{"gene":"INTS13","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2018,"finding":"INTS13 functions as an independent sub-module of the Integrator complex that targets enhancers through Early Growth Response transcription factors EGR1/2 and their co-factor NAB2, binding poised monocytic enhancers to elicit chromatin looping and activation, thereby driving monocytic/macrophagic differentiation. Independent depletion of INTS13, EGR1, or NAB2 each impairs monocytic differentiation of cell lines and primary human progenitors.","method":"ChIP-seq, chromatin conformation assays (looping), siRNA/shRNA depletion in cell lines and primary progenitors, co-immunoprecipitation with EGR1/2 and NAB2","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, chromatin looping, KD in both cell lines and primary human progenitors) in a single focused study with clear functional readout","pmids":["30008316"],"is_preprint":false},{"year":2020,"finding":"INTS10, INTS13 (Asunder), and INTS14 form a separable, functional Integrator sub-module. The crystal structure of INTS13-INTS14 reveals a strongly entwined complex with a unique chain interlink and structural homology to the Ku70-Ku80 DNA repair complex. This module displays nucleic acid-binding affinity, preferring RNA hairpins. INTS13 directly binds the Integrator cleavage module via a conserved C-terminal motif, which is required for snRNA processing and spermatogenesis. The module plays an accessory role in snRNA maturation and a stronger role in transcription termination after pausing.","method":"Structural determination (crystal structure of INTS13-INTS14), in vitro nucleic acid binding assays, pulldown/co-purification, C-terminal motif mutagenesis, functional snRNA processing and transcription termination assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with in vitro binding assays and mutagenesis, multiple orthogonal methods in single rigorous study","pmids":["32647223"],"is_preprint":false},{"year":2022,"finding":"INTS13 utilizes its C-terminus to bind the Integrator cleavage module; germline variants p.S652L and p.K668Nfs*9 disrupt this interaction. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of ciliary genes; INTS13 knockdown in Xenopus embryos causes motile cilia anomalies, establishing INTS13 as required for ciliogenesis.","method":"Homozygosity mapping and exome sequencing (patient variants), co-immunoprecipitation/pulldown of C-terminal interaction, siRNA depletion in human cells with ciliogenesis readout, Xenopus morpholino knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with mutagenesis, loss-of-function in two independent model systems (human cells and Xenopus) with specific cellular phenotypes","pmids":["36229431"],"is_preprint":false},{"year":2023,"finding":"INTS15 assembles primarily with the INTS13/14/10 module and interfaces with the Integrator-PP2A module. INTS15 modulates RNA polymerase II pausing at a subset of genes.","method":"Proteomics (mass spectrometry), AlphaFold2 structure prediction, functional genomics (ChIP-seq/PRO-seq for RNAPII pausing)","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus functional genomics in single lab; AlphaFold2 predictions are in silico but supported by experimental proteomics","pmids":["36920904"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of the complete Integrator-PP2A complex reveal that INTS10-INTS13-INTS14-INTS15 form a scorpion-tail-shaped module whose 'sting' may open the DSIF DNA clamp to facilitate RNA Pol II termination in the promoter-proximal region.","method":"Cryo-electron microscopy (three functional states: pre-termination, post-termination, and free Integrator-PP2A complex)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures at multiple functional states providing direct structural evidence for module architecture and mechanistic role in termination","pmids":["38570683"],"is_preprint":false},{"year":2024,"finding":"Structures of human Integrator sub-complexes INTS10/13/14/15 and INTS5/8/10/15 were determined. An in silico protein-protein interaction screen identified ZNF655 as a direct interacting partner of INTS13 within the fully assembled Integrator. INTS13 is proposed to act as a platform for TF recruitment that modulates Integrator stability at specific loci.","method":"Cryo-EM structure determination of sub-complexes, in silico protein-protein interaction screen (AlphaFold2-based) of >1,500 human TFs, structural modeling of fully assembled Integrator-PEC","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — cryo-EM structures are high quality, but ZNF655 interaction is from in silico screen; direct experimental validation of ZNF655 binding not described in abstract","pmids":["38823386"],"is_preprint":false},{"year":2005,"finding":"Mat89Bb (Drosophila ortholog of INTS13) was identified as a substrate of PAN GU kinase. RNAi ablation of Mat89Bb in Drosophila produces a polyploid phenotype similar to pan gu mutants; Mat89Bb morpholino knockdown in Xenopus embryos causes arrest with polyploid nuclei; RNAi in HeLa cells produces multinucleated cells, establishing an evolutionarily conserved role in cell cycle regulation.","method":"In vitro expression cloning screen (DIVEC) for PAN GU kinase substrates, RNAi in Drosophila and HeLa cells, morpholino knockdown in Xenopus embryos","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical substrate identification plus loss-of-function in three independent model systems with consistent cell cycle phenotypes","pmids":["15737938"],"is_preprint":false},{"year":2025,"finding":"ZNF384 was identified as an upstream transcription factor that directly binds the INTS13 promoter and positively regulates INTS13 expression. INTS13 in turn regulates hnRNPC expression as a downstream effector; restoration of hnRNPC reverses anti-proliferative/anti-invasive effects of INTS13 silencing in cervical cancer cells, defining a ZNF384-INTS13-hnRNPC signaling axis.","method":"ChIP assay (ZNF384 binding to INTS13 promoter), CRISPR/Cas9 knockout and siRNA silencing of INTS13, hnRNPC rescue experiments, in vivo xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with rescue experiments and in vivo validation, single lab with multiple orthogonal approaches","pmids":["41429980"],"is_preprint":false},{"year":2026,"finding":"ZBTB26 interacts with the Integrator auxiliary module via both INTS10 and INTS13, directly binds a specific DNA motif, co-occupies select promoters and enhancers with Integrator, and is required for recruitment of Integrator to target loci involved in stimulus response, development, and differentiation. The ZBTB26-Integrator axis sustains active promoter/enhancer states and drives defined transcriptional programs.","method":"Co-immunoprecipitation (ZBTB26-INTS10/INTS13 interaction), ChIP-seq (co-occupancy), ZBTB26 depletion with Integrator recruitment readout, transcriptional profiling","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ChIP-seq in single lab with functional KD readout; single study without independent replication","pmids":["42219880"],"is_preprint":false}],"current_model":"INTS13 is a subunit of the Integrator complex that forms a structural module (INTS10-INTS13-INTS14-INTS15) with nucleic acid-binding capacity, acts as a direct linker between this module and the Integrator cleavage module via its conserved C-terminal motif, participates in a scorpion-tail-shaped arm that opens the DSIF DNA clamp to facilitate RNA Pol II termination, serves as a platform for transcription factor recruitment (EGR1/2-NAB2, ZNF655, ZBTB26) to direct enhancer activation and gene-specific transcription, is required for ciliogenesis and myeloid differentiation, and was originally identified as a PAN GU kinase substrate with an evolutionarily conserved role in cell cycle regulation."},"narrative":{"mechanistic_narrative":"INTS13 is a subunit of the Integrator complex that nucleates a separable auxiliary sub-module with INTS10, INTS14, and INTS15, coupling this module to the catalytic core of the complex and to gene-specific transcriptional regulation [PMID:32647223, PMID:36920904]. Structurally, INTS13 forms a strongly entwined heterodimer with INTS14 that resembles the Ku70-Ku80 DNA-repair complex and confers nucleic acid-binding activity to the module, with a preference for RNA hairpins [PMID:32647223]. A conserved C-terminal motif of INTS13 directly tethers the sub-module to the Integrator cleavage module, an interaction required for snRNA processing and disrupted by germline variants (p.S652L, p.K668Nfs*9) [PMID:32647223, PMID:36229431]. Within the assembled Integrator-PP2A complex, the INTS10-INTS13-INTS14-INTS15 module adopts a scorpion-tail-shaped architecture whose protruding 'sting' opens the DSIF DNA clamp to promote promoter-proximal RNA Pol II termination after pausing [PMID:32647223, PMID:38570683]. Beyond its catalytic coupling role, INTS13 serves as a recruitment platform that links Integrator to sequence-specific transcription factors—including EGR1/2 with their cofactor NAB2, ZNF655, and ZBTB26—directing Integrator to specific promoters and enhancers, sustaining active chromatin states, and driving defined transcriptional programs such as monocytic/macrophagic differentiation [PMID:30008316, PMID:38823386, PMID:42219880]. INTS13 is also required for ciliogenesis in human cells and Xenopus embryos [PMID:36229431], and its Drosophila ortholog (Mat89Bb) is a PAN GU kinase substrate with a conserved role in cell cycle control [PMID:15737938].","teleology":[{"year":2005,"claim":"Before its incorporation into Integrator was known, the gene's ortholog was placed in cell-cycle control by identifying it as a kinase substrate whose loss causes polyploidy across species.","evidence":"In vitro expression cloning screen for PAN GU kinase substrates plus RNAi in Drosophila and HeLa and morpholino knockdown in Xenopus","pmids":["15737938"],"confidence":"High","gaps":["Did not connect the protein to transcription or the Integrator complex","Mechanism by which phosphorylation controls cell-cycle/ploidy not defined","No molecular target or biochemical activity assigned"]},{"year":2018,"claim":"Established that INTS13 acts as a semi-autonomous Integrator sub-module that targets enhancers via specific transcription factors to drive a defined differentiation program.","evidence":"ChIP-seq, chromatin looping assays, siRNA/shRNA depletion in cell lines and primary human progenitors, and co-IP with EGR1/2 and NAB2","pmids":["30008316"],"confidence":"High","gaps":["Structural basis of TF recruitment unresolved","Whether the catalytic core is required for the enhancer/differentiation function not dissected","Generality beyond monocytic differentiation unknown"]},{"year":2020,"claim":"Defined the molecular architecture of the sub-module and the physical link to the cleavage core, explaining how INTS13 contributes to snRNA processing and termination.","evidence":"Crystal structure of INTS13-INTS14, in vitro nucleic acid binding assays, co-purification, and C-terminal motif mutagenesis with snRNA processing and termination readouts","pmids":["32647223"],"confidence":"High","gaps":["Functional consequence of RNA-hairpin binding in cells not established","Significance of Ku-like fold for activity unclear","How the module is positioned relative to Pol II not yet visualized"]},{"year":2022,"claim":"Linked the C-terminal cleavage-module interaction to human disease and a new cellular process by showing INTS13 is required for ciliogenesis.","evidence":"Patient homozygosity mapping/exome sequencing, co-IP with C-terminal mutagenesis, siRNA depletion with ciliogenesis readout in human cells, and Xenopus knockdown","pmids":["36229431"],"confidence":"High","gaps":["Which ciliary genes are directly Integrator-regulated not defined","Whether cilia phenotype reflects transcription termination versus another role unclear","Connection between cleavage-module binding and ciliary gene control mechanistic detail absent"]},{"year":2023,"claim":"Identified INTS15 as a fourth member of the module and connected the module to RNA Pol II pausing regulation.","evidence":"Mass-spectrometry proteomics, AlphaFold2 prediction, and ChIP-seq/PRO-seq for pausing","pmids":["36920904"],"confidence":"Medium","gaps":["AlphaFold2 interface predictions await experimental structure","Direct contribution of INTS13 versus INTS15 to pausing not separated","Subset of genes affected not mechanistically explained"]},{"year":2024,"claim":"Provided direct structural mechanism: the module forms a scorpion-tail arm whose tip opens the DSIF clamp to drive promoter-proximal termination.","evidence":"Cryo-EM of the Integrator-PP2A complex in pre-termination, post-termination, and free states","pmids":["38570683"],"confidence":"High","gaps":["DSIF-clamp opening shown structurally but not validated by mutagenesis of INTS13 contacts","Trigger that engages the 'sting' at specific genes unknown"]},{"year":2024,"claim":"Expanded the recruitment-platform model by identifying a transcription factor (ZNF655) predicted to bind INTS13 within assembled Integrator and modulate locus-specific stability.","evidence":"Cryo-EM of INTS10/13/14/15 and INTS5/8/10/15 sub-complexes plus an in silico AlphaFold2 screen of >1,500 TFs and structural modeling","pmids":["38823386"],"confidence":"Medium","gaps":["ZNF655 interaction is in silico and lacks direct experimental binding validation","Functional consequence of ZNF655-INTS13 binding not tested","Generality of TF-platform model across loci unproven"]},{"year":2025,"claim":"Placed INTS13 in a cancer signaling axis as both a regulated gene and an upstream effector of a downstream RNA-binding protein.","evidence":"ChIP for ZNF384 promoter binding, CRISPR/Cas9 knockout and siRNA silencing of INTS13, hnRNPC rescue, and xenograft model in cervical cancer cells","pmids":["41429980"],"confidence":"Medium","gaps":["Mechanism by which INTS13 regulates hnRNPC (transcriptional vs processing) not defined","Whether the axis depends on Integrator catalytic activity unknown","Single-cancer-context finding without broader validation"]},{"year":2026,"claim":"Demonstrated a second TF (ZBTB26) physically recruits Integrator via INTS10/INTS13 to co-occupied promoters/enhancers, reinforcing INTS13 as a TF-docking platform driving gene programs.","evidence":"Reciprocal co-IP, ChIP-seq co-occupancy, ZBTB26 depletion with Integrator-recruitment readout, and transcriptional profiling","pmids":["42219880"],"confidence":"Medium","gaps":["Single-lab study without independent replication","Relative contributions of INTS10 versus INTS13 to ZBTB26 binding not separated","Whether recruitment alters termination versus activation locally unresolved"]},{"year":null,"claim":"How INTS13's distinct activities—catalytic coupling to the cleavage module, DSIF-clamp opening, RNA-hairpin binding, and gene-specific TF docking—are coordinated and selectively deployed at individual loci remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking the structural termination role with locus-specific TF recruitment","Determinants of which genes use INTS13 as an enhancer platform versus a termination factor unknown","Direct biochemical role of INTS13 RNA-hairpin binding in vivo undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,8]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2]}],"complexes":["Integrator complex","INTS10-INTS13-INTS14-INTS15 module","Integrator-PP2A complex"],"partners":["INTS14","INTS10","INTS15","EGR1","NAB2","ZNF655","ZBTB26","HNRNPC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NVM9","full_name":"Integrator complex subunit 13","aliases":["Cell cycle regulator Mat89Bb homolog","Germ cell tumor 1","Protein asunder homolog","Sarcoma antigen NY-SAR-95"],"length_aa":706,"mass_kda":80.2,"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:32647223). Within the integrator complex, INTS13 is part of the integrator tail module and acts as a platform for the recruitment of transcription factors at promoters (PubMed:38823386, PubMed:38906142). At prophase, mediates recruitment of cytoplasmic dynein to the nuclear envelope, a step important for proper centrosome-nucleus coupling (PubMed:23097494, PubMed:23904267). At G2/M phase, may be required for proper spindle formation and execution of cytokinesis (PubMed:23097494, PubMed:23904267)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9NVM9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INTS13","classification":"Not Classified","n_dependent_lines":440,"n_total_lines":1208,"dependency_fraction":0.36423841059602646},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PPP2CA","stoichiometry":4.0},{"gene":"SSRP1","stoichiometry":4.0},{"gene":"SUPT5H","stoichiometry":4.0},{"gene":"POLR2K","stoichiometry":0.2},{"gene":"SEM1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/INTS13","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":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INTS13"},"hgnc":{"alias_symbol":["FLJ10637","NET48","Mat89Bb","SPATA30"],"prev_symbol":["C12orf11","ASUN"]},"alphafold":{"accession":"Q9NVM9","domains":[{"cath_id":"3.40.50.410","chopping":"8-30_44-255","consensus_level":"high","plddt":94.5836,"start":8,"end":255},{"cath_id":"-","chopping":"258-300_311-388","consensus_level":"high","plddt":84.3079,"start":258,"end":388},{"cath_id":"-","chopping":"415-516_524-561","consensus_level":"medium","plddt":90.204,"start":415,"end":561}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVM9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVM9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVM9-F1-predicted_aligned_error_v6.png","plddt_mean":78.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INTS13","jax_strain_url":"https://www.jax.org/strain/search?query=INTS13"},"sequence":{"accession":"Q9NVM9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NVM9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NVM9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVM9"}},"corpus_meta":[{"pmid":"30008316","id":"PMC_30008316","title":"Targeted Enhancer Activation by a Subunit of the Integrator Complex.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/30008316","citation_count":59,"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":"28468258","id":"PMC_28468258","title":"Pan-Cancer Mutational and Transcriptional Analysis of the Integrator Complex.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28468258","citation_count":48,"is_preprint":false},{"pmid":"36920904","id":"PMC_36920904","title":"A combinatorial approach to uncover an additional Integrator subunit.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36920904","citation_count":29,"is_preprint":false},{"pmid":"36229431","id":"PMC_36229431","title":"INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36229431","citation_count":27,"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":"38130634","id":"PMC_38130634","title":"A pan-cancer analysis of the oncogenic role of Golgi transport 1B in human tumors.","date":"2023","source":"Journal of translational internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38130634","citation_count":27,"is_preprint":false},{"pmid":"15737938","id":"PMC_15737938","title":"Drosophila genome-scale screen for PAN GU kinase substrates identifies Mat89Bb as a cell cycle regulator.","date":"2005","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/15737938","citation_count":19,"is_preprint":false},{"pmid":"9799434","id":"PMC_9799434","title":"A testis-specifically expressed gene is embedded within a cluster of maternally expressed genes at 89B in Drosophila melanogaster.","date":"1998","source":"Development genes and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/9799434","citation_count":7,"is_preprint":false},{"pmid":"37563198","id":"PMC_37563198","title":"A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37563198","citation_count":3,"is_preprint":false},{"pmid":"41429980","id":"PMC_41429980","title":"Unveiling the ZNF384-INTS13-hnRNPC axis as a therapeutic vulnerability in cervical cancer.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41429980","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":"37034680","id":"PMC_37034680","title":"A microdeletion del(12)(p11.21p11.23) with a cryptic unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome.","date":"2023","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/37034680","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8792,"output_tokens":2657,"usd":0.033115,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9773,"output_tokens":3663,"usd":0.07022,"stage2_stop_reason":"end_turn"},"total_usd":0.103335,"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\": 2018,\n      \"finding\": \"INTS13 functions as an independent sub-module of the Integrator complex that targets enhancers through Early Growth Response transcription factors EGR1/2 and their co-factor NAB2, binding poised monocytic enhancers to elicit chromatin looping and activation, thereby driving monocytic/macrophagic differentiation. Independent depletion of INTS13, EGR1, or NAB2 each impairs monocytic differentiation of cell lines and primary human progenitors.\",\n      \"method\": \"ChIP-seq, chromatin conformation assays (looping), siRNA/shRNA depletion in cell lines and primary progenitors, co-immunoprecipitation with EGR1/2 and NAB2\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, chromatin looping, KD in both cell lines and primary human progenitors) in a single focused study with clear functional readout\",\n      \"pmids\": [\"30008316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"INTS10, INTS13 (Asunder), and INTS14 form a separable, functional Integrator sub-module. The crystal structure of INTS13-INTS14 reveals a strongly entwined complex with a unique chain interlink and structural homology to the Ku70-Ku80 DNA repair complex. This module displays nucleic acid-binding affinity, preferring RNA hairpins. INTS13 directly binds the Integrator cleavage module via a conserved C-terminal motif, which is required for snRNA processing and spermatogenesis. The module plays an accessory role in snRNA maturation and a stronger role in transcription termination after pausing.\",\n      \"method\": \"Structural determination (crystal structure of INTS13-INTS14), in vitro nucleic acid binding assays, pulldown/co-purification, C-terminal motif mutagenesis, functional snRNA processing and transcription termination assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with in vitro binding assays and mutagenesis, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"32647223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"INTS13 utilizes its C-terminus to bind the Integrator cleavage module; germline variants p.S652L and p.K668Nfs*9 disrupt this interaction. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of ciliary genes; INTS13 knockdown in Xenopus embryos causes motile cilia anomalies, establishing INTS13 as required for ciliogenesis.\",\n      \"method\": \"Homozygosity mapping and exome sequencing (patient variants), co-immunoprecipitation/pulldown of C-terminal interaction, siRNA depletion in human cells with ciliogenesis readout, Xenopus morpholino knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with mutagenesis, loss-of-function in two independent model systems (human cells and Xenopus) with specific cellular phenotypes\",\n      \"pmids\": [\"36229431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"INTS15 assembles primarily with the INTS13/14/10 module and interfaces with the Integrator-PP2A module. INTS15 modulates RNA polymerase II pausing at a subset of genes.\",\n      \"method\": \"Proteomics (mass spectrometry), AlphaFold2 structure prediction, functional genomics (ChIP-seq/PRO-seq for RNAPII pausing)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus functional genomics in single lab; AlphaFold2 predictions are in silico but supported by experimental proteomics\",\n      \"pmids\": [\"36920904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of the complete Integrator-PP2A complex reveal that INTS10-INTS13-INTS14-INTS15 form a scorpion-tail-shaped module whose 'sting' may open the DSIF DNA clamp to facilitate RNA Pol II termination in the promoter-proximal region.\",\n      \"method\": \"Cryo-electron microscopy (three functional states: pre-termination, post-termination, and free Integrator-PP2A complex)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures at multiple functional states providing direct structural evidence for module architecture and mechanistic role in termination\",\n      \"pmids\": [\"38570683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Structures of human Integrator sub-complexes INTS10/13/14/15 and INTS5/8/10/15 were determined. An in silico protein-protein interaction screen identified ZNF655 as a direct interacting partner of INTS13 within the fully assembled Integrator. INTS13 is proposed to act as a platform for TF recruitment that modulates Integrator stability at specific loci.\",\n      \"method\": \"Cryo-EM structure determination of sub-complexes, in silico protein-protein interaction screen (AlphaFold2-based) of >1,500 human TFs, structural modeling of fully assembled Integrator-PEC\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — cryo-EM structures are high quality, but ZNF655 interaction is from in silico screen; direct experimental validation of ZNF655 binding not described in abstract\",\n      \"pmids\": [\"38823386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mat89Bb (Drosophila ortholog of INTS13) was identified as a substrate of PAN GU kinase. RNAi ablation of Mat89Bb in Drosophila produces a polyploid phenotype similar to pan gu mutants; Mat89Bb morpholino knockdown in Xenopus embryos causes arrest with polyploid nuclei; RNAi in HeLa cells produces multinucleated cells, establishing an evolutionarily conserved role in cell cycle regulation.\",\n      \"method\": \"In vitro expression cloning screen (DIVEC) for PAN GU kinase substrates, RNAi in Drosophila and HeLa cells, morpholino knockdown in Xenopus embryos\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical substrate identification plus loss-of-function in three independent model systems with consistent cell cycle phenotypes\",\n      \"pmids\": [\"15737938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZNF384 was identified as an upstream transcription factor that directly binds the INTS13 promoter and positively regulates INTS13 expression. INTS13 in turn regulates hnRNPC expression as a downstream effector; restoration of hnRNPC reverses anti-proliferative/anti-invasive effects of INTS13 silencing in cervical cancer cells, defining a ZNF384-INTS13-hnRNPC signaling axis.\",\n      \"method\": \"ChIP assay (ZNF384 binding to INTS13 promoter), CRISPR/Cas9 knockout and siRNA silencing of INTS13, hnRNPC rescue experiments, in vivo xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with rescue experiments and in vivo validation, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"41429980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZBTB26 interacts with the Integrator auxiliary module via both INTS10 and INTS13, directly binds a specific DNA motif, co-occupies select promoters and enhancers with Integrator, and is required for recruitment of Integrator to target loci involved in stimulus response, development, and differentiation. The ZBTB26-Integrator axis sustains active promoter/enhancer states and drives defined transcriptional programs.\",\n      \"method\": \"Co-immunoprecipitation (ZBTB26-INTS10/INTS13 interaction), ChIP-seq (co-occupancy), ZBTB26 depletion with Integrator recruitment readout, transcriptional profiling\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ChIP-seq in single lab with functional KD readout; single study without independent replication\",\n      \"pmids\": [\"42219880\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTS13 is a subunit of the Integrator complex that forms a structural module (INTS10-INTS13-INTS14-INTS15) with nucleic acid-binding capacity, acts as a direct linker between this module and the Integrator cleavage module via its conserved C-terminal motif, participates in a scorpion-tail-shaped arm that opens the DSIF DNA clamp to facilitate RNA Pol II termination, serves as a platform for transcription factor recruitment (EGR1/2-NAB2, ZNF655, ZBTB26) to direct enhancer activation and gene-specific transcription, is required for ciliogenesis and myeloid differentiation, and was originally identified as a PAN GU kinase substrate with an evolutionarily conserved role in cell cycle regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INTS13 is a subunit of the Integrator complex that nucleates a separable auxiliary sub-module with INTS10, INTS14, and INTS15, coupling this module to the catalytic core of the complex and to gene-specific transcriptional regulation [#1, #3]. Structurally, INTS13 forms a strongly entwined heterodimer with INTS14 that resembles the Ku70-Ku80 DNA-repair complex and confers nucleic acid-binding activity to the module, with a preference for RNA hairpins [#1]. A conserved C-terminal motif of INTS13 directly tethers the sub-module to the Integrator cleavage module, an interaction required for snRNA processing and disrupted by germline variants (p.S652L, p.K668Nfs*9) [#1, #2]. Within the assembled Integrator-PP2A complex, the INTS10-INTS13-INTS14-INTS15 module adopts a scorpion-tail-shaped architecture whose protruding 'sting' opens the DSIF DNA clamp to promote promoter-proximal RNA Pol II termination after pausing [#1, #4]. Beyond its catalytic coupling role, INTS13 serves as a recruitment platform that links Integrator to sequence-specific transcription factors—including EGR1/2 with their cofactor NAB2, ZNF655, and ZBTB26—directing Integrator to specific promoters and enhancers, sustaining active chromatin states, and driving defined transcriptional programs such as monocytic/macrophagic differentiation [#0, #5, #8]. INTS13 is also required for ciliogenesis in human cells and Xenopus embryos [#2], and its Drosophila ortholog (Mat89Bb) is a PAN GU kinase substrate with a conserved role in cell cycle control [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Before its incorporation into Integrator was known, the gene's ortholog was placed in cell-cycle control by identifying it as a kinase substrate whose loss causes polyploidy across species.\",\n      \"evidence\": \"In vitro expression cloning screen for PAN GU kinase substrates plus RNAi in Drosophila and HeLa and morpholino knockdown in Xenopus\",\n      \"pmids\": [\"15737938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not connect the protein to transcription or the Integrator complex\",\n        \"Mechanism by which phosphorylation controls cell-cycle/ploidy not defined\",\n        \"No molecular target or biochemical activity assigned\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that INTS13 acts as a semi-autonomous Integrator sub-module that targets enhancers via specific transcription factors to drive a defined differentiation program.\",\n      \"evidence\": \"ChIP-seq, chromatin looping assays, siRNA/shRNA depletion in cell lines and primary human progenitors, and co-IP with EGR1/2 and NAB2\",\n      \"pmids\": [\"30008316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of TF recruitment unresolved\",\n        \"Whether the catalytic core is required for the enhancer/differentiation function not dissected\",\n        \"Generality beyond monocytic differentiation unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the molecular architecture of the sub-module and the physical link to the cleavage core, explaining how INTS13 contributes to snRNA processing and termination.\",\n      \"evidence\": \"Crystal structure of INTS13-INTS14, in vitro nucleic acid binding assays, co-purification, and C-terminal motif mutagenesis with snRNA processing and termination readouts\",\n      \"pmids\": [\"32647223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of RNA-hairpin binding in cells not established\",\n        \"Significance of Ku-like fold for activity unclear\",\n        \"How the module is positioned relative to Pol II not yet visualized\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked the C-terminal cleavage-module interaction to human disease and a new cellular process by showing INTS13 is required for ciliogenesis.\",\n      \"evidence\": \"Patient homozygosity mapping/exome sequencing, co-IP with C-terminal mutagenesis, siRNA depletion with ciliogenesis readout in human cells, and Xenopus knockdown\",\n      \"pmids\": [\"36229431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which ciliary genes are directly Integrator-regulated not defined\",\n        \"Whether cilia phenotype reflects transcription termination versus another role unclear\",\n        \"Connection between cleavage-module binding and ciliary gene control mechanistic detail absent\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified INTS15 as a fourth member of the module and connected the module to RNA Pol II pausing regulation.\",\n      \"evidence\": \"Mass-spectrometry proteomics, AlphaFold2 prediction, and ChIP-seq/PRO-seq for pausing\",\n      \"pmids\": [\"36920904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"AlphaFold2 interface predictions await experimental structure\",\n        \"Direct contribution of INTS13 versus INTS15 to pausing not separated\",\n        \"Subset of genes affected not mechanistically explained\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided direct structural mechanism: the module forms a scorpion-tail arm whose tip opens the DSIF clamp to drive promoter-proximal termination.\",\n      \"evidence\": \"Cryo-EM of the Integrator-PP2A complex in pre-termination, post-termination, and free states\",\n      \"pmids\": [\"38570683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"DSIF-clamp opening shown structurally but not validated by mutagenesis of INTS13 contacts\",\n        \"Trigger that engages the 'sting' at specific genes unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded the recruitment-platform model by identifying a transcription factor (ZNF655) predicted to bind INTS13 within assembled Integrator and modulate locus-specific stability.\",\n      \"evidence\": \"Cryo-EM of INTS10/13/14/15 and INTS5/8/10/15 sub-complexes plus an in silico AlphaFold2 screen of >1,500 TFs and structural modeling\",\n      \"pmids\": [\"38823386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"ZNF655 interaction is in silico and lacks direct experimental binding validation\",\n        \"Functional consequence of ZNF655-INTS13 binding not tested\",\n        \"Generality of TF-platform model across loci unproven\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed INTS13 in a cancer signaling axis as both a regulated gene and an upstream effector of a downstream RNA-binding protein.\",\n      \"evidence\": \"ChIP for ZNF384 promoter binding, CRISPR/Cas9 knockout and siRNA silencing of INTS13, hnRNPC rescue, and xenograft model in cervical cancer cells\",\n      \"pmids\": [\"41429980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which INTS13 regulates hnRNPC (transcriptional vs processing) not defined\",\n        \"Whether the axis depends on Integrator catalytic activity unknown\",\n        \"Single-cancer-context finding without broader validation\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated a second TF (ZBTB26) physically recruits Integrator via INTS10/INTS13 to co-occupied promoters/enhancers, reinforcing INTS13 as a TF-docking platform driving gene programs.\",\n      \"evidence\": \"Reciprocal co-IP, ChIP-seq co-occupancy, ZBTB26 depletion with Integrator-recruitment readout, and transcriptional profiling\",\n      \"pmids\": [\"42219880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study without independent replication\",\n        \"Relative contributions of INTS10 versus INTS13 to ZBTB26 binding not separated\",\n        \"Whether recruitment alters termination versus activation locally unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How INTS13's distinct activities—catalytic coupling to the cleavage module, DSIF-clamp opening, RNA-hairpin binding, and gene-specific TF docking—are coordinated and selectively deployed at individual loci remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying model linking the structural termination role with locus-specific TF recruitment\",\n        \"Determinants of which genes use INTS13 as an enhancer platform versus a termination factor unknown\",\n        \"Direct biochemical role of INTS13 RNA-hairpin binding in vivo undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\n      \"Integrator complex\",\n      \"INTS10-INTS13-INTS14-INTS15 module\",\n      \"Integrator-PP2A complex\"\n    ],\n    \"partners\": [\n      \"INTS14\",\n      \"INTS10\",\n      \"INTS15\",\n      \"EGR1\",\n      \"NAB2\",\n      \"ZNF655\",\n      \"ZBTB26\",\n      \"hnRNPC\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}