesis identifying Q221 cleavage site, INTS10 knockdown/overexpression with viral replication readout, U1/U2 snRNA overexpression/knockdown assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro protease assay with mutagenesis identifying cleavage site, plus functional knockdown assays; single lab\",\n      \"pmids\": [\"41596640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZBTB26 interacts with the Integrator auxiliary module via INTS10 and INTS13, binds specific DNA motifs, and co-occupies select promoters and enhancers with Integrator. ZBTB26 is required for recruitment of Integrator to target loci, and the ZBTB26-Integrator axis sustains active transcriptional states at specific promoters and enhancers, extending Integrator's function to transcriptional activation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, ZBTB26 knockdown with transcriptional readouts, genome-wide occupancy analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction data combined with ChIP-seq and loss-of-function transcriptional assays; single lab\",\n      \"pmids\": [\"42219880\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTS10 is a core subunit of the metazoan Integrator complex that forms a distinct INTS10-INTS13-INTS14(-INTS15) auxiliary/arm module with nucleic acid-binding activity (preferring RNA hairpins); this module, whose structure has been resolved by cryo-EM, uses INTS13 as a platform to recruit transcription factors (e.g., ZNF655, SOX2) and connect target transcripts to Integrator's catalytic core, thereby facilitating Pol II promoter-proximal termination, snRNA 3′-end processing, and enhancer-driven cell fate decisions, while also functioning as an antiviral factor that suppresses HBV replication via IRF3 and is targeted for cleavage by enteroviral 3C protease to subvert host snRNA biogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INTS10 is a core subunit of the metazoan Integrator complex that, together with INTS13 and INTS14 (and INTS15), forms a separable, structurally defined auxiliary module distinct from the catalytic INTS4/9/11 core [#0, #1]. The INTS10-INTS13-INTS14 module binds DNA and RNA with a preference for RNA hairpins and connects to Integrator's cleavage module through a conserved C-terminal motif in INTS13, positioning it to bridge target transcripts to the catalytic core; functionally this module plays an accessory role in snRNA maturation but exerts a stronger influence on transcription termination after Pol II pausing [#0]. Cryo-EM of the complete Integrator-PP2A assembly shows INTS10-INTS13-INTS14-INTS15 forming a scorpion-tail-shaped module whose 'sting' can open the DSIF DNA clamp in the pre-termination complex, providing a structural basis for its role in promoter-proximal termination [#2]. Within this module INTS13 acts as a recruitment platform for sequence-specific transcription factors including ZNF655 and ZBTB26, which target Integrator to specific promoters and enhancers and modulate transcriptional attenuation and activation [#3, #8]. Beyond transcription regulation, INTS10 governs cell-fate decisions, stabilizing SOX2 binding at neural enhancers upon exit from pluripotency such that its depletion shifts cells toward mesenchymal identity [#5], and it acts as an antiviral factor: it suppresses HBV replication via IRF3 [#4] and its 3'-end snRNA-processing function is subverted by enteroviral 3C protease, which cleaves INTS10 at Q221 to impair U1/U2 snRNA biogenesis [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that INTS10 is not merely a peripheral Integrator subunit but the anchor of a distinct, biochemically separable module with intrinsic nucleic-acid-binding activity that physically bridges the catalytic cleavage module to target transcripts.\",\n      \"evidence\": \"Biochemical reconstitution, X-ray crystallography of INTS13-INTS14, cross-linking MS, and RNA/DNA binding plus functional snRNA and termination assays\",\n      \"pmids\": [\"32647223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve full-length INTS10 structure within assembled Integrator\", \"Mechanism by which RNA-hairpin preference selects substrates not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the INTS10/13/14 module as architecturally separate from the catalytic INTS4/9/11 ternary core, clarifying division of labor within Integrator.\",\n      \"evidence\": \"Biochemical fractionation and 3.5 Å cryo-EM of the INTS4/9/11 catalytic core\",\n      \"pmids\": [\"33548203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the INTS10-containing module itself not resolved here\", \"Physical coupling geometry between module and catalytic core unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed INTS10 within the complete Integrator-PP2A holoenzyme and provided a mechanical model for how the module drives Pol II termination by opening the DSIF clamp.\",\n      \"evidence\": \"Cryo-EM structures of the Integrator-PP2A complex in multiple functional states\",\n      \"pmids\": [\"38570683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration that the 'sting' opens DSIF in cells not shown\", \"Dynamics of the conformational transition not captured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed INTS10 (via INTS13) serves as a transcription-factor docking platform, explaining how Integrator is targeted to specific genomic loci for attenuation.\",\n      \"evidence\": \"Cryo-EM of INTS10/13/14/15 and INTS5/8/10/15 sub-complexes plus in silico TF screen and biochemical validation of ZNF655-INTS13 binding\",\n      \"pmids\": [\"38823386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of TF recruitment beyond ZNF655 not established here\", \"Direct contribution of INTS10 versus INTS13 to TF binding not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"First functional role for INTS10 outside transcription machinery: an antiviral factor restricting HBV through the IRF3 pathway, with clinical correlation to viral persistence.\",\n      \"evidence\": \"Cell-based HBV replication assays, eQTL analysis, and clinical plasma INTS10 measurements\",\n      \"pmids\": [\"27244555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between INTS10 and IRF3 not mechanistically resolved\", \"Single lab; whether antiviral activity requires Integrator assembly unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that INTS10 protein abundance depends on minor-spliceosome processing of its own minor intron, linking RNU4ATAC dysfunction to Integrator assembly defects.\",\n      \"evidence\": \"RT-PCR splicing and western blot in RNU4ATAC compound-heterozygous patient lymphoblastoid cells\",\n      \"pmids\": [\"36537210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct causal contribution of INTS10 loss to patient phenotype not isolated\", \"Single patient-cell study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected INTS10 to cell-fate determination, showing it stabilizes SOX2 at neural enhancers to enforce neural over mesenchymal identity during exit from pluripotency.\",\n      \"evidence\": \"INTS10 depletion, ChIP and SOX2 chromatin-binding assays, and cell-fate marker analysis\",\n      \"pmids\": [\"39592860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of SOX2 stabilization by the module not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified INTS10 as a direct target of viral subversion, with CVB3 3C protease cleaving it at Q221 to disable host U snRNA biogenesis and promote viral replication.\",\n      \"evidence\": \"3Cpro cleavage assay with Q221 mutagenesis, INTS10 knockdown/overexpression with viral readouts, and U1/U2 snRNA manipulation\",\n      \"pmids\": [\"41596640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cleavage disrupts module assembly versus catalytic coupling not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended INTS10's regulatory repertoire to transcriptional activation by showing ZBTB26 recruits Integrator via INTS10/INTS13 to sustain active states at promoters and enhancers.\",\n      \"evidence\": \"Co-IP, ChIP-seq, and ZBTB26 knockdown with transcriptional and occupancy readouts\",\n      \"pmids\": [\"42219880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of INTS10 versus INTS13 to ZBTB26 binding not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the INTS10 module's nucleic-acid preferences and TF-docking activity are integrated to choose between termination, snRNA processing, and enhancer activation at individual loci remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking RNA-hairpin recognition to locus selection\", \"Determinants partitioning attenuation versus activation outcomes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 3, 8]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [\n      \"Integrator complex\",\n      \"INTS10-INTS13-INTS14(-INTS15) auxiliary module\"\n    ],\n    \"partners\": [\n      \"INTS13\",\n      \"INTS14\",\n      \"INTS15\",\n      \"ZNF655\",\n      \"ZBTB26\",\n      \"SOX2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}