{"gene":"SNAPC4","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":1998,"finding":"SNAP190 (SNAPC4) contains an unusual Myb DNA binding domain consisting of four complete repeats (Ra–Rd) and a half repeat (Rh); a truncated protein with only the last two Myb repeats (Rc and Rd) can bind to the PSE, indicating the Myb domain directly contributes to PSE recognition by the SNAP complex.","method":"cDNA cloning, truncation mutagenesis, and DNA binding assays in vitro","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro DNA-binding assay with defined truncation mutants, replicated across multiple subunit combinations in a focused mechanistic study","pmids":["9418884"],"is_preprint":false},{"year":1998,"finding":"SNAP190 (SNAPC4) is required for snRNA gene transcription by both RNA polymerase II and III and interacts directly with SNAP45, establishing its role as an essential scaffold subunit of SNAPc.","method":"Co-immunoprecipitation, transcription reconstitution assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interactions and functional transcription reconstitution demonstrated, replicated in subsequent reconstitution studies","pmids":["9418884"],"is_preprint":false},{"year":1998,"finding":"SNAP190 (SNAPC4) directly interacts with Oct-1, and this interaction mediates cooperative binding of SNAPc to the PSE; a switched-specificity SNAP190 mutant that interacts with Oct-1 POU E7R but not wild-type Oct-1 POU demonstrates the interaction is a direct protein–protein contact that results in transcriptional activation.","method":"In vitro binding assays, switched-specificity mutagenesis, transcription activation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct protein–protein interaction confirmed by switched-specificity mutagenesis, functional consequence shown by transcription assay, two independent papers","pmids":["9418884","9832505"],"is_preprint":false},{"year":1998,"finding":"A functional five-subunit recombinant SNAPc (SNAP43, SNAP45, SNAP50, SNAP190, and newly identified SNAP19) can be reconstituted from recombinant proteins; this complex binds specifically to the PSE and directs both RNA polymerase II and III snRNA gene transcription, establishing that the same core SNAPc nucleates both initiation complexes.","method":"Recombinant protein reconstitution, PSE DNA binding assay, in vitro transcription","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — full reconstitution from defined recombinant subunits with functional transcription output","pmids":["9732265"],"is_preprint":false},{"year":2000,"finding":"Detailed subunit–subunit interaction mapping within SNAPc showed that SNAP190 (SNAPC4) makes direct contacts with SNAP43 and SNAP45, and complexes containing little more than these interaction domains retain specific PSE binding, defining the minimal architecture required for DNA recognition.","method":"Deletion/truncation mutagenesis, co-immunoprecipitation, PSE binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic domain mapping with multiple truncation constructs and binding readouts","pmids":["11056176"],"is_preprint":false},{"year":2002,"finding":"X-ray crystal structure of the Oct-1 POU domain/U1 octamer/SNAP190 peptide ternary complex revealed that the SNAP190 peptide (residues 884–910) makes extensive contacts with the Oct-1 POU-specific domain and with the DNA phosphate backbone, and that this interface is distinct from that used by OCA-B.","method":"X-ray crystallography at 2.3 Å resolution","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution crystal structure with functional context from binding assays in the same study","pmids":["12414730"],"is_preprint":false},{"year":2002,"finding":"A 50-amino-acid region within the N-terminal third of SNAP190 (SNAPC4) is required for cooperative binding with TBP in the context of mini-SNAPc and is sufficient for TBP cooperative binding when fused to a heterologous DNA binding domain, identifying this region as a TBP recruitment determinant in U6 transcription.","method":"Deletion mutagenesis, TBP recruitment assay, in vitro transcription","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — domain sufficiency shown by heterologous fusion, functional transcription output included","pmids":["12391172"],"is_preprint":false},{"year":2003,"finding":"The SNAP190 Myb DNA binding domain directly interacts with the TBP DNA binding domain and is sufficient for recruiting TBP to the U6 TATA box; SNAP190 Myb domain also stimulates assembly of TBP–Brf2 complex, thereby facilitating RNA polymerase III preinitiation complex assembly.","method":"TBP recruitment assays, co-immunoprecipitation, in vitro transcription with truncated SNAP190 constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined truncations, multiple functional readouts","pmids":["12621023"],"is_preprint":false},{"year":2007,"finding":"Protein kinase CK2 phosphorylates the N-terminal half of SNAP190 (SNAPC4) at two regions (amino acids 20–63 and 514–545), and this phosphorylation inhibits SNAPc DNA binding and U6 transcription activity through allosteric inhibition of the SNAP190 Myb DNA binding domain.","method":"In vitro kinase assay, site-directed mutagenesis of CK2 consensus sites, SNAPc DNA binding assay, in vitro transcription","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation with mutagenesis and functional transcription/DNA-binding readouts","pmids":["17670747"],"is_preprint":false},{"year":2008,"finding":"Down-regulation of SNAP190 (SNAPC4), distinct from SNAP45, leads to an accumulation of cells with G0/G1 DNA content, indicating SNAP190 is specifically required for cell cycle progression at G1 rather than mitosis.","method":"siRNA knockdown, flow cytometry cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean knockdown with specific cell-cycle phenotype, single lab, single method","pmids":["18356157"],"is_preprint":false},{"year":2012,"finding":"In zebrafish, the snapc4(s445) mutation truncates the C-terminus of Snapc4, deleting the domain required for interaction with Snapc2 (a vertebrate-specific SNAPc subunit); this hypomorphic allele alters expression of a subset of snRNAs and causes apoptosis of biliary epithelial cells and loss of the intrahepatic biliary network.","method":"Forward genetic screen, whole-genome sequencing, loss-of-function zebrafish mutant analysis, apoptosis assay, snRNA expression profiling","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with molecular (snRNA expression) and cellular (apoptosis/biliary network) phenotypes, domain-deletion mechanism specified","pmids":["22222761"],"is_preprint":false},{"year":2012,"finding":"Chromatin immunoprecipitation sequencing showed that SNAPC4 occupancy is limited to snRNA gene loci genome-wide, whereas SNAPC1 occupancy extends broadly to protein-coding genes, establishing that SNAPC4 function is restricted to snRNA promoters in vivo.","method":"ChIP-seq with SNAPC4 and SNAPC1 antibodies","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genome-wide ChIP-seq, single lab, defining localization with functional implication","pmids":["22966203"],"is_preprint":false},{"year":2012,"finding":"In zebrafish, a loss-of-function nonsense mutation in snapc4 causes severe hypoplasia of the exocrine pancreas; morpholino knockdown confirmed that loss of snapc4 is causally responsible for this phenotype.","method":"Whole-genome sequencing for mutation identification, morpholino knockdown in zebrafish","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combined mutant + morpholino knockdown in zebrafish, two independent loss-of-function approaches","pmids":["22496837"],"is_preprint":false},{"year":2012,"finding":"Drosophila melanogaster SNAP190 Myb repeats were mapped by site-specific protein–DNA photo-cross-linking to specific nucleotides of the U1 snRNA gene PSE, revealing the topological arrangement of all 4.5 Myb repeats on DNA and showing that multiple repeats contact DNA simultaneously.","method":"Site-specific protein–DNA photo-cross-linking assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct structural mapping by photo-cross-linking, single lab, Drosophila ortholog","pmids":["23038247"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of human SNAPc (N-terminal domain of SNAP190/SNAPC4, SNAP50, and SNAP43) bound to the U6-1 PSE at 3.49 Å resolution revealed a 'wrap-around' DNA binding mode; the SNAP190 Myb domain cooperates with three SNAP50 motifs to recognize both major and minor grooves of the PSE, explaining PSE sequence conservation.","method":"Cryo-electron microscopy structure determination at 3.49 Å","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — near-atomic cryo-EM structure with functional validation of interaction motifs, single study but high-resolution structural data","pmids":["36369505"],"is_preprint":false},{"year":2023,"finding":"Bi-allelic loss-of-function variants in SNAPC4 in human patients reduce SNAPC4 protein abundance, decrease snRNA expression, and cause global dysregulation of alternative splicing; CRISPR-mediated depletion of SNAPC4 in HeLa cells recapitulated decreased snRNA expression and splicing dysregulation, establishing SNAPC4 as essential for normal snRNA-dependent spliceosome function.","method":"Patient fibroblast analysis, CRISPR genomic editing in HeLa cells, snRNA expression profiling, global alternative splicing analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthogonal patient cell and CRISPR cell-line experiments with molecular (snRNA, splicing) readouts, multiple affected families","pmids":["36965478"],"is_preprint":false},{"year":2025,"finding":"SUMOylation-deficient SNAPC1 (2KR mutant) fails to maintain basal snRNA transcription and shows impaired interaction with SNAPC4, despite still being recruited to the PSE, indicating that SNAPC1 SUMOylation is required for its productive interaction with SNAPC4 within the SNAPc complex.","method":"CRISPR/dCas9-SENP1 targeted deSUMOylation, inducible degron depletion of endogenous SNAPC1, SUMOylation-deficient mutant rescue, co-immunoprecipitation of tagged SNAPC3 and SNAPC4, snRNA expression assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal tools (degron, CRISPR deSUMOylation, mutant rescue, Co-IP), single lab, 2025 paper not yet replicated","pmids":["40956881"],"is_preprint":false}],"current_model":"SNAPC4 (SNAP190) is the largest subunit of the five-subunit SNAPc complex; it uses its 4.5-repeat Myb domain to directly recognize the PSE at snRNA promoters (confirmed by crystal/cryo-EM structure and mutagenesis), recruits TBP to the adjacent TATA box via Myb–TBP contacts, interacts directly with the Oct-1 POU domain to cooperatively stimulate snRNA transcription by both RNA polymerases II and III, is negatively regulated by CK2 phosphorylation of its N-terminus (which allosterically inhibits its Myb domain), and is essential in vivo for normal snRNA expression, spliceosome function, and cell cycle G1 progression, with its interaction with SNAPC1 further regulated by SNAPC1 SUMOylation."},"narrative":{"mechanistic_narrative":"SNAPC4 (SNAP190) is the largest subunit and central scaffold of the small nuclear RNA-activating protein complex (SNAPc), the factor that directs transcription of snRNA genes by both RNA polymerase II and III [PMID:9418884, PMID:9732265]. It contains an unusual Myb DNA-binding domain of 4.5 repeats (Ra–Rd plus a half repeat) that directly contacts the proximal sequence element (PSE) of snRNA promoters, with multiple repeats engaging DNA simultaneously [PMID:9418884, PMID:23038247]; in the assembled complex the Myb domain cooperates with SNAP50 motifs in a 'wrap-around' mode that reads both major and minor grooves of the PSE, explaining PSE sequence conservation [PMID:36369505]. As scaffold, SNAPC4 makes direct contacts with SNAP43 and SNAP45 that define the minimal architecture for PSE recognition [PMID:9418884, PMID:11056176]. SNAPC4 nucleates preinitiation complex assembly through several direct partner contacts: a 50-residue N-terminal region and the Myb domain recruit TBP to the adjacent TATA box and stimulate TBP–Brf2 assembly for Pol III initiation [PMID:12391172, PMID:12621023], and a defined peptide (residues 884–910) contacts the Oct-1 POU domain to mediate cooperative SNAPc binding and transcriptional activation [PMID:9418884, PMID:9832505, PMID:12414730]. Its activity is constrained by CK2 phosphorylation of the N-terminal half, which allosterically inhibits the Myb domain and SNAPc DNA binding [PMID:17670747], and its productive incorporation into SNAPc depends on SUMOylation of the partner subunit SNAPC1 [PMID:40956881]. Genome-wide, SNAPC4 occupancy is restricted to snRNA gene loci [PMID:22966203], and the protein is required for snRNA expression, spliceosome function, and G1 cell cycle progression [PMID:18356157, PMID:36965478]. Bi-allelic loss-of-function variants in SNAPC4 reduce snRNA expression and globally dysregulate alternative splicing in patients [PMID:36965478].","teleology":[{"year":1998,"claim":"Established that SNAPC4 is an essential scaffold of SNAPc that both binds the PSE through a novel Myb domain and is required for snRNA transcription by two polymerases.","evidence":"cDNA cloning, truncation mutagenesis and DNA-binding assays plus co-IP and transcription reconstitution in vitro","pmids":["9418884"],"confidence":"High","gaps":["Topology of the 4.5 Myb repeats on DNA not yet resolved","How Pol II versus Pol III specificity is determined was not addressed"]},{"year":1998,"claim":"Showed that SNAPC4 contacts Oct-1 directly to mediate cooperative PSE binding and activation, defining how an enhancer-binding factor couples to the basal snRNA machinery.","evidence":"In vitro binding assays with switched-specificity SNAP190/Oct-1 POU mutants and transcription activation assays","pmids":["9418884","9832505"],"confidence":"High","gaps":["Atomic interface not yet defined","Did not establish whether the contact operates at both Pol II and Pol III promoters"]},{"year":1998,"claim":"Demonstrated that a five-subunit recombinant SNAPc reconstitutes PSE-specific binding and directs both Pol II and Pol III transcription, proving the same core complex nucleates both initiation pathways.","evidence":"Recombinant reconstitution from defined subunits, PSE binding and in vitro transcription","pmids":["9732265"],"confidence":"High","gaps":["Stoichiometry and quaternary arrangement of subunits not resolved","Determinants directing Pol II versus Pol III not identified"]},{"year":2000,"claim":"Mapped the SNAPC4 contacts to SNAP43 and SNAP45 that constitute the minimal architecture required for PSE recognition, framing SNAPC4 as the assembly hub.","evidence":"Deletion/truncation mutagenesis, co-IP and PSE binding assays","pmids":["11056176"],"confidence":"High","gaps":["Structural basis of the minimal complex not determined","Role of SNAP50 in DNA contact not resolved at this stage"]},{"year":2002,"claim":"Resolved how SNAPC4 recruits TBP and Oct-1, identifying distinct N-terminal and peptide determinants for general transcription factor assembly.","evidence":"X-ray crystallography of the Oct-1 POU/octamer/SNAP190 peptide ternary complex and deletion/TBP-recruitment transcription assays","pmids":["12414730","12391172"],"confidence":"High","gaps":["Full-length SNAPC4 architecture not captured","How CK2-regulated regions relate to these determinants not yet linked"]},{"year":2003,"claim":"Showed the SNAPC4 Myb domain itself recruits TBP and stimulates TBP–Brf2 assembly, mechanistically connecting PSE recognition to Pol III preinitiation complex formation.","evidence":"TBP recruitment assays, co-IP and in vitro transcription with truncated SNAP190 constructs","pmids":["12621023"],"confidence":"High","gaps":["Equivalent Pol II PIC bridging not addressed here","Structural model of the Myb–TBP interface not available"]},{"year":2007,"claim":"Identified CK2 phosphorylation of the SNAPC4 N-terminus as a negative regulatory mechanism that allosterically inhibits the Myb DNA-binding domain.","evidence":"In vitro kinase assay, CK2-site mutagenesis, SNAPc DNA-binding and transcription assays","pmids":["17670747"],"confidence":"High","gaps":["In vivo physiological trigger of CK2 regulation not established","Structural basis of the allosteric inhibition not resolved"]},{"year":2008,"claim":"Linked SNAPC4 function to cell proliferation by showing its specific requirement for G1 progression, distinct from SNAP45.","evidence":"siRNA knockdown and flow cytometry cell-cycle analysis","pmids":["18356157"],"confidence":"Medium","gaps":["Single lab, single method","Causal snRNA target driving the G1 arrest not identified"]},{"year":2012,"claim":"Established in vivo that SNAPC4 occupancy is restricted to snRNA loci and that its loss in zebrafish disrupts snRNA expression and tissue development, defining its biological specificity.","evidence":"ChIP-seq in human cells plus forward-genetic and morpholino loss-of-function zebrafish analyses with snRNA profiling and apoptosis/organ phenotypes","pmids":["22966203","22222761","22496837"],"confidence":"Medium","gaps":["Why specific tissues (biliary, exocrine pancreas) are sensitive not mechanistically explained","Differential SNAPC4 versus SNAPC1 genomic targeting basis unresolved"]},{"year":2012,"claim":"Mapped the topological arrangement of all 4.5 Myb repeats on the PSE, showing simultaneous multi-repeat DNA contacts.","evidence":"Site-specific protein–DNA photo-cross-linking of Drosophila SNAP190","pmids":["23038247"],"confidence":"Medium","gaps":["Single lab using an ortholog","Atomic-resolution structure not yet available at this stage"]},{"year":2022,"claim":"Provided a near-atomic structural mechanism showing the SNAPC4 Myb domain cooperates with SNAP50 to wrap around and read both grooves of the PSE.","evidence":"Cryo-EM structure of human SNAPc N-terminal module bound to U6-1 PSE at 3.49 Å","pmids":["36369505"],"confidence":"High","gaps":["Full-length SNAPc with all five subunits not resolved","Structural transition upon TBP/Oct-1/Pol recruitment not captured"]},{"year":2023,"claim":"Established SNAPC4 as a human disease gene by showing bi-allelic loss-of-function variants reduce snRNA and dysregulate global splicing, with CRISPR depletion recapitulating the molecular phenotype.","evidence":"Patient fibroblast analysis and CRISPR editing in HeLa cells with snRNA and alternative splicing profiling across multiple families","pmids":["36965478"],"confidence":"High","gaps":["Genotype–phenotype relationship across affected tissues not fully defined","Which dysregulated splicing events drive pathology not identified"]},{"year":2025,"claim":"Showed that SNAPC1 SUMOylation is required for its productive interaction with SNAPC4, adding a post-translational layer controlling SNAPc assembly and basal snRNA transcription.","evidence":"CRISPR/dCas9-SENP1 deSUMOylation, degron depletion, SUMO-deficient mutant rescue and co-IP of tagged SNAPC3/SNAPC4 with snRNA assays","pmids":["40956881"],"confidence":"Medium","gaps":["Single lab, not yet independently replicated","Whether SNAPC4 itself is SUMO-regulated not addressed"]},{"year":null,"claim":"It remains unresolved how the same SNAPC4-containing core is differentially directed to assemble Pol II versus Pol III preinitiation complexes and how its regulatory phosphorylation and partner SUMOylation are integrated with cell-cycle and developmental signals.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length SNAPC4 within an intact PIC","Signaling inputs controlling CK2/SUMO regulation in vivo unknown","Tissue-specific vulnerability to SNAPC4 loss unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,13,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,3,7]},{"term_id":"GO:0140223","term_label":"general transcription initiation factor activity","supporting_discovery_ids":[6,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[15]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9]}],"complexes":["SNAPc"],"partners":["SNAPC1","SNAPC2","SNAP45","SNAP43","SNAP50","TBP","POU2F1","BRF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5SXM2","full_name":"snRNA-activating protein complex subunit 4","aliases":["Proximal sequence element-binding transcription factor subunit alpha","PSE-binding factor subunit alpha","PTF subunit alpha","snRNA-activating protein complex 190 kDa subunit","SNAPc 190 kDa subunit"],"length_aa":1469,"mass_kda":159.4,"function":"Part of the SNAPc complex required for the transcription of both RNA polymerase II and III small-nuclear RNA genes. Binds to the proximal sequence element (PSE), a non-TATA-box basal promoter element common to these 2 types of genes. Recruits TBP and BRF2 to the U6 snRNA TATA box","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q5SXM2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SNAPC4","classification":"Common Essential","n_dependent_lines":1170,"n_total_lines":1208,"dependency_fraction":0.9685430463576159},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ARFGAP3","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SNAPC4","total_profiled":1310},"omim":[{"mim_id":"620515","title":"NEURODEVELOPMENTAL DISORDER WITH MOTOR REGRESSION, PROGRESSIVE SPASTIC PARAPLEGIA, AND OROMOTOR DYSFUNCTION; NEDRSO","url":"https://www.omim.org/entry/620515"},{"mim_id":"605979","title":"SMALL NUCLEAR RNA-ACTIVATING PROTEIN COMPLEX, POLYPEPTIDE 5; SNAPC5","url":"https://www.omim.org/entry/605979"},{"mim_id":"602777","title":"SMALL NUCLEAR RNA-ACTIVATING PROTEIN COMPLEX, POLYPEPTIDE 4; SNAPC4","url":"https://www.omim.org/entry/602777"},{"mim_id":"600591","title":"SMALL NUCLEAR RNA-ACTIVATING PROTEIN COMPLEX, POLYPEPTIDE 1; SNAPC1","url":"https://www.omim.org/entry/600591"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNAPC4"},"hgnc":{"alias_symbol":["SNAP190","PTFalpha","FLJ13451"],"prev_symbol":[]},"alphafold":{"accession":"Q5SXM2","domains":[{"cath_id":"-","chopping":"171-293","consensus_level":"medium","plddt":82.4293,"start":171,"end":293},{"cath_id":"1.10.10.60","chopping":"402-450","consensus_level":"medium","plddt":86.3188,"start":402,"end":450},{"cath_id":"-","chopping":"1275-1332_1345-1380","consensus_level":"high","plddt":59.3464,"start":1275,"end":1380}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5SXM2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5SXM2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5SXM2-F1-predicted_aligned_error_v6.png","plddt_mean":51.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNAPC4","jax_strain_url":"https://www.jax.org/strain/search?query=SNAPC4"},"sequence":{"accession":"Q5SXM2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5SXM2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5SXM2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5SXM2"}},"corpus_meta":[{"pmid":"9418884","id":"PMC_9418884","title":"The large subunit of basal transcription factor SNAPc is a Myb domain protein that interacts with Oct-1.","date":"1998","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9418884","citation_count":82,"is_preprint":false},{"pmid":"14645506","id":"PMC_14645506","title":"STAT5 and Oct-1 form a stable complex that modulates cyclin D1 expression.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14645506","citation_count":76,"is_preprint":false},{"pmid":"9732265","id":"PMC_9732265","title":"SNAP19 mediates the assembly of a functional core promoter complex (SNAPc) shared by RNA polymerases II and III.","date":"1998","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/9732265","citation_count":73,"is_preprint":false},{"pmid":"20463747","id":"PMC_20463747","title":"Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene.","date":"2010","source":"Genes and 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RNA-activating protein 190 Myb DNA binding domain stimulates TATA box-binding protein-TATA box recognition.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12621023","citation_count":22,"is_preprint":false},{"pmid":"26590821","id":"PMC_26590821","title":"Determination of IL1 R2, ANTXR2, CARD9, and SNAPC4 single nucleotide polymorphisms in Iranian patients with ankylosing spondylitis.","date":"2015","source":"Rheumatology international","url":"https://pubmed.ncbi.nlm.nih.gov/26590821","citation_count":20,"is_preprint":false},{"pmid":"22222761","id":"PMC_22222761","title":"Mutation of zebrafish Snapc4 is associated with loss of the intrahepatic biliary network.","date":"2011","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/22222761","citation_count":18,"is_preprint":false},{"pmid":"24334645","id":"PMC_24334645","title":"Evidence for genetic association of CARD9 and SNAPC4 with ankylosing spondylitis in a Chinese 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Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/11856838","citation_count":1,"is_preprint":false},{"pmid":"40956881","id":"PMC_40956881","title":"SUMO conjugation to promoter-proximal sequence elements-associated proteins impacts on snRNA transcription.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/40956881","citation_count":0,"is_preprint":false},{"pmid":"39022845","id":"PMC_39022845","title":"Multiregion exome sequencing indicates a monoclonal origin of esophageal spindle-cell squamous cell carcinoma.","date":"2024","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39022845","citation_count":0,"is_preprint":false},{"pmid":"40553397","id":"PMC_40553397","title":"UBE3C promotes pancreatic ductal adenocarcinoma progression by catalysing p53 ubiquitination.","date":"2025","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/40553397","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15723,"output_tokens":3847,"usd":0.052437,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11749,"output_tokens":4227,"usd":0.08221,"stage2_stop_reason":"end_turn"},"total_usd":0.134647,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"SNAP190 (SNAPC4) contains an unusual Myb DNA binding domain consisting of four complete repeats (Ra–Rd) and a half repeat (Rh); a truncated protein with only the last two Myb repeats (Rc and Rd) can bind to the PSE, indicating the Myb domain directly contributes to PSE recognition by the SNAP complex.\",\n      \"method\": \"cDNA cloning, truncation mutagenesis, and DNA binding assays in vitro\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro DNA-binding assay with defined truncation mutants, replicated across multiple subunit combinations in a focused mechanistic study\",\n      \"pmids\": [\"9418884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SNAP190 (SNAPC4) is required for snRNA gene transcription by both RNA polymerase II and III and interacts directly with SNAP45, establishing its role as an essential scaffold subunit of SNAPc.\",\n      \"method\": \"Co-immunoprecipitation, transcription reconstitution assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interactions and functional transcription reconstitution demonstrated, replicated in subsequent reconstitution studies\",\n      \"pmids\": [\"9418884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SNAP190 (SNAPC4) directly interacts with Oct-1, and this interaction mediates cooperative binding of SNAPc to the PSE; a switched-specificity SNAP190 mutant that interacts with Oct-1 POU E7R but not wild-type Oct-1 POU demonstrates the interaction is a direct protein–protein contact that results in transcriptional activation.\",\n      \"method\": \"In vitro binding assays, switched-specificity mutagenesis, transcription activation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct protein–protein interaction confirmed by switched-specificity mutagenesis, functional consequence shown by transcription assay, two independent papers\",\n      \"pmids\": [\"9418884\", \"9832505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A functional five-subunit recombinant SNAPc (SNAP43, SNAP45, SNAP50, SNAP190, and newly identified SNAP19) can be reconstituted from recombinant proteins; this complex binds specifically to the PSE and directs both RNA polymerase II and III snRNA gene transcription, establishing that the same core SNAPc nucleates both initiation complexes.\",\n      \"method\": \"Recombinant protein reconstitution, PSE DNA binding assay, in vitro transcription\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full reconstitution from defined recombinant subunits with functional transcription output\",\n      \"pmids\": [\"9732265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Detailed subunit–subunit interaction mapping within SNAPc showed that SNAP190 (SNAPC4) makes direct contacts with SNAP43 and SNAP45, and complexes containing little more than these interaction domains retain specific PSE binding, defining the minimal architecture required for DNA recognition.\",\n      \"method\": \"Deletion/truncation mutagenesis, co-immunoprecipitation, PSE binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic domain mapping with multiple truncation constructs and binding readouts\",\n      \"pmids\": [\"11056176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"X-ray crystal structure of the Oct-1 POU domain/U1 octamer/SNAP190 peptide ternary complex revealed that the SNAP190 peptide (residues 884–910) makes extensive contacts with the Oct-1 POU-specific domain and with the DNA phosphate backbone, and that this interface is distinct from that used by OCA-B.\",\n      \"method\": \"X-ray crystallography at 2.3 Å resolution\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution crystal structure with functional context from binding assays in the same study\",\n      \"pmids\": [\"12414730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A 50-amino-acid region within the N-terminal third of SNAP190 (SNAPC4) is required for cooperative binding with TBP in the context of mini-SNAPc and is sufficient for TBP cooperative binding when fused to a heterologous DNA binding domain, identifying this region as a TBP recruitment determinant in U6 transcription.\",\n      \"method\": \"Deletion mutagenesis, TBP recruitment assay, in vitro transcription\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain sufficiency shown by heterologous fusion, functional transcription output included\",\n      \"pmids\": [\"12391172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The SNAP190 Myb DNA binding domain directly interacts with the TBP DNA binding domain and is sufficient for recruiting TBP to the U6 TATA box; SNAP190 Myb domain also stimulates assembly of TBP–Brf2 complex, thereby facilitating RNA polymerase III preinitiation complex assembly.\",\n      \"method\": \"TBP recruitment assays, co-immunoprecipitation, in vitro transcription with truncated SNAP190 constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined truncations, multiple functional readouts\",\n      \"pmids\": [\"12621023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Protein kinase CK2 phosphorylates the N-terminal half of SNAP190 (SNAPC4) at two regions (amino acids 20–63 and 514–545), and this phosphorylation inhibits SNAPc DNA binding and U6 transcription activity through allosteric inhibition of the SNAP190 Myb DNA binding domain.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis of CK2 consensus sites, SNAPc DNA binding assay, in vitro transcription\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation with mutagenesis and functional transcription/DNA-binding readouts\",\n      \"pmids\": [\"17670747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Down-regulation of SNAP190 (SNAPC4), distinct from SNAP45, leads to an accumulation of cells with G0/G1 DNA content, indicating SNAP190 is specifically required for cell cycle progression at G1 rather than mitosis.\",\n      \"method\": \"siRNA knockdown, flow cytometry cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean knockdown with specific cell-cycle phenotype, single lab, single method\",\n      \"pmids\": [\"18356157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish, the snapc4(s445) mutation truncates the C-terminus of Snapc4, deleting the domain required for interaction with Snapc2 (a vertebrate-specific SNAPc subunit); this hypomorphic allele alters expression of a subset of snRNAs and causes apoptosis of biliary epithelial cells and loss of the intrahepatic biliary network.\",\n      \"method\": \"Forward genetic screen, whole-genome sequencing, loss-of-function zebrafish mutant analysis, apoptosis assay, snRNA expression profiling\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with molecular (snRNA expression) and cellular (apoptosis/biliary network) phenotypes, domain-deletion mechanism specified\",\n      \"pmids\": [\"22222761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Chromatin immunoprecipitation sequencing showed that SNAPC4 occupancy is limited to snRNA gene loci genome-wide, whereas SNAPC1 occupancy extends broadly to protein-coding genes, establishing that SNAPC4 function is restricted to snRNA promoters in vivo.\",\n      \"method\": \"ChIP-seq with SNAPC4 and SNAPC1 antibodies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genome-wide ChIP-seq, single lab, defining localization with functional implication\",\n      \"pmids\": [\"22966203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish, a loss-of-function nonsense mutation in snapc4 causes severe hypoplasia of the exocrine pancreas; morpholino knockdown confirmed that loss of snapc4 is causally responsible for this phenotype.\",\n      \"method\": \"Whole-genome sequencing for mutation identification, morpholino knockdown in zebrafish\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combined mutant + morpholino knockdown in zebrafish, two independent loss-of-function approaches\",\n      \"pmids\": [\"22496837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Drosophila melanogaster SNAP190 Myb repeats were mapped by site-specific protein–DNA photo-cross-linking to specific nucleotides of the U1 snRNA gene PSE, revealing the topological arrangement of all 4.5 Myb repeats on DNA and showing that multiple repeats contact DNA simultaneously.\",\n      \"method\": \"Site-specific protein–DNA photo-cross-linking assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct structural mapping by photo-cross-linking, single lab, Drosophila ortholog\",\n      \"pmids\": [\"23038247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of human SNAPc (N-terminal domain of SNAP190/SNAPC4, SNAP50, and SNAP43) bound to the U6-1 PSE at 3.49 Å resolution revealed a 'wrap-around' DNA binding mode; the SNAP190 Myb domain cooperates with three SNAP50 motifs to recognize both major and minor grooves of the PSE, explaining PSE sequence conservation.\",\n      \"method\": \"Cryo-electron microscopy structure determination at 3.49 Å\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — near-atomic cryo-EM structure with functional validation of interaction motifs, single study but high-resolution structural data\",\n      \"pmids\": [\"36369505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Bi-allelic loss-of-function variants in SNAPC4 in human patients reduce SNAPC4 protein abundance, decrease snRNA expression, and cause global dysregulation of alternative splicing; CRISPR-mediated depletion of SNAPC4 in HeLa cells recapitulated decreased snRNA expression and splicing dysregulation, establishing SNAPC4 as essential for normal snRNA-dependent spliceosome function.\",\n      \"method\": \"Patient fibroblast analysis, CRISPR genomic editing in HeLa cells, snRNA expression profiling, global alternative splicing analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthogonal patient cell and CRISPR cell-line experiments with molecular (snRNA, splicing) readouts, multiple affected families\",\n      \"pmids\": [\"36965478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SUMOylation-deficient SNAPC1 (2KR mutant) fails to maintain basal snRNA transcription and shows impaired interaction with SNAPC4, despite still being recruited to the PSE, indicating that SNAPC1 SUMOylation is required for its productive interaction with SNAPC4 within the SNAPc complex.\",\n      \"method\": \"CRISPR/dCas9-SENP1 targeted deSUMOylation, inducible degron depletion of endogenous SNAPC1, SUMOylation-deficient mutant rescue, co-immunoprecipitation of tagged SNAPC3 and SNAPC4, snRNA expression assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal tools (degron, CRISPR deSUMOylation, mutant rescue, Co-IP), single lab, 2025 paper not yet replicated\",\n      \"pmids\": [\"40956881\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNAPC4 (SNAP190) is the largest subunit of the five-subunit SNAPc complex; it uses its 4.5-repeat Myb domain to directly recognize the PSE at snRNA promoters (confirmed by crystal/cryo-EM structure and mutagenesis), recruits TBP to the adjacent TATA box via Myb–TBP contacts, interacts directly with the Oct-1 POU domain to cooperatively stimulate snRNA transcription by both RNA polymerases II and III, is negatively regulated by CK2 phosphorylation of its N-terminus (which allosterically inhibits its Myb domain), and is essential in vivo for normal snRNA expression, spliceosome function, and cell cycle G1 progression, with its interaction with SNAPC1 further regulated by SNAPC1 SUMOylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNAPC4 (SNAP190) is the largest subunit and central scaffold of the small nuclear RNA-activating protein complex (SNAPc), the factor that directs transcription of snRNA genes by both RNA polymerase II and III [#1, #3]. It contains an unusual Myb DNA-binding domain of 4.5 repeats (Ra–Rd plus a half repeat) that directly contacts the proximal sequence element (PSE) of snRNA promoters, with multiple repeats engaging DNA simultaneously [#0, #13]; in the assembled complex the Myb domain cooperates with SNAP50 motifs in a 'wrap-around' mode that reads both major and minor grooves of the PSE, explaining PSE sequence conservation [#14]. As scaffold, SNAPC4 makes direct contacts with SNAP43 and SNAP45 that define the minimal architecture for PSE recognition [#1, #4]. SNAPC4 nucleates preinitiation complex assembly through several direct partner contacts: a 50-residue N-terminal region and the Myb domain recruit TBP to the adjacent TATA box and stimulate TBP–Brf2 assembly for Pol III initiation [#6, #7], and a defined peptide (residues 884–910) contacts the Oct-1 POU domain to mediate cooperative SNAPc binding and transcriptional activation [#2, #5]. Its activity is constrained by CK2 phosphorylation of the N-terminal half, which allosterically inhibits the Myb domain and SNAPc DNA binding [#8], and its productive incorporation into SNAPc depends on SUMOylation of the partner subunit SNAPC1 [#16]. Genome-wide, SNAPC4 occupancy is restricted to snRNA gene loci [#11], and the protein is required for snRNA expression, spliceosome function, and G1 cell cycle progression [#9, #15]. Bi-allelic loss-of-function variants in SNAPC4 reduce snRNA expression and globally dysregulate alternative splicing in patients [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that SNAPC4 is an essential scaffold of SNAPc that both binds the PSE through a novel Myb domain and is required for snRNA transcription by two polymerases.\",\n      \"evidence\": \"cDNA cloning, truncation mutagenesis and DNA-binding assays plus co-IP and transcription reconstitution in vitro\",\n      \"pmids\": [\"9418884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Topology of the 4.5 Myb repeats on DNA not yet resolved\", \"How Pol II versus Pol III specificity is determined was not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed that SNAPC4 contacts Oct-1 directly to mediate cooperative PSE binding and activation, defining how an enhancer-binding factor couples to the basal snRNA machinery.\",\n      \"evidence\": \"In vitro binding assays with switched-specificity SNAP190/Oct-1 POU mutants and transcription activation assays\",\n      \"pmids\": [\"9418884\", \"9832505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic interface not yet defined\", \"Did not establish whether the contact operates at both Pol II and Pol III promoters\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated that a five-subunit recombinant SNAPc reconstitutes PSE-specific binding and directs both Pol II and Pol III transcription, proving the same core complex nucleates both initiation pathways.\",\n      \"evidence\": \"Recombinant reconstitution from defined subunits, PSE binding and in vitro transcription\",\n      \"pmids\": [\"9732265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and quaternary arrangement of subunits not resolved\", \"Determinants directing Pol II versus Pol III not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapped the SNAPC4 contacts to SNAP43 and SNAP45 that constitute the minimal architecture required for PSE recognition, framing SNAPC4 as the assembly hub.\",\n      \"evidence\": \"Deletion/truncation mutagenesis, co-IP and PSE binding assays\",\n      \"pmids\": [\"11056176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the minimal complex not determined\", \"Role of SNAP50 in DNA contact not resolved at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved how SNAPC4 recruits TBP and Oct-1, identifying distinct N-terminal and peptide determinants for general transcription factor assembly.\",\n      \"evidence\": \"X-ray crystallography of the Oct-1 POU/octamer/SNAP190 peptide ternary complex and deletion/TBP-recruitment transcription assays\",\n      \"pmids\": [\"12414730\", \"12391172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length SNAPC4 architecture not captured\", \"How CK2-regulated regions relate to these determinants not yet linked\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed the SNAPC4 Myb domain itself recruits TBP and stimulates TBP–Brf2 assembly, mechanistically connecting PSE recognition to Pol III preinitiation complex formation.\",\n      \"evidence\": \"TBP recruitment assays, co-IP and in vitro transcription with truncated SNAP190 constructs\",\n      \"pmids\": [\"12621023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Equivalent Pol II PIC bridging not addressed here\", \"Structural model of the Myb–TBP interface not available\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified CK2 phosphorylation of the SNAPC4 N-terminus as a negative regulatory mechanism that allosterically inhibits the Myb DNA-binding domain.\",\n      \"evidence\": \"In vitro kinase assay, CK2-site mutagenesis, SNAPc DNA-binding and transcription assays\",\n      \"pmids\": [\"17670747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological trigger of CK2 regulation not established\", \"Structural basis of the allosteric inhibition not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked SNAPC4 function to cell proliferation by showing its specific requirement for G1 progression, distinct from SNAP45.\",\n      \"evidence\": \"siRNA knockdown and flow cytometry cell-cycle analysis\",\n      \"pmids\": [\"18356157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single method\", \"Causal snRNA target driving the G1 arrest not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established in vivo that SNAPC4 occupancy is restricted to snRNA loci and that its loss in zebrafish disrupts snRNA expression and tissue development, defining its biological specificity.\",\n      \"evidence\": \"ChIP-seq in human cells plus forward-genetic and morpholino loss-of-function zebrafish analyses with snRNA profiling and apoptosis/organ phenotypes\",\n      \"pmids\": [\"22966203\", \"22222761\", \"22496837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why specific tissues (biliary, exocrine pancreas) are sensitive not mechanistically explained\", \"Differential SNAPC4 versus SNAPC1 genomic targeting basis unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped the topological arrangement of all 4.5 Myb repeats on the PSE, showing simultaneous multi-repeat DNA contacts.\",\n      \"evidence\": \"Site-specific protein–DNA photo-cross-linking of Drosophila SNAP190\",\n      \"pmids\": [\"23038247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab using an ortholog\", \"Atomic-resolution structure not yet available at this stage\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a near-atomic structural mechanism showing the SNAPC4 Myb domain cooperates with SNAP50 to wrap around and read both grooves of the PSE.\",\n      \"evidence\": \"Cryo-EM structure of human SNAPc N-terminal module bound to U6-1 PSE at 3.49 Å\",\n      \"pmids\": [\"36369505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length SNAPc with all five subunits not resolved\", \"Structural transition upon TBP/Oct-1/Pol recruitment not captured\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established SNAPC4 as a human disease gene by showing bi-allelic loss-of-function variants reduce snRNA and dysregulate global splicing, with CRISPR depletion recapitulating the molecular phenotype.\",\n      \"evidence\": \"Patient fibroblast analysis and CRISPR editing in HeLa cells with snRNA and alternative splicing profiling across multiple families\",\n      \"pmids\": [\"36965478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype–phenotype relationship across affected tissues not fully defined\", \"Which dysregulated splicing events drive pathology not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that SNAPC1 SUMOylation is required for its productive interaction with SNAPC4, adding a post-translational layer controlling SNAPc assembly and basal snRNA transcription.\",\n      \"evidence\": \"CRISPR/dCas9-SENP1 deSUMOylation, degron depletion, SUMO-deficient mutant rescue and co-IP of tagged SNAPC3/SNAPC4 with snRNA assays\",\n      \"pmids\": [\"40956881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not yet independently replicated\", \"Whether SNAPC4 itself is SUMO-regulated not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the same SNAPC4-containing core is differentially directed to assemble Pol II versus Pol III preinitiation complexes and how its regulatory phosphorylation and partner SUMOylation are integrated with cell-cycle and developmental signals.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full-length SNAPC4 within an intact PIC\", \"Signaling inputs controlling CK2/SUMO regulation in vivo unknown\", \"Tissue-specific vulnerability to SNAPC4 loss unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 13, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 3, 7]},\n      {\"term_id\": \"GO:0140223\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\"SNAPc\"],\n    \"partners\": [\"SNAPC1\", \"SNAPC2\", \"SNAP45\", \"SNAP43\", \"SNAP50\", \"TBP\", \"POU2F1\", \"BRF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}