{"gene":"INTS9","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2005,"finding":"RC-74 (INTS9) is exclusively nuclear and forms a complex with RC-68 (INTS11) in HeLa and mouse cells. RC-74 lacks the histidine motif required for catalysis (unlike INTS11/RC-68 which retains it), and does not interact with CPSF-73 or CPSF-160, indicating that the RC-68/RC-74 complex is a separate entity from the canonical CPSF complex involved in a distinct pre-mRNA processing event.","method":"Co-immunoprecipitation, subcellular fractionation, sequence analysis, RNAi-mediated depletion with cell cycle phenotype readout","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and fractionation in two cell lines, RNAi phenotype, but single lab and no in vitro reconstitution","pmids":["15684398"],"is_preprint":false},{"year":2005,"finding":"RNAi-mediated depletion of RC-68 (INTS11), the catalytic partner of RC-74 (INTS9), arrests HeLa cells early in G1 phase while cells continue to grow, indicating a role for the RC-68/RC-74 complex in cell cycle progression through G1 into S phase.","method":"RNA interference with cell cycle analysis by flow cytometry","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNAi with defined cell cycle phenotype, single lab, single method","pmids":["15684398"],"is_preprint":false},{"year":2012,"finding":"INTS9 and INTS11 form a specific heterodimer mediated by a discrete C-terminal domain (CTD) of INTS9 and a corresponding region within the C-terminus of INTS11 adjacent to the predicted active site. This heterodimeric interaction is required for snRNA 3' end processing, as overexpression of the interaction domains alone causes dominant-negative snRNA misprocessing, and INTS11 lacking the INTS9-interaction domain cannot restore snRNA 3' end processing after RNAi depletion.","method":"Domain mapping, cell-based complementation assay, RNAi, dominant-negative overexpression","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complementation assay with domain mutants plus dominant-negative experiment, single lab","pmids":["22252320"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of the INTS9-INTS11 CTD complex at 2.1-Å resolution reveals that the complex is composed of a continuous nine-stranded β-sheet with four strands from INTS9 and five from INTS11, with highly conserved residues forming an extensive interface. Structure-based mutagenesis confirmed that this interaction is crucial for snRNA 3' end processing.","method":"X-ray crystallography, yeast two-hybrid, co-immunoprecipitation, structure-based mutagenesis, snRNA 3' end processing functional assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and orthogonal binding assays in a single rigorous study","pmids":["28396433"],"is_preprint":false},{"year":2018,"finding":"INTS4 is a specific and conserved interaction partner of the INTS9/INTS11 heterodimer, forming a heterotrimeric cleavage module (INTS4/9/11). INTS4 does not interact with either INTS9 or INTS11 individually and requires both. INTS4 possesses N-terminal HEAT repeats and a β-sheet-rich C-terminal region both important for binding INTS9/INTS11. This trimeric complex is the most critical for UsnRNA biogenesis, Cajal body structural integrity, and histone locus body formation.","method":"Co-immunoprecipitation, domain mapping, UsnRNA 3' end processing assay, Cajal body/histone locus body imaging","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping, multiple functional readouts (snRNA processing, Cajal body, histone locus bodies), replicated across subunit combinations","pmids":["29471365"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of the INTS4/9/11 ternary complex at 3.5-Å resolution reveals spatial organization of the catalytic nuclease INTS11 bound to its catalytically impaired homolog INTS9 via several interdependent interfaces, with INTS4 playing a key role in stabilizing the nuclease domains. All three proteins form a composite electropositive groove suggesting a putative RNA-binding path within the complex.","method":"Cryo-electron microscopy at 3.5-Å resolution, biochemical characterization of subcomplexes","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic cryo-EM structure with biochemical characterization of modular architecture","pmids":["33548203"],"is_preprint":false},{"year":2021,"finding":"WDR73 interacts with INTS9 and INTS11 components of the Integrator complex and is implicated in two Integrator-regulated cellular pathways: UsnRNA 3' end processing and mediating the transcriptional response to EGF stimulation.","method":"Co-immunoprecipitation, UsnRNA processing assay, transcriptional response assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with functional pathway assays, single lab, limited mechanistic depth in abstract","pmids":["33686175"],"is_preprint":false},{"year":2022,"finding":"Inositol hexakisphosphate (IP6) stably associates with the Integrator cleavage module (INTS4-INTS9-INTS11) at a highly electropositive pocket at the interface among all three subunits, 55 Å from the INTS11 active site. IP6 binding is conserved in human ICM and is required for Integrator function in snRNA 3' end processing and mRNA transcription attenuation; mutations in the IP6 binding site or disruption of IP6 biosynthesis significantly reduce Integrator function.","method":"Cryo-EM structure at 2.74 Å (Drosophila ICM), biochemical IP6-binding confirmation in human ICM, site-directed mutagenesis, snRNA processing assay, mRNA transcription attenuation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus mutagenesis plus functional assays across two species, single study with multiple orthogonal methods","pmids":["36180473"],"is_preprint":false},{"year":2022,"finding":"BRAT1 tightly interacts with INTS9/INTS11 subunits of the Integrator complex, and BRAT1 deletion disrupts Integrator functions including UsnRNA and snoRNA 3' end processing, replication-dependent histone pre-mRNA processing, and coding gene expression.","method":"Co-immunoprecipitation, BRAT1 knockout cells, RNA processing assays, transcriptomic analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional RNA processing assays with KO cells, single lab, multiple orthogonal readouts","pmids":["36028512"],"is_preprint":false},{"year":2022,"finding":"SUMOylation of INTS11 (at Lys381, Lys462, Lys475) is regulated by SUMO isopeptidases USPL1 and SENP6 and modulates INTS11 subcellular localization and Integrator activity. An INTS11 SUMOylation-deficient mutant retains interaction with INTS4 and INTS9 but loses interactions with other Integrator subunits, suggesting SUMO conjugation on INTS11 regulates complex assembly.","method":"SUMO site mutagenesis, subcellular localization imaging, Co-immunoprecipitation, snRNA 3' end processing assay, USPL1/SENP6 overexpression","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of SUMO sites with functional readouts and Co-IP, single lab, multiple methods","pmids":["36454007"],"is_preprint":false},{"year":2024,"finding":"BRAT1 and WDR73 are critical biogenesis factors for the Integrator cleavage module (INTS4-9-11). BRAT1 and WDR73 maintain INTS9-11 inactive during maturation by physically blocking the INTS11 endonuclease active site and prevent premature INTS4 association. BRAT1 facilitates nuclear import of the INTS9-11 heterodimer, and final BRAT1 release requires locking of the mature cleavage module conformation by IP6.","method":"Biochemical reconstitution, structural analysis, nuclear import assays, functional complementation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with structural and functional validation, mechanistic assembly pathway established, single rigorous study with multiple orthogonal methods","pmids":["39032489"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structure of the human INTS9-INTS11-BRAT1 complex reveals that the conserved C-terminus of BRAT1 is captured in the active site of INTS11, with a cysteine residue directly coordinating the metal ions, explaining how BRAT1 acts as a cytoplasmic chaperone that stabilizes INTS11 and is required for Integrator function in the nucleus.","method":"Cryo-EM structure determination, co-immunoprecipitation, neural organoid transcriptomic analysis, active-site mutagenesis inference from structure","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with defined active-site coordination mechanism and functional validation in neural organoids, single rigorous study","pmids":["39032490"],"is_preprint":false},{"year":2024,"finding":"INTS11 and INTS9 form a distinct trimeric complex with BRAT1, and this complex is required for activation of REST-responsive neuronal genes during differentiation. BRAT1 recruits INTS11 to promoters of neuronal genes, and disease-causing mutations in BRAT1 (e.g., E522K) diminish association with INTS11/INTS9, preventing transcriptional activation and neuronal differentiation.","method":"Co-immunoprecipitation, ChIP, BRAT1 depletion/reconstitution with differentiation assay (NT2 cells), mouse ESC neuronal differentiation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, loss-of-function with reconstitution using disease mutants, multiple cell models, single lab","pmids":["38805275"],"is_preprint":false},{"year":2023,"finding":"INTS9 and INTS11 subunits of the Integrator complex interact with BRAT1 to form a trimeric complex in HEK293T and NT2 cells. Disease-causing mutations in BRAT1 (E522K) diminish its association with the INTS11/INTS9 heterodimer, and BRAT1 depletion disrupts INTS11 recruitment to neuronal gene promoters and impairs neural differentiation.","method":"Co-immunoprecipitation, ChIP, RNAi-mediated depletion, differentiation assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ChIP with functional differentiation readout, preprint, single lab; findings corroborated by peer-reviewed PMID:38805275","pmids":["37609215"],"is_preprint":true},{"year":2026,"finding":"ZC3H18, a component linking nuclear exosome adaptors to transcription termination, directly recognizes the INTS9/INTS11 endonuclease module of the Integrator complex via a dedicated domain, as shown by in vitro biochemical approaches and cryo-EM.","method":"Cryo-EM, in vitro biochemical binding assays, in silico structure prediction-guided interface identification","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cryo-EM and in vitro biochemistry with computational guidance, single lab, single study","pmids":["41641703"],"is_preprint":false}],"current_model":"INTS9 (RC-74) is a catalytically inactive paralog of CPSF100 that forms an obligate heterodimer with the endonuclease INTS11 (RC-68) through their C-terminal domains, creating a nine-stranded β-sheet interface essential for Integrator endonuclease activity; together with INTS4, these three proteins form the Integrator cleavage module (ICM) whose assembly and activity requires inositol hexakisphosphate (IP6) as an essential co-factor, with the cytoplasmic chaperone BRAT1 blocking the INTS11 active site during maturation and facilitating nuclear import of the INTS9-INTS11 dimer before INTS4 joins the mature ICM; the ICM performs endonucleolytic cleavage for snRNA/eRNA 3'-end processing and transcription attenuation of coding genes, and additionally forms a trimeric complex with BRAT1 to activate key neuronal genes during neuronal differentiation."},"narrative":{"mechanistic_narrative":"INTS9 is a catalytically inactive subunit of the Integrator complex that pairs with the endonuclease INTS11 to enable RNA 3'-end processing and transcriptional regulation [PMID:15684398, PMID:22252320]. Originally identified as the exclusively nuclear protein RC-74 that lacks the histidine motif required for catalysis but stably associates with the active nuclease RC-68 (INTS11), INTS9 forms a complex distinct from canonical CPSF machinery [PMID:15684398]. The INTS9-INTS11 interaction is mediated by a discrete C-terminal domain of each protein that assembles into a continuous nine-stranded β-sheet interface, an architecture essential for snRNA 3'-end processing [PMID:22252320, PMID:28396433]. INTS4 joins this heterodimer—binding only when both INTS9 and INTS11 are present—to form the heterotrimeric Integrator cleavage module (INTS4/9/11) that drives UsnRNA biogenesis, Cajal body integrity, and histone locus body formation, with INTS4 stabilizing the nuclease domains and all three subunits contributing to a composite electropositive RNA-binding groove [PMID:29471365, PMID:33548203]. Inositol hexakisphosphate binds an electropositive pocket at the three-subunit interface and is required for cleavage module function in snRNA processing and mRNA transcription attenuation [PMID:36180473]. Module biogenesis is chaperoned by BRAT1, which blocks the INTS11 active site via a C-terminal cysteine coordinating the catalytic metal ions, keeps the INTS9-INTS11 dimer inactive during maturation, facilitates its nuclear import, and is released upon IP6-dependent locking of the mature module [PMID:39032489, PMID:39032490]. Beyond constitutive processing, the INTS9-INTS11-BRAT1 trimer activates REST-responsive neuronal genes during differentiation, and disease-causing BRAT1 mutations that weaken association with INTS9/INTS11 impair this activation [PMID:38805275].","teleology":[{"year":2005,"claim":"Established that INTS9 (RC-74) is a nuclear, catalytically dead partner of the INTS11 (RC-68) endonuclease, defining a processing entity separate from canonical CPSF.","evidence":"Co-immunoprecipitation, subcellular fractionation, and sequence analysis in HeLa and mouse cells, with RNAi cell cycle readout","pmids":["15684398"],"confidence":"Medium","gaps":["No in vitro reconstitution of the dimer","RNA substrate not yet identified","G1 arrest phenotype not mechanistically tied to a specific processing event"]},{"year":2012,"claim":"Mapped the INTS9-INTS11 interaction to discrete C-terminal domains and showed this contact is functionally required for snRNA 3'-end processing.","evidence":"Domain mapping, cell-based complementation, RNAi, and dominant-negative overexpression","pmids":["22252320"],"confidence":"Medium","gaps":["No structural detail of the interface","Does not address how the dimer engages RNA"]},{"year":2017,"claim":"Resolved the atomic basis of the INTS9-INTS11 interaction as a continuous nine-stranded β-sheet, explaining the obligate nature of the heterodimer.","evidence":"2.1-Å X-ray crystallography with yeast two-hybrid, Co-IP, and structure-based mutagenesis validated by snRNA processing assay","pmids":["28396433"],"confidence":"High","gaps":["Structure limited to CTDs, not full-length proteins","No view of the assembled cleavage module or RNA"]},{"year":2018,"claim":"Defined INTS4 as the third obligate subunit completing the heterotrimeric cleavage module and linked the module to nuclear body integrity.","evidence":"Co-IP, domain mapping, UsnRNA processing, and Cajal/histone locus body imaging","pmids":["29471365"],"confidence":"High","gaps":["No structure of the trimer","Mechanism of RNA recognition unresolved"]},{"year":2021,"claim":"Provided the near-atomic architecture of the INTS4/9/11 module, showing INTS4 stabilizes the nuclease domains and a shared electropositive groove suggests the RNA path.","evidence":"3.5-Å cryo-EM with biochemical subcomplex characterization","pmids":["33548203"],"confidence":"High","gaps":["RNA not captured in the structure","Cofactor requirements not yet identified"]},{"year":2022,"claim":"Identified IP6 as an essential structural cofactor bound at the tri-subunit interface required for cleavage module activity.","evidence":"2.74-Å Drosophila cryo-EM, human ICM biochemistry, mutagenesis, snRNA processing and transcription attenuation assays","pmids":["36180473"],"confidence":"High","gaps":["How IP6 (55 Å from active site) influences catalysis allosterically not fully defined"]},{"year":2022,"claim":"Showed that BRAT1 physically associates with INTS9/INTS11 and is required for multiple Integrator RNA processing functions, and that INTS11 SUMOylation regulates complex assembly.","evidence":"Co-IP with BRAT1 knockout cells and RNA processing assays; INTS11 SUMO-site mutagenesis with localization and Co-IP readouts","pmids":["36028512","36454007"],"confidence":"Medium","gaps":["Mechanism of BRAT1 action not yet structural","Functional consequence of SUMOylation on catalysis not directly measured"]},{"year":2024,"claim":"Defined the assembly pathway in which BRAT1 (with WDR73) chaperones the cytoplasmic INTS9-11 dimer by occluding the INTS11 active site, mediates nuclear import, and is released upon IP6-dependent maturation.","evidence":"Biochemical reconstitution, cryo-EM of INTS9-INTS11-BRAT1 showing a BRAT1 cysteine coordinating active-site metals, nuclear import and complementation assays","pmids":["39032489","39032490"],"confidence":"High","gaps":["Precise role of WDR73 relative to BRAT1 not fully separated","Timing of INTS4 incorporation in vivo not directly observed"]},{"year":2024,"claim":"Demonstrated a non-canonical role for the INTS9-INTS11-BRAT1 trimer in activating REST-responsive neuronal genes, linking the module to neuronal differentiation and BRAT1 disease mutations.","evidence":"Co-IP, ChIP, BRAT1 depletion/reconstitution with disease mutants in NT2 and mouse ESC differentiation; corroborated by prior preprint","pmids":["38805275","37609215"],"confidence":"Medium","gaps":["Whether transcriptional activation requires INTS11 catalysis unresolved","Single lab; mechanism of promoter recruitment incompletely defined"]},{"year":2026,"claim":"Connected the INTS9/INTS11 module to downstream RNA surveillance by showing the exosome-linked factor ZC3H18 directly recognizes the endonuclease module.","evidence":"Cryo-EM and in vitro binding assays with structure-prediction-guided interface mapping","pmids":["41641703"],"confidence":"Medium","gaps":["Functional consequence of ZC3H18 binding for termination not yet established in cells","Single study"]},{"year":null,"claim":"How INTS9 contributes to RNA substrate selection and how the module switches between constitutive 3'-end processing and gene-activating roles remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of the module bound to RNA substrate","Determinants directing the trimer to attenuation versus neuronal gene activation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[2,3,4,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,10]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,3,4,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,8,12]}],"complexes":["Integrator cleavage module (INTS4-INTS9-INTS11)","INTS9-INTS11 heterodimer","INTS9-INTS11-BRAT1 trimer"],"partners":["INTS11","INTS4","BRAT1","WDR73","ZC3H18"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NV88","full_name":"Integrator complex subunit 9","aliases":["Protein related to CPSF subunits of 74 kDa","RC-74"],"length_aa":658,"mass_kda":73.8,"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:25201415, PubMed:33243860, PubMed:33548203, 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, PubMed:22252320, PubMed:26308897, PubMed:30737432). Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the integrator complex (PubMed:23904267)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9NV88/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/INTS9","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000104299","cell_line_id":"CID001876","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"INTS3","stoichiometry":10.0},{"gene":"NELFB","stoichiometry":10.0},{"gene":"NDUFA3","stoichiometry":10.0},{"gene":"INTS14","stoichiometry":4.0},{"gene":"CSNK2A2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"INTS5","stoichiometry":0.2},{"gene":"GAPDH","stoichiometry":0.2},{"gene":"POLR2B","stoichiometry":0.2},{"gene":"POLR2E","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001876","total_profiled":1310},"omim":[{"mim_id":"611354","title":"INTEGRATOR COMPLEX SUBUNIT 11; INTS11","url":"https://www.omim.org/entry/611354"},{"mim_id":"611352","title":"INTEGRATOR COMPLEX SUBUNIT 9; INTS9","url":"https://www.omim.org/entry/611352"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INTS9"},"hgnc":{"alias_symbol":["FLJ10871","CPSF2L","RC-74"],"prev_symbol":[]},"alphafold":{"accession":"Q9NV88","domains":[{"cath_id":"3.60.15.10","chopping":"1-30_87-145_182-267_451-505","consensus_level":"high","plddt":95.9237,"start":1,"end":505},{"cath_id":"3.40.50.10890","chopping":"273-444","consensus_level":"high","plddt":95.5397,"start":273,"end":444},{"cath_id":"3.30.310","chopping":"584-656","consensus_level":"high","plddt":87.1719,"start":584,"end":656}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NV88","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NV88-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NV88-F1-predicted_aligned_error_v6.png","plddt_mean":90.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INTS9","jax_strain_url":"https://www.jax.org/strain/search?query=INTS9"},"sequence":{"accession":"Q9NV88","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NV88.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NV88/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NV88"}},"corpus_meta":[{"pmid":"15684398","id":"PMC_15684398","title":"A CPSF-73 homologue is required for cell cycle progression but not cell growth and interacts with a protein having features of CPSF-100.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15684398","citation_count":85,"is_preprint":false},{"pmid":"29471365","id":"PMC_29471365","title":"Integrator subunit 4 is a 'Symplekin-like' scaffold that associates with INTS9/11 to form the Integrator cleavage module.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29471365","citation_count":67,"is_preprint":false},{"pmid":"28396433","id":"PMC_28396433","title":"Molecular basis for the interaction between Integrator subunits IntS9 and IntS11 and its functional importance.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28396433","citation_count":62,"is_preprint":false},{"pmid":"22252320","id":"PMC_22252320","title":"snRNA 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sinica.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/32165292","citation_count":3,"is_preprint":false},{"pmid":"39147981","id":"PMC_39147981","title":"DNA Methylation Patterns Associated with Tinnitus in Young Adults-A Pilot Study.","date":"2024","source":"Journal of the Association for Research in Otolaryngology : JARO","url":"https://pubmed.ncbi.nlm.nih.gov/39147981","citation_count":2,"is_preprint":false},{"pmid":"41641703","id":"PMC_41641703","title":"Direct coupling of the human nuclear exosome adaptors NEXT and PAXT with transcription termination and processing machineries.","date":"2026","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/41641703","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11481,"output_tokens":3996,"usd":0.047191,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11675,"output_tokens":3532,"usd":0.073337,"stage2_stop_reason":"end_turn"},"total_usd":0.120528,"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\": 2005,\n      \"finding\": \"RC-74 (INTS9) is exclusively nuclear and forms a complex with RC-68 (INTS11) in HeLa and mouse cells. RC-74 lacks the histidine motif required for catalysis (unlike INTS11/RC-68 which retains it), and does not interact with CPSF-73 or CPSF-160, indicating that the RC-68/RC-74 complex is a separate entity from the canonical CPSF complex involved in a distinct pre-mRNA processing event.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, sequence analysis, RNAi-mediated depletion with cell cycle phenotype readout\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and fractionation in two cell lines, RNAi phenotype, but single lab and no in vitro reconstitution\",\n      \"pmids\": [\"15684398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RNAi-mediated depletion of RC-68 (INTS11), the catalytic partner of RC-74 (INTS9), arrests HeLa cells early in G1 phase while cells continue to grow, indicating a role for the RC-68/RC-74 complex in cell cycle progression through G1 into S phase.\",\n      \"method\": \"RNA interference with cell cycle analysis by flow cytometry\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNAi with defined cell cycle phenotype, single lab, single method\",\n      \"pmids\": [\"15684398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"INTS9 and INTS11 form a specific heterodimer mediated by a discrete C-terminal domain (CTD) of INTS9 and a corresponding region within the C-terminus of INTS11 adjacent to the predicted active site. This heterodimeric interaction is required for snRNA 3' end processing, as overexpression of the interaction domains alone causes dominant-negative snRNA misprocessing, and INTS11 lacking the INTS9-interaction domain cannot restore snRNA 3' end processing after RNAi depletion.\",\n      \"method\": \"Domain mapping, cell-based complementation assay, RNAi, dominant-negative overexpression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complementation assay with domain mutants plus dominant-negative experiment, single lab\",\n      \"pmids\": [\"22252320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of the INTS9-INTS11 CTD complex at 2.1-Å resolution reveals that the complex is composed of a continuous nine-stranded β-sheet with four strands from INTS9 and five from INTS11, with highly conserved residues forming an extensive interface. Structure-based mutagenesis confirmed that this interaction is crucial for snRNA 3' end processing.\",\n      \"method\": \"X-ray crystallography, yeast two-hybrid, co-immunoprecipitation, structure-based mutagenesis, snRNA 3' end processing functional assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and orthogonal binding assays in a single rigorous study\",\n      \"pmids\": [\"28396433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"INTS4 is a specific and conserved interaction partner of the INTS9/INTS11 heterodimer, forming a heterotrimeric cleavage module (INTS4/9/11). INTS4 does not interact with either INTS9 or INTS11 individually and requires both. INTS4 possesses N-terminal HEAT repeats and a β-sheet-rich C-terminal region both important for binding INTS9/INTS11. This trimeric complex is the most critical for UsnRNA biogenesis, Cajal body structural integrity, and histone locus body formation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, UsnRNA 3' end processing assay, Cajal body/histone locus body imaging\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping, multiple functional readouts (snRNA processing, Cajal body, histone locus bodies), replicated across subunit combinations\",\n      \"pmids\": [\"29471365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of the INTS4/9/11 ternary complex at 3.5-Å resolution reveals spatial organization of the catalytic nuclease INTS11 bound to its catalytically impaired homolog INTS9 via several interdependent interfaces, with INTS4 playing a key role in stabilizing the nuclease domains. All three proteins form a composite electropositive groove suggesting a putative RNA-binding path within the complex.\",\n      \"method\": \"Cryo-electron microscopy at 3.5-Å resolution, biochemical characterization of subcomplexes\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic cryo-EM structure with biochemical characterization of modular architecture\",\n      \"pmids\": [\"33548203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDR73 interacts with INTS9 and INTS11 components of the Integrator complex and is implicated in two Integrator-regulated cellular pathways: UsnRNA 3' end processing and mediating the transcriptional response to EGF stimulation.\",\n      \"method\": \"Co-immunoprecipitation, UsnRNA processing assay, transcriptional response assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with functional pathway assays, single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"33686175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Inositol hexakisphosphate (IP6) stably associates with the Integrator cleavage module (INTS4-INTS9-INTS11) at a highly electropositive pocket at the interface among all three subunits, 55 Å from the INTS11 active site. IP6 binding is conserved in human ICM and is required for Integrator function in snRNA 3' end processing and mRNA transcription attenuation; mutations in the IP6 binding site or disruption of IP6 biosynthesis significantly reduce Integrator function.\",\n      \"method\": \"Cryo-EM structure at 2.74 Å (Drosophila ICM), biochemical IP6-binding confirmation in human ICM, site-directed mutagenesis, snRNA processing assay, mRNA transcription attenuation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus mutagenesis plus functional assays across two species, single study with multiple orthogonal methods\",\n      \"pmids\": [\"36180473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BRAT1 tightly interacts with INTS9/INTS11 subunits of the Integrator complex, and BRAT1 deletion disrupts Integrator functions including UsnRNA and snoRNA 3' end processing, replication-dependent histone pre-mRNA processing, and coding gene expression.\",\n      \"method\": \"Co-immunoprecipitation, BRAT1 knockout cells, RNA processing assays, transcriptomic analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional RNA processing assays with KO cells, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"36028512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SUMOylation of INTS11 (at Lys381, Lys462, Lys475) is regulated by SUMO isopeptidases USPL1 and SENP6 and modulates INTS11 subcellular localization and Integrator activity. An INTS11 SUMOylation-deficient mutant retains interaction with INTS4 and INTS9 but loses interactions with other Integrator subunits, suggesting SUMO conjugation on INTS11 regulates complex assembly.\",\n      \"method\": \"SUMO site mutagenesis, subcellular localization imaging, Co-immunoprecipitation, snRNA 3' end processing assay, USPL1/SENP6 overexpression\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of SUMO sites with functional readouts and Co-IP, single lab, multiple methods\",\n      \"pmids\": [\"36454007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRAT1 and WDR73 are critical biogenesis factors for the Integrator cleavage module (INTS4-9-11). BRAT1 and WDR73 maintain INTS9-11 inactive during maturation by physically blocking the INTS11 endonuclease active site and prevent premature INTS4 association. BRAT1 facilitates nuclear import of the INTS9-11 heterodimer, and final BRAT1 release requires locking of the mature cleavage module conformation by IP6.\",\n      \"method\": \"Biochemical reconstitution, structural analysis, nuclear import assays, functional complementation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with structural and functional validation, mechanistic assembly pathway established, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"39032489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of the human INTS9-INTS11-BRAT1 complex reveals that the conserved C-terminus of BRAT1 is captured in the active site of INTS11, with a cysteine residue directly coordinating the metal ions, explaining how BRAT1 acts as a cytoplasmic chaperone that stabilizes INTS11 and is required for Integrator function in the nucleus.\",\n      \"method\": \"Cryo-EM structure determination, co-immunoprecipitation, neural organoid transcriptomic analysis, active-site mutagenesis inference from structure\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with defined active-site coordination mechanism and functional validation in neural organoids, single rigorous study\",\n      \"pmids\": [\"39032490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"INTS11 and INTS9 form a distinct trimeric complex with BRAT1, and this complex is required for activation of REST-responsive neuronal genes during differentiation. BRAT1 recruits INTS11 to promoters of neuronal genes, and disease-causing mutations in BRAT1 (e.g., E522K) diminish association with INTS11/INTS9, preventing transcriptional activation and neuronal differentiation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, BRAT1 depletion/reconstitution with differentiation assay (NT2 cells), mouse ESC neuronal differentiation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, loss-of-function with reconstitution using disease mutants, multiple cell models, single lab\",\n      \"pmids\": [\"38805275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"INTS9 and INTS11 subunits of the Integrator complex interact with BRAT1 to form a trimeric complex in HEK293T and NT2 cells. Disease-causing mutations in BRAT1 (E522K) diminish its association with the INTS11/INTS9 heterodimer, and BRAT1 depletion disrupts INTS11 recruitment to neuronal gene promoters and impairs neural differentiation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, RNAi-mediated depletion, differentiation assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ChIP with functional differentiation readout, preprint, single lab; findings corroborated by peer-reviewed PMID:38805275\",\n      \"pmids\": [\"37609215\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZC3H18, a component linking nuclear exosome adaptors to transcription termination, directly recognizes the INTS9/INTS11 endonuclease module of the Integrator complex via a dedicated domain, as shown by in vitro biochemical approaches and cryo-EM.\",\n      \"method\": \"Cryo-EM, in vitro biochemical binding assays, in silico structure prediction-guided interface identification\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cryo-EM and in vitro biochemistry with computational guidance, single lab, single study\",\n      \"pmids\": [\"41641703\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTS9 (RC-74) is a catalytically inactive paralog of CPSF100 that forms an obligate heterodimer with the endonuclease INTS11 (RC-68) through their C-terminal domains, creating a nine-stranded β-sheet interface essential for Integrator endonuclease activity; together with INTS4, these three proteins form the Integrator cleavage module (ICM) whose assembly and activity requires inositol hexakisphosphate (IP6) as an essential co-factor, with the cytoplasmic chaperone BRAT1 blocking the INTS11 active site during maturation and facilitating nuclear import of the INTS9-INTS11 dimer before INTS4 joins the mature ICM; the ICM performs endonucleolytic cleavage for snRNA/eRNA 3'-end processing and transcription attenuation of coding genes, and additionally forms a trimeric complex with BRAT1 to activate key neuronal genes during neuronal differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INTS9 is a catalytically inactive subunit of the Integrator complex that pairs with the endonuclease INTS11 to enable RNA 3'-end processing and transcriptional regulation [#0, #2]. Originally identified as the exclusively nuclear protein RC-74 that lacks the histidine motif required for catalysis but stably associates with the active nuclease RC-68 (INTS11), INTS9 forms a complex distinct from canonical CPSF machinery [#0]. The INTS9-INTS11 interaction is mediated by a discrete C-terminal domain of each protein that assembles into a continuous nine-stranded β-sheet interface, an architecture essential for snRNA 3'-end processing [#2, #3]. INTS4 joins this heterodimer—binding only when both INTS9 and INTS11 are present—to form the heterotrimeric Integrator cleavage module (INTS4/9/11) that drives UsnRNA biogenesis, Cajal body integrity, and histone locus body formation, with INTS4 stabilizing the nuclease domains and all three subunits contributing to a composite electropositive RNA-binding groove [#4, #5]. Inositol hexakisphosphate binds an electropositive pocket at the three-subunit interface and is required for cleavage module function in snRNA processing and mRNA transcription attenuation [#7]. Module biogenesis is chaperoned by BRAT1, which blocks the INTS11 active site via a C-terminal cysteine coordinating the catalytic metal ions, keeps the INTS9-INTS11 dimer inactive during maturation, facilitates its nuclear import, and is released upon IP6-dependent locking of the mature module [#10, #11]. Beyond constitutive processing, the INTS9-INTS11-BRAT1 trimer activates REST-responsive neuronal genes during differentiation, and disease-causing BRAT1 mutations that weaken association with INTS9/INTS11 impair this activation [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that INTS9 (RC-74) is a nuclear, catalytically dead partner of the INTS11 (RC-68) endonuclease, defining a processing entity separate from canonical CPSF.\",\n      \"evidence\": \"Co-immunoprecipitation, subcellular fractionation, and sequence analysis in HeLa and mouse cells, with RNAi cell cycle readout\",\n      \"pmids\": [\"15684398\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No in vitro reconstitution of the dimer\", \"RNA substrate not yet identified\", \"G1 arrest phenotype not mechanistically tied to a specific processing event\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped the INTS9-INTS11 interaction to discrete C-terminal domains and showed this contact is functionally required for snRNA 3'-end processing.\",\n      \"evidence\": \"Domain mapping, cell-based complementation, RNAi, and dominant-negative overexpression\",\n      \"pmids\": [\"22252320\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural detail of the interface\", \"Does not address how the dimer engages RNA\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the atomic basis of the INTS9-INTS11 interaction as a continuous nine-stranded β-sheet, explaining the obligate nature of the heterodimer.\",\n      \"evidence\": \"2.1-Å X-ray crystallography with yeast two-hybrid, Co-IP, and structure-based mutagenesis validated by snRNA processing assay\",\n      \"pmids\": [\"28396433\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structure limited to CTDs, not full-length proteins\", \"No view of the assembled cleavage module or RNA\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined INTS4 as the third obligate subunit completing the heterotrimeric cleavage module and linked the module to nuclear body integrity.\",\n      \"evidence\": \"Co-IP, domain mapping, UsnRNA processing, and Cajal/histone locus body imaging\",\n      \"pmids\": [\"29471365\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structure of the trimer\", \"Mechanism of RNA recognition unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the near-atomic architecture of the INTS4/9/11 module, showing INTS4 stabilizes the nuclease domains and a shared electropositive groove suggests the RNA path.\",\n      \"evidence\": \"3.5-Å cryo-EM with biochemical subcomplex characterization\",\n      \"pmids\": [\"33548203\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"RNA not captured in the structure\", \"Cofactor requirements not yet identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified IP6 as an essential structural cofactor bound at the tri-subunit interface required for cleavage module activity.\",\n      \"evidence\": \"2.74-Å Drosophila cryo-EM, human ICM biochemistry, mutagenesis, snRNA processing and transcription attenuation assays\",\n      \"pmids\": [\"36180473\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How IP6 (55 Å from active site) influences catalysis allosterically not fully defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that BRAT1 physically associates with INTS9/INTS11 and is required for multiple Integrator RNA processing functions, and that INTS11 SUMOylation regulates complex assembly.\",\n      \"evidence\": \"Co-IP with BRAT1 knockout cells and RNA processing assays; INTS11 SUMO-site mutagenesis with localization and Co-IP readouts\",\n      \"pmids\": [\"36028512\", \"36454007\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of BRAT1 action not yet structural\", \"Functional consequence of SUMOylation on catalysis not directly measured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the assembly pathway in which BRAT1 (with WDR73) chaperones the cytoplasmic INTS9-11 dimer by occluding the INTS11 active site, mediates nuclear import, and is released upon IP6-dependent maturation.\",\n      \"evidence\": \"Biochemical reconstitution, cryo-EM of INTS9-INTS11-BRAT1 showing a BRAT1 cysteine coordinating active-site metals, nuclear import and complementation assays\",\n      \"pmids\": [\"39032489\", \"39032490\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Precise role of WDR73 relative to BRAT1 not fully separated\", \"Timing of INTS4 incorporation in vivo not directly observed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a non-canonical role for the INTS9-INTS11-BRAT1 trimer in activating REST-responsive neuronal genes, linking the module to neuronal differentiation and BRAT1 disease mutations.\",\n      \"evidence\": \"Co-IP, ChIP, BRAT1 depletion/reconstitution with disease mutants in NT2 and mouse ESC differentiation; corroborated by prior preprint\",\n      \"pmids\": [\"38805275\", \"37609215\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether transcriptional activation requires INTS11 catalysis unresolved\", \"Single lab; mechanism of promoter recruitment incompletely defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected the INTS9/INTS11 module to downstream RNA surveillance by showing the exosome-linked factor ZC3H18 directly recognizes the endonuclease module.\",\n      \"evidence\": \"Cryo-EM and in vitro binding assays with structure-prediction-guided interface mapping\",\n      \"pmids\": [\"41641703\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of ZC3H18 binding for termination not yet established in cells\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How INTS9 contributes to RNA substrate selection and how the module switches between constitutive 3'-end processing and gene-activating roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structure of the module bound to RNA substrate\", \"Determinants directing the trimer to attenuation versus neuronal gene activation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [2, 3, 4, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 3, 4, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 8, 12]}\n    ],\n    \"complexes\": [\n      \"Integrator cleavage module (INTS4-INTS9-INTS11)\",\n      \"INTS9-INTS11 heterodimer\",\n      \"INTS9-INTS11-BRAT1 trimer\"\n    ],\n    \"partners\": [\n      \"INTS11\",\n      \"INTS4\",\n      \"BRAT1\",\n      \"WDR73\",\n      \"ZC3H18\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}