{"gene":"INTS6","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2021,"finding":"Crystal structure of the INTS3/INTS6 complex revealed that two INTS3c subunits dimerize and interact with INTS6c via conserved residues; INTS3 dimerization is required for recognizing longer ssDNA, and perturbation of INTS3c dimerization or disruption of the INTS3c/INTS6c interaction impairs DSB repair.","method":"X-ray crystallography (2.4 Å resolution), biochemical pulldown assays, site-directed mutagenesis, DSB repair functional assays","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and biochemical assays in a single rigorous study","pmids":["34400606"],"is_preprint":false},{"year":2024,"finding":"INTS6 associates with the heterotrimeric SOSS1 complex (INTS3, INIP, hSSB1) to form a tetrameric SOSS1 complex; INTS6 binds DNA:RNA hybrids, promotes PP2A recruitment to DSBs facilitating RNAPII dephosphorylation, prevents accumulation of damage-associated RNA transcripts (DARTs), and interacts with and promotes senataxin (SETX) recruitment to resolve R-loops at DSBs.","method":"Co-immunoprecipitation, biochemical binding assays (DNA:RNA hybrid binding), proximity ligation, functional DSB repair assays, RNAPII phosphorylation analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, multiple orthogonal biochemical assays, functional rescue, single lab","pmids":["39445827"],"is_preprint":false},{"year":2023,"finding":"IntS6 (Integrator subunit 6) over-expression in Drosophila blocks Integrator function at a subset of protein-coding genes (but not snRNAs or other attenuated loci) by titrating PP2A subunits; IntS6 functions analogously to a PP2A regulatory B subunit to modulate transcription termination efficiency at select gene loci.","method":"Genetic over-expression in Drosophila, RNA-seq, PP2A subunit interaction assays, epistasis with canonical PP2A B subunits","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple orthogonal methods (over-expression, PP2A interaction, transcriptomics), single lab","pmids":["37995689"],"is_preprint":false},{"year":2025,"finding":"INTS6 deficiency in a conditional mouse KO model disrupts early neurogenesis, cortical lamination, and synaptic development; INTS6 loss alters RNAPII dynamics and disrupts transcriptional regulation of synaptic genes. CDK9 inhibition reduced RNAPII phosphorylation and rescued the neurosphere overproliferation and abnormal dendritic spine phenotype caused by Ints6 deficiency.","method":"Conditional KO mouse model, behavioral assays, immunohistochemistry, RNAPII ChIP, neurosphere assays, CDK9 inhibitor rescue experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular and molecular phenotype, pharmacological rescue, multiple orthogonal methods","pmids":["40966122"],"is_preprint":false},{"year":2013,"finding":"In zebrafish, maternal-effect loss of Ints6 causes de-repression of dorsal organizer genes, failure to maintain BMP ligand expression, failure to fully express vox and ved (Wnt8a mediators), and severe dorsalization with multiple axial domains and ectopic dorsal forerunner cells; restoring BMP signaling or limiting Nodal signaling rescues wild-type patterning, placing Ints6 upstream of the BMP/Nodal/Wnt8a axis in dorsoventral patterning.","method":"Forward genetic screen, maternal-effect recessive mutation analysis, epistasis (BMP/Nodal pathway rescue), in situ hybridization, zebrafish embryology","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with pathway rescue experiments, multiple phenotypic and molecular readouts","pmids":["24204286"],"is_preprint":false},{"year":2001,"finding":"DICE1 (INTS6) encodes a protein with a DEAD box motif characteristic of ATP-dependent helicases and contains helicase superfamily II motifs; GFP-fusion experiments showed preferential nuclear localization of the DICE1 protein, and CpG sites flanking a predicted TATA box are hypermethylated in tumor cells with decreased DICE1 expression.","method":"GFP-fusion protein live imaging, genomic structure determination, bisulfite sequencing/methylation analysis","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct GFP localization experiment, methylation analysis; single lab, multiple methods","pmids":["11939413"],"is_preprint":false},{"year":1998,"finding":"DBI-1 (INTS6/DICE1) protein localizes to the nucleus and overexpression of DBI-1 in cells containing the wild-type IGF-1 receptor diminishes the mitogenic response to IGF-1.","method":"Antibody localization (immunofluorescence), overexpression with IGF-1 mitogenic response assay (thymidine incorporation or growth assay)","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, direct localization by antibody and functional overexpression assay","pmids":["9473344"],"is_preprint":false},{"year":2004,"finding":"Ectopic expression of DICE1 cDNA (as GFP fusion) inhibits colony formation of human NSCLC cell lines (SK-MES-1, NCI-H520) and prostate carcinoma (DU145), and suppresses growth in soft agar of IGF-IR-transformed Balb/c 3T3 cells, demonstrating growth-suppressive activity that interferes with anchorage-independent growth dependent on IGF-I signaling.","method":"Stable transfection, colony formation assay, soft-agar anchorage-independent growth assay","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss/gain-of-function with defined cellular phenotype, replicated across multiple cell lines","pmids":["15254679"],"is_preprint":false},{"year":2009,"finding":"Exogenous re-expression of INTS6/DICE1 in androgen-independent PC3 and DU145 prostate cancer cells suppresses colony formation and causes G1 phase cell cycle arrest (not immediate apoptosis); expression profiling revealed upregulation of Wnt pathway inhibitors (CXXC4, FZD7, TCF7L1) and downregulation of cyclin D1, linking INTS6 function to Wnt signaling and cell cycle regulation.","method":"Ectopic cDNA expression, colony formation assay, flow cytometry cell cycle analysis, gene expression profiling (microarray)","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple orthogonal methods (cell cycle, colony, expression profiling), single lab","pmids":["19906297"],"is_preprint":false},{"year":2005,"finding":"Reduced DICE1 (INTS6) expression in prostate cancer cell lines DU145 and LNCaP is associated with hypermethylation of the DICE1 promoter; treatment with the demethylating agent 5-azacytidine restores DICE1 expression, and hypermethylation of DICE1 CpG promoter sites was observed in 4/8 prostate cancers.","method":"Bisulfite sequencing, promoter activity luciferase assay, 5-azacytidine demethylation treatment, RT-PCR","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue (demethylation restores expression), promoter activity assays, bisulfite sequencing; single lab","pmids":["16007164"],"is_preprint":false},{"year":2006,"finding":"C. elegans DIC-1 (DICE1/INTS6 homolog) localizes to the inner mitochondrial membrane as cytoplasmic foci, and its RNAi knockdown causes abnormal mitochondrial morphology with internal vesicles, increased ced-3-dependent apoptosis in the germline, and embryonic lethality, demonstrating an essential role in mitochondrial inner membrane/cristae topology.","method":"RNA interference, immunofluorescence microscopy, cryoelectron microscopy, genetic epistasis (ced-3 dependence)","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with defined ultrastructural phenotype (cryo-EM), genetic epistasis; C. elegans ortholog, may not reflect mammalian function","pmids":["16914495"],"is_preprint":false},{"year":2018,"finding":"Small RNA-induced upregulation of INTS6 in castration-resistant prostate cancer cells suppresses cell proliferation and motility, and this effect is associated with downregulation of Wnt/β-catenin signaling; impairment of β-catenin degradation reverses the tumor suppressive effects of INTS6.","method":"Small activating RNA transfection, cell proliferation and motility assays, Western blot for β-catenin pathway components, rescue by β-catenin degradation inhibitor","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain-of-function with epistasis rescue (β-catenin inhibitor), multiple readouts; single lab","pmids":["29895194"],"is_preprint":false},{"year":2021,"finding":"Downregulation of INTS6 in colorectal cancer cells induces G1/S-phase cell cycle arrest and suppresses growth, while overexpression promotes growth; mechanistically, INTS6 increases levels of phosphorylated AKT (p-AKT) and ERK (p-ERK), and the growth-promoting effect is blocked by AKT and ERK inhibitors; INTS6 also affects c-Myc and CDK2 expression downstream of PI3K/AKT and MAPK signaling.","method":"siRNA knockdown, overexpression, flow cytometry, Western blot (p-AKT, p-ERK, c-Myc, CDK2), kinase inhibitor treatment, xenograft tumor assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss- and gain-of-function with pharmacological epistasis (inhibitor rescue), multiple downstream readouts; single lab","pmids":["34508742"],"is_preprint":false},{"year":2013,"finding":"DICE1 (INTS6) is a cellular target of EBV-encoded miR-BART3* miRNA in nasopharyngeal carcinoma; miR-BART3* targets the 3'-UTR of DICE1 mRNA and down-regulates endogenous DICE1 protein; inhibition of miR-BART3* increases DICE1 protein expression; miR-BART3* expression overcomes the growth-suppressive activity of DICE1.","method":"3'-UTR luciferase reporter assay, anti-miRNA oligonucleotide inhibition, Western blot, colony formation assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct target site identification and functional validation with multiple orthogonal methods; single lab","pmids":["23280823"],"is_preprint":false},{"year":2015,"finding":"INTS6 and its pseudogene INTS6P1 compete for binding of oncomiR-17-5p; INTS6P1 acts as a competing endogenous RNA (ceRNA) to protect INTS6 mRNA from miR-17-5p-mediated repression, and both INTS6 and INTS6P1 exert tumor-suppressive roles in hepatocellular carcinoma through this regulatory circuit.","method":"Luciferase reporter assay (miRNA target site), overexpression and knockdown functional assays (growth curves, cell death, migration, in vivo xenograft), microarray expression analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple orthogonal functional assays with miRNA target validation; single lab","pmids":["25686840"],"is_preprint":false},{"year":2024,"finding":"In C. elegans, INTS-6 is necessary for RAD-51 foci formation after X-ray radiation, and CDK-1 Tyr-15 phosphorylation depends on the presence of INTS-6, demonstrating a role for INTS-6 in the DNA damage response.","method":"RNAi knockdown, immunofluorescence (RAD-51 foci), Western blot (CDK-1 pY15), X-ray irradiation","journal":"microPublication biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single-method per endpoint, C. elegans ortholog","pmids":["39575199"],"is_preprint":false}],"current_model":"INTS6 is a subunit of the Integrator complex that functions as a scaffold bridging INTS3/SOSS1 to recruit PP2A to RNA Pol II at DNA double-strand breaks, facilitating RNAPII dephosphorylation and R-loop resolution via senataxin; it also tunes Integrator-dependent premature transcription termination at a subset of protein-coding genes by modulating PP2A phosphatase module activity, regulates early neurogenesis and synaptic development through RNAPII transcriptional dynamics, and acts as a tumor suppressor in multiple cancer types by promoting G1 cell cycle arrest and modulating Wnt/β-catenin and IGF-1 signaling."},"narrative":{"mechanistic_narrative":"INTS6 is a subunit of the Integrator complex that couples RNA polymerase II transcriptional control to genome maintenance by directing the PP2A phosphatase module to chromatin [PMID:39445827, PMID:37995689]. Crystallographic and biochemical analysis shows that INTS6 binds INTS3, with two INTS3 protomers dimerizing to engage INTS6 through conserved residues required for double-strand break (DSB) repair [PMID:34400606]. At DSBs, INTS6 joins the heterotrimeric SOSS1 complex (INTS3, INIP, hSSB1) to form a tetrameric assembly, binds DNA:RNA hybrids, promotes PP2A-mediated dephosphorylation of RNAPII, prevents accumulation of damage-associated RNA transcripts, and recruits senataxin to resolve R-loops [PMID:39445827]. The same PP2A-tuning activity governs Integrator-dependent transcription: INTS6 behaves analogously to a PP2A regulatory B subunit, and its overexpression titrates PP2A to modulate premature transcription termination at a subset of protein-coding genes [PMID:37995689]. Through these effects on RNAPII dynamics, INTS6 controls early neurogenesis, cortical lamination, and synaptic development, with the underlying RNAPII hyperphosphorylation and overproliferation phenotypes reversible by CDK9 inhibition [PMID:40966122], and it acts upstream of the BMP/Nodal/Wnt8a axis in vertebrate dorsoventral patterning [PMID:24204286]. INTS6 additionally functions as a frequently silenced tumor suppressor: its re-expression induces G1 arrest and suppresses colony formation across prostate, lung, colorectal, and liver cancer models, in part by upregulating Wnt-pathway inhibitors and downregulating cyclin D1 [PMID:19906297, PMID:29895194, PMID:15254679], while its promoter is hypermethylated and its transcript is repressed by EBV miR-BART3* and oncomiR-17-5p in various malignancies [PMID:16007164, PMID:23280823, PMID:25686840].","teleology":[{"year":1998,"claim":"Established the first functional handle on the gene by showing its product is nuclear and antagonizes growth-factor mitogenic signaling, framing it as a candidate growth suppressor.","evidence":"Antibody immunofluorescence and IGF-1 mitogenic response assay after overexpression","pmids":["9473344"],"confidence":"Medium","gaps":["No molecular mechanism linking the protein to IGF-1R signaling","No link to transcription or the Integrator complex yet"]},{"year":2001,"claim":"Defined the gene structure and a DEAD-box/helicase superfamily II motif and nuclear localization, while implicating promoter CpG hypermethylation in its silencing in tumors.","evidence":"GFP-fusion live imaging, genomic structure determination, bisulfite methylation analysis","pmids":["11939413"],"confidence":"Medium","gaps":["Predicted helicase activity never demonstrated biochemically","Did not establish a transcriptional or DSB function"]},{"year":2005,"claim":"Showed that promoter hypermethylation causally silences the gene in prostate cancer, since demethylation restores expression, supporting an epigenetically inactivated tumor suppressor.","evidence":"Bisulfite sequencing, promoter luciferase assays, 5-azacytidine demethylation in DU145/LNCaP cells","pmids":["16007164"],"confidence":"Medium","gaps":["Did not define the downstream effector pathway of suppression","Limited primary-tumor sample number"]},{"year":2006,"claim":"Revealed an unexpected mitochondrial role in the worm ortholog, where loss disrupts inner-membrane topology and triggers apoptosis, raising the question of whether the gene's function is nuclear or organellar.","evidence":"RNAi, immunofluorescence, cryo-EM, ced-3 epistasis in C. elegans","pmids":["16914495"],"confidence":"Medium","gaps":["Mitochondrial localization not confirmed for the mammalian protein","Relationship between mitochondrial and later nuclear/transcriptional roles unresolved"]},{"year":2009,"claim":"Connected the suppressor activity to a defined cellular program—G1 arrest with Wnt-inhibitor upregulation and cyclin D1 loss—providing the first pathway-level mechanism.","evidence":"Ectopic expression, cell cycle flow cytometry, colony formation, microarray profiling in PC3/DU145","pmids":["19906297"],"confidence":"Medium","gaps":["Correlative expression changes, not shown to be direct targets","Did not link Wnt regulation to a transcription-termination mechanism"]},{"year":2013,"claim":"Demonstrated that the gene is targeted for repression by viral and cellular regulators and that it operates upstream of a developmental signaling axis, broadening its biological reach.","evidence":"EBV miR-BART3* 3'-UTR reporter assays in nasopharyngeal carcinoma; zebrafish maternal-effect mutant epistasis on BMP/Nodal/Wnt8a","pmids":["23280823","24204286"],"confidence":"High","gaps":["Mechanism by which the gene controls the BMP/Nodal/Wnt8a axis not defined","Whether developmental and tumor-suppressor functions share a mechanism unknown"]},{"year":2014,"claim":"Defined a ceRNA circuit in which a pseudogene protects the transcript from oncomiR-17-5p, adding a post-transcriptional layer to tumor suppression in liver cancer.","evidence":"Luciferase miRNA-target assays, overexpression/knockdown, xenografts in HCC","pmids":["25686840"],"confidence":"Medium","gaps":["Does not connect transcript regulation to protein-level mechanism","ceRNA stoichiometry in vivo not quantified"]},{"year":2018,"claim":"Pinned tumor suppression mechanistically on Wnt/β-catenin, since blocking β-catenin degradation reverses the growth-suppressive effect.","evidence":"Small activating RNA, proliferation/motility assays, β-catenin pathway Western blots and rescue in CRPC cells","pmids":["29895194"],"confidence":"Medium","gaps":["Direct molecular link between the protein and β-catenin stability not shown","Single cancer context"]},{"year":2021,"claim":"Reframed the gene's biochemistry by solving the INTS3/INTS6 structure, establishing it as an Integrator subunit whose INTS3-dimer interface is required for DSB repair.","evidence":"2.4 Å crystal structure, pulldowns, mutagenesis, DSB repair assays; plus colorectal cancer loss/gain-of-function with PI3K/AKT-MAPK epistasis","pmids":["34400606","34508742"],"confidence":"High","gaps":["Structure did not show how PP2A is engaged","Reconciliation of helicase-motif annotation with structural role unaddressed"]},{"year":2023,"claim":"Identified the gene as a PP2A-regulatory-B-subunit-like factor that tunes Integrator-dependent transcription termination at select protein-coding genes by titrating PP2A.","evidence":"Drosophila overexpression, RNA-seq, PP2A interaction assays, epistasis with canonical PP2A B subunits","pmids":["37995689"],"confidence":"High","gaps":["Gene-selectivity determinants of which loci are affected not defined","Direct structural basis of PP2A engagement not resolved"]},{"year":2024,"claim":"Unified the DSB and transcription roles, showing the protein assembles into tetrameric SOSS1, binds DNA:RNA hybrids, drives PP2A-mediated RNAPII dephosphorylation, and recruits senataxin to clear R-loops at breaks.","evidence":"Reciprocal Co-IP, DNA:RNA hybrid binding, proximity ligation, RNAPII phosphorylation and DSB repair assays; plus C. elegans DNA-damage-response RAD-51/CDK-1 data","pmids":["39445827","39575199"],"confidence":"High","gaps":["Stoichiometry of PP2A handoff between SOSS1 and chromatin not resolved","C. elegans DDR finding is single-method per endpoint and not independently confirmed"]},{"year":2025,"claim":"Demonstrated a physiological requirement in mammalian brain development, where loss disrupts neurogenesis and synaptic gene transcription via altered RNAPII dynamics, rescuable by CDK9 inhibition.","evidence":"Conditional KO mouse, IHC, RNAPII ChIP, neurosphere assays, CDK9 inhibitor rescue, behavior","pmids":["40966122"],"confidence":"High","gaps":["Which synaptic-gene targets are directly Integrator-controlled not fully defined","Link between neurodevelopmental phenotype and human disease not established"]},{"year":null,"claim":"How INTS6's PP2A-recruitment scaffold integrates its DSB-repair, transcription-termination, developmental, and tumor-suppressor activities into a single mechanistic framework remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the INTS6-PP2A-RNAPII assembly","Whether Wnt and IGF-1 tumor-suppressor effects are direct consequences of Integrator/PP2A activity is unknown","No human disease mutation directly tied to INTS6 in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4]}],"complexes":["Integrator complex","SOSS1 complex"],"partners":["INTS3","INIP","HSSB1","SETX","PP2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UL03","full_name":"Integrator complex subunit 6","aliases":["DBI-1","Protein deleted in cancer 1","DICE1"],"length_aa":887,"mass_kda":100.4,"function":"Component of the integrator complex, a multiprotein complex that terminates RNA polymerase II (Pol II) transcription in the promoter-proximal region of genes (PubMed:33243860, PubMed:34004147, PubMed:39504960). 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 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:34004147, PubMed:38570683, PubMed:39504960). 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). Within the integrator complex, INTS6 acts as a molecular adapter that promotes assembly of protein phosphatase 2A (PP2A) subunits to the integrator core complex, promoting recruitment of PP2A to transcription pause-release checkpoint (PubMed:33243860, PubMed:34004147). Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the integrator complex (PubMed:23904267). May have a tumor suppressor role; an ectopic expression suppressing tumor cell growth (PubMed:15254679, PubMed:16239144)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q9UL03/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/INTS6","classification":"Common Essential","n_dependent_lines":933,"n_total_lines":1208,"dependency_fraction":0.7723509933774835},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"POLR2B","stoichiometry":0.2},{"gene":"POLR2E","stoichiometry":0.2},{"gene":"POLR2F","stoichiometry":0.2},{"gene":"POLR2K","stoichiometry":0.2},{"gene":"PPP2CA","stoichiometry":0.2},{"gene":"SEM1","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"SUPT5H","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/INTS6","total_profiled":1310},"omim":[{"mim_id":"604331","title":"INTEGRATOR COMPLEX SUBUNIT 6; INTS6","url":"https://www.omim.org/entry/604331"},{"mim_id":"600592","title":"MINICHROMOSOME MAINTENANCE COMPLEX COMPONENT 7; MCM7","url":"https://www.omim.org/entry/600592"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INTS6"},"hgnc":{"alias_symbol":["DICE1","HDB","Notchl2","DBI-1","DDX26A","INT6"],"prev_symbol":["DDX26"]},"alphafold":{"accession":"Q9UL03","domains":[{"cath_id":"3.40.50.410","chopping":"2-179_188-228","consensus_level":"high","plddt":90.3695,"start":2,"end":228},{"cath_id":"-","chopping":"234-243_259-440","consensus_level":"high","plddt":91.7326,"start":234,"end":440},{"cath_id":"-","chopping":"815-881","consensus_level":"high","plddt":86.97,"start":815,"end":881}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UL03","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UL03-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UL03-F1-predicted_aligned_error_v6.png","plddt_mean":72.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INTS6","jax_strain_url":"https://www.jax.org/strain/search?query=INTS6"},"sequence":{"accession":"Q9UL03","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UL03.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UL03/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UL03"}},"corpus_meta":[{"pmid":"23280823","id":"PMC_23280823","title":"Targeting of DICE1 tumor suppressor by Epstein-Barr virus-encoded miR-BART3* microRNA in nasopharyngeal carcinoma.","date":"2013","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23280823","citation_count":92,"is_preprint":false},{"pmid":"25686840","id":"PMC_25686840","title":"Pseudogene INTS6P1 regulates its cognate gene INTS6 through competitive binding of miR-17-5p in hepatocellular carcinoma.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25686840","citation_count":60,"is_preprint":false},{"pmid":"10467397","id":"PMC_10467397","title":"Isolation of DICE1: a gene frequently affected by LOH and downregulated in lung carcinomas.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10467397","citation_count":56,"is_preprint":false},{"pmid":"24204286","id":"PMC_24204286","title":"The integrator complex subunit 6 (Ints6) confines the dorsal organizer in vertebrate embryogenesis.","date":"2013","source":"PLoS 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of the INTS3/INTS6 complex revealed that two INTS3c subunits dimerize and interact with INTS6c via conserved residues; INTS3 dimerization is required for recognizing longer ssDNA, and perturbation of INTS3c dimerization or disruption of the INTS3c/INTS6c interaction impairs DSB repair.\",\n      \"method\": \"X-ray crystallography (2.4 Å resolution), biochemical pulldown assays, site-directed mutagenesis, DSB repair functional assays\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and biochemical assays in a single rigorous study\",\n      \"pmids\": [\"34400606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"INTS6 associates with the heterotrimeric SOSS1 complex (INTS3, INIP, hSSB1) to form a tetrameric SOSS1 complex; INTS6 binds DNA:RNA hybrids, promotes PP2A recruitment to DSBs facilitating RNAPII dephosphorylation, prevents accumulation of damage-associated RNA transcripts (DARTs), and interacts with and promotes senataxin (SETX) recruitment to resolve R-loops at DSBs.\",\n      \"method\": \"Co-immunoprecipitation, biochemical binding assays (DNA:RNA hybrid binding), proximity ligation, functional DSB repair assays, RNAPII phosphorylation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, multiple orthogonal biochemical assays, functional rescue, single lab\",\n      \"pmids\": [\"39445827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IntS6 (Integrator subunit 6) over-expression in Drosophila blocks Integrator function at a subset of protein-coding genes (but not snRNAs or other attenuated loci) by titrating PP2A subunits; IntS6 functions analogously to a PP2A regulatory B subunit to modulate transcription termination efficiency at select gene loci.\",\n      \"method\": \"Genetic over-expression in Drosophila, RNA-seq, PP2A subunit interaction assays, epistasis with canonical PP2A B subunits\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple orthogonal methods (over-expression, PP2A interaction, transcriptomics), single lab\",\n      \"pmids\": [\"37995689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"INTS6 deficiency in a conditional mouse KO model disrupts early neurogenesis, cortical lamination, and synaptic development; INTS6 loss alters RNAPII dynamics and disrupts transcriptional regulation of synaptic genes. CDK9 inhibition reduced RNAPII phosphorylation and rescued the neurosphere overproliferation and abnormal dendritic spine phenotype caused by Ints6 deficiency.\",\n      \"method\": \"Conditional KO mouse model, behavioral assays, immunohistochemistry, RNAPII ChIP, neurosphere assays, CDK9 inhibitor rescue experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular and molecular phenotype, pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"40966122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In zebrafish, maternal-effect loss of Ints6 causes de-repression of dorsal organizer genes, failure to maintain BMP ligand expression, failure to fully express vox and ved (Wnt8a mediators), and severe dorsalization with multiple axial domains and ectopic dorsal forerunner cells; restoring BMP signaling or limiting Nodal signaling rescues wild-type patterning, placing Ints6 upstream of the BMP/Nodal/Wnt8a axis in dorsoventral patterning.\",\n      \"method\": \"Forward genetic screen, maternal-effect recessive mutation analysis, epistasis (BMP/Nodal pathway rescue), in situ hybridization, zebrafish embryology\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with pathway rescue experiments, multiple phenotypic and molecular readouts\",\n      \"pmids\": [\"24204286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"DICE1 (INTS6) encodes a protein with a DEAD box motif characteristic of ATP-dependent helicases and contains helicase superfamily II motifs; GFP-fusion experiments showed preferential nuclear localization of the DICE1 protein, and CpG sites flanking a predicted TATA box are hypermethylated in tumor cells with decreased DICE1 expression.\",\n      \"method\": \"GFP-fusion protein live imaging, genomic structure determination, bisulfite sequencing/methylation analysis\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct GFP localization experiment, methylation analysis; single lab, multiple methods\",\n      \"pmids\": [\"11939413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"DBI-1 (INTS6/DICE1) protein localizes to the nucleus and overexpression of DBI-1 in cells containing the wild-type IGF-1 receptor diminishes the mitogenic response to IGF-1.\",\n      \"method\": \"Antibody localization (immunofluorescence), overexpression with IGF-1 mitogenic response assay (thymidine incorporation or growth assay)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, direct localization by antibody and functional overexpression assay\",\n      \"pmids\": [\"9473344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ectopic expression of DICE1 cDNA (as GFP fusion) inhibits colony formation of human NSCLC cell lines (SK-MES-1, NCI-H520) and prostate carcinoma (DU145), and suppresses growth in soft agar of IGF-IR-transformed Balb/c 3T3 cells, demonstrating growth-suppressive activity that interferes with anchorage-independent growth dependent on IGF-I signaling.\",\n      \"method\": \"Stable transfection, colony formation assay, soft-agar anchorage-independent growth assay\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss/gain-of-function with defined cellular phenotype, replicated across multiple cell lines\",\n      \"pmids\": [\"15254679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Exogenous re-expression of INTS6/DICE1 in androgen-independent PC3 and DU145 prostate cancer cells suppresses colony formation and causes G1 phase cell cycle arrest (not immediate apoptosis); expression profiling revealed upregulation of Wnt pathway inhibitors (CXXC4, FZD7, TCF7L1) and downregulation of cyclin D1, linking INTS6 function to Wnt signaling and cell cycle regulation.\",\n      \"method\": \"Ectopic cDNA expression, colony formation assay, flow cytometry cell cycle analysis, gene expression profiling (microarray)\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple orthogonal methods (cell cycle, colony, expression profiling), single lab\",\n      \"pmids\": [\"19906297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Reduced DICE1 (INTS6) expression in prostate cancer cell lines DU145 and LNCaP is associated with hypermethylation of the DICE1 promoter; treatment with the demethylating agent 5-azacytidine restores DICE1 expression, and hypermethylation of DICE1 CpG promoter sites was observed in 4/8 prostate cancers.\",\n      \"method\": \"Bisulfite sequencing, promoter activity luciferase assay, 5-azacytidine demethylation treatment, RT-PCR\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue (demethylation restores expression), promoter activity assays, bisulfite sequencing; single lab\",\n      \"pmids\": [\"16007164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"C. elegans DIC-1 (DICE1/INTS6 homolog) localizes to the inner mitochondrial membrane as cytoplasmic foci, and its RNAi knockdown causes abnormal mitochondrial morphology with internal vesicles, increased ced-3-dependent apoptosis in the germline, and embryonic lethality, demonstrating an essential role in mitochondrial inner membrane/cristae topology.\",\n      \"method\": \"RNA interference, immunofluorescence microscopy, cryoelectron microscopy, genetic epistasis (ced-3 dependence)\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with defined ultrastructural phenotype (cryo-EM), genetic epistasis; C. elegans ortholog, may not reflect mammalian function\",\n      \"pmids\": [\"16914495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Small RNA-induced upregulation of INTS6 in castration-resistant prostate cancer cells suppresses cell proliferation and motility, and this effect is associated with downregulation of Wnt/β-catenin signaling; impairment of β-catenin degradation reverses the tumor suppressive effects of INTS6.\",\n      \"method\": \"Small activating RNA transfection, cell proliferation and motility assays, Western blot for β-catenin pathway components, rescue by β-catenin degradation inhibitor\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain-of-function with epistasis rescue (β-catenin inhibitor), multiple readouts; single lab\",\n      \"pmids\": [\"29895194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Downregulation of INTS6 in colorectal cancer cells induces G1/S-phase cell cycle arrest and suppresses growth, while overexpression promotes growth; mechanistically, INTS6 increases levels of phosphorylated AKT (p-AKT) and ERK (p-ERK), and the growth-promoting effect is blocked by AKT and ERK inhibitors; INTS6 also affects c-Myc and CDK2 expression downstream of PI3K/AKT and MAPK signaling.\",\n      \"method\": \"siRNA knockdown, overexpression, flow cytometry, Western blot (p-AKT, p-ERK, c-Myc, CDK2), kinase inhibitor treatment, xenograft tumor assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss- and gain-of-function with pharmacological epistasis (inhibitor rescue), multiple downstream readouts; single lab\",\n      \"pmids\": [\"34508742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DICE1 (INTS6) is a cellular target of EBV-encoded miR-BART3* miRNA in nasopharyngeal carcinoma; miR-BART3* targets the 3'-UTR of DICE1 mRNA and down-regulates endogenous DICE1 protein; inhibition of miR-BART3* increases DICE1 protein expression; miR-BART3* expression overcomes the growth-suppressive activity of DICE1.\",\n      \"method\": \"3'-UTR luciferase reporter assay, anti-miRNA oligonucleotide inhibition, Western blot, colony formation assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct target site identification and functional validation with multiple orthogonal methods; single lab\",\n      \"pmids\": [\"23280823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"INTS6 and its pseudogene INTS6P1 compete for binding of oncomiR-17-5p; INTS6P1 acts as a competing endogenous RNA (ceRNA) to protect INTS6 mRNA from miR-17-5p-mediated repression, and both INTS6 and INTS6P1 exert tumor-suppressive roles in hepatocellular carcinoma through this regulatory circuit.\",\n      \"method\": \"Luciferase reporter assay (miRNA target site), overexpression and knockdown functional assays (growth curves, cell death, migration, in vivo xenograft), microarray expression analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple orthogonal functional assays with miRNA target validation; single lab\",\n      \"pmids\": [\"25686840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In C. elegans, INTS-6 is necessary for RAD-51 foci formation after X-ray radiation, and CDK-1 Tyr-15 phosphorylation depends on the presence of INTS-6, demonstrating a role for INTS-6 in the DNA damage response.\",\n      \"method\": \"RNAi knockdown, immunofluorescence (RAD-51 foci), Western blot (CDK-1 pY15), X-ray irradiation\",\n      \"journal\": \"microPublication biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single-method per endpoint, C. elegans ortholog\",\n      \"pmids\": [\"39575199\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTS6 is a subunit of the Integrator complex that functions as a scaffold bridging INTS3/SOSS1 to recruit PP2A to RNA Pol II at DNA double-strand breaks, facilitating RNAPII dephosphorylation and R-loop resolution via senataxin; it also tunes Integrator-dependent premature transcription termination at a subset of protein-coding genes by modulating PP2A phosphatase module activity, regulates early neurogenesis and synaptic development through RNAPII transcriptional dynamics, and acts as a tumor suppressor in multiple cancer types by promoting G1 cell cycle arrest and modulating Wnt/β-catenin and IGF-1 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INTS6 is a subunit of the Integrator complex that couples RNA polymerase II transcriptional control to genome maintenance by directing the PP2A phosphatase module to chromatin [#1, #2]. Crystallographic and biochemical analysis shows that INTS6 binds INTS3, with two INTS3 protomers dimerizing to engage INTS6 through conserved residues required for double-strand break (DSB) repair [#0]. At DSBs, INTS6 joins the heterotrimeric SOSS1 complex (INTS3, INIP, hSSB1) to form a tetrameric assembly, binds DNA:RNA hybrids, promotes PP2A-mediated dephosphorylation of RNAPII, prevents accumulation of damage-associated RNA transcripts, and recruits senataxin to resolve R-loops [#1]. The same PP2A-tuning activity governs Integrator-dependent transcription: INTS6 behaves analogously to a PP2A regulatory B subunit, and its overexpression titrates PP2A to modulate premature transcription termination at a subset of protein-coding genes [#2]. Through these effects on RNAPII dynamics, INTS6 controls early neurogenesis, cortical lamination, and synaptic development, with the underlying RNAPII hyperphosphorylation and overproliferation phenotypes reversible by CDK9 inhibition [#3], and it acts upstream of the BMP/Nodal/Wnt8a axis in vertebrate dorsoventral patterning [#4]. INTS6 additionally functions as a frequently silenced tumor suppressor: its re-expression induces G1 arrest and suppresses colony formation across prostate, lung, colorectal, and liver cancer models, in part by upregulating Wnt-pathway inhibitors and downregulating cyclin D1 [#8, #11, #7], while its promoter is hypermethylated and its transcript is repressed by EBV miR-BART3* and oncomiR-17-5p in various malignancies [#9, #13, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the first functional handle on the gene by showing its product is nuclear and antagonizes growth-factor mitogenic signaling, framing it as a candidate growth suppressor.\",\n      \"evidence\": \"Antibody immunofluorescence and IGF-1 mitogenic response assay after overexpression\",\n      \"pmids\": [\"9473344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism linking the protein to IGF-1R signaling\", \"No link to transcription or the Integrator complex yet\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the gene structure and a DEAD-box/helicase superfamily II motif and nuclear localization, while implicating promoter CpG hypermethylation in its silencing in tumors.\",\n      \"evidence\": \"GFP-fusion live imaging, genomic structure determination, bisulfite methylation analysis\",\n      \"pmids\": [\"11939413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Predicted helicase activity never demonstrated biochemically\", \"Did not establish a transcriptional or DSB function\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that promoter hypermethylation causally silences the gene in prostate cancer, since demethylation restores expression, supporting an epigenetically inactivated tumor suppressor.\",\n      \"evidence\": \"Bisulfite sequencing, promoter luciferase assays, 5-azacytidine demethylation in DU145/LNCaP cells\",\n      \"pmids\": [\"16007164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the downstream effector pathway of suppression\", \"Limited primary-tumor sample number\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed an unexpected mitochondrial role in the worm ortholog, where loss disrupts inner-membrane topology and triggers apoptosis, raising the question of whether the gene's function is nuclear or organellar.\",\n      \"evidence\": \"RNAi, immunofluorescence, cryo-EM, ced-3 epistasis in C. elegans\",\n      \"pmids\": [\"16914495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial localization not confirmed for the mammalian protein\", \"Relationship between mitochondrial and later nuclear/transcriptional roles unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected the suppressor activity to a defined cellular program—G1 arrest with Wnt-inhibitor upregulation and cyclin D1 loss—providing the first pathway-level mechanism.\",\n      \"evidence\": \"Ectopic expression, cell cycle flow cytometry, colony formation, microarray profiling in PC3/DU145\",\n      \"pmids\": [\"19906297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative expression changes, not shown to be direct targets\", \"Did not link Wnt regulation to a transcription-termination mechanism\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that the gene is targeted for repression by viral and cellular regulators and that it operates upstream of a developmental signaling axis, broadening its biological reach.\",\n      \"evidence\": \"EBV miR-BART3* 3'-UTR reporter assays in nasopharyngeal carcinoma; zebrafish maternal-effect mutant epistasis on BMP/Nodal/Wnt8a\",\n      \"pmids\": [\"23280823\", \"24204286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the gene controls the BMP/Nodal/Wnt8a axis not defined\", \"Whether developmental and tumor-suppressor functions share a mechanism unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a ceRNA circuit in which a pseudogene protects the transcript from oncomiR-17-5p, adding a post-transcriptional layer to tumor suppression in liver cancer.\",\n      \"evidence\": \"Luciferase miRNA-target assays, overexpression/knockdown, xenografts in HCC\",\n      \"pmids\": [\"25686840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not connect transcript regulation to protein-level mechanism\", \"ceRNA stoichiometry in vivo not quantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Pinned tumor suppression mechanistically on Wnt/\\u03b2-catenin, since blocking \\u03b2-catenin degradation reverses the growth-suppressive effect.\",\n      \"evidence\": \"Small activating RNA, proliferation/motility assays, \\u03b2-catenin pathway Western blots and rescue in CRPC cells\",\n      \"pmids\": [\"29895194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between the protein and \\u03b2-catenin stability not shown\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reframed the gene's biochemistry by solving the INTS3/INTS6 structure, establishing it as an Integrator subunit whose INTS3-dimer interface is required for DSB repair.\",\n      \"evidence\": \"2.4 \\u00c5 crystal structure, pulldowns, mutagenesis, DSB repair assays; plus colorectal cancer loss/gain-of-function with PI3K/AKT-MAPK epistasis\",\n      \"pmids\": [\"34400606\", \"34508742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure did not show how PP2A is engaged\", \"Reconciliation of helicase-motif annotation with structural role unaddressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the gene as a PP2A-regulatory-B-subunit-like factor that tunes Integrator-dependent transcription termination at select protein-coding genes by titrating PP2A.\",\n      \"evidence\": \"Drosophila overexpression, RNA-seq, PP2A interaction assays, epistasis with canonical PP2A B subunits\",\n      \"pmids\": [\"37995689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Gene-selectivity determinants of which loci are affected not defined\", \"Direct structural basis of PP2A engagement not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Unified the DSB and transcription roles, showing the protein assembles into tetrameric SOSS1, binds DNA:RNA hybrids, drives PP2A-mediated RNAPII dephosphorylation, and recruits senataxin to clear R-loops at breaks.\",\n      \"evidence\": \"Reciprocal Co-IP, DNA:RNA hybrid binding, proximity ligation, RNAPII phosphorylation and DSB repair assays; plus C. elegans DNA-damage-response RAD-51/CDK-1 data\",\n      \"pmids\": [\"39445827\", \"39575199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of PP2A handoff between SOSS1 and chromatin not resolved\", \"C. elegans DDR finding is single-method per endpoint and not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a physiological requirement in mammalian brain development, where loss disrupts neurogenesis and synaptic gene transcription via altered RNAPII dynamics, rescuable by CDK9 inhibition.\",\n      \"evidence\": \"Conditional KO mouse, IHC, RNAPII ChIP, neurosphere assays, CDK9 inhibitor rescue, behavior\",\n      \"pmids\": [\"40966122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which synaptic-gene targets are directly Integrator-controlled not fully defined\", \"Link between neurodevelopmental phenotype and human disease not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How INTS6's PP2A-recruitment scaffold integrates its DSB-repair, transcription-termination, developmental, and tumor-suppressor activities into a single mechanistic framework remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the INTS6-PP2A-RNAPII assembly\", \"Whether Wnt and IGF-1 tumor-suppressor effects are direct consequences of Integrator/PP2A activity is unknown\", \"No human disease mutation directly tied to INTS6 in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\n      \"Integrator complex\",\n      \"SOSS1 complex\"\n    ],\n    \"partners\": [\n      \"INTS3\",\n      \"INIP\",\n      \"hSSB1\",\n      \"SETX\",\n      \"PP2A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}