{"gene":"SNAPC4","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":1998,"finding":"SNAP190 (SNAPC4) is the largest subunit of SNAPc and contains an unusual Myb DNA-binding domain with four complete repeats (Ra–Rd) and a half repeat (Rh); a truncated protein with only repeats Rc and Rd can bind the PSE, demonstrating that the SNAP190 Myb domain directly contacts the PSE. SNAP190 also interacts with SNAP45 and with Oct-1.","method":"cDNA cloning, recombinant protein PSE-binding assay, protein–protein interaction assays (co-immunoprecipitation/pulldown)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (DNA-binding assays, interaction assays, transcription reconstitution) in foundational paper","pmids":["9418884"],"is_preprint":false},{"year":1998,"finding":"SNAPc can be reconstituted from five recombinant subunits (SNAP43, SNAP45, SNAP50, SNAP190, and the newly identified SNAP19) to form a complex that binds specifically to the PSE and directs both RNA polymerase II and III snRNA gene transcription, establishing SNAP190 as an essential core component.","method":"Recombinant protein co-expression and reconstitution, PSE-binding assay, in vitro transcription","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — full reconstitution of complex with functional validation of transcription","pmids":["9732265"],"is_preprint":false},{"year":1998,"finding":"The Oct-1 POU domain directly contacts a specific small region of SNAP190 (SNAPC4) to cooperatively recruit SNAPc to the PSE and activate snRNA transcription; a switched-specificity SNAP190 mutant that interacts with Oct-1 POU E7R but not wild-type Oct-1 POU confirmed the direct protein–protein contact. The SNAP190 interacting region is similar to the OBF-1/OCA-B Oct-1 coactivator region.","method":"Protein–protein interaction assay, switched-specificity mutagenesis, in vitro transcription","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with switched-specificity control plus functional transcription assay","pmids":["9832505"],"is_preprint":false},{"year":2000,"finding":"A detailed map of subunit–subunit contacts within SNAPc was established: SNAP190 (SNAPC4) directly contacts SNAP45 and SNAP43; specific domains required for each pairwise contact were defined, and complexes containing only these minimal interaction domains retain specific PSE-binding activity.","method":"Deletion mapping, pulldown/co-immunoprecipitation, PSE-binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — systematic deletion mapping with multiple interaction pairs validated by PSE binding","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 protein contacts with the Oct-1 POU-specific domain and with DNA phosphate backbone within the enhancer, mechanistically explaining cooperative recruitment of SNAPc by Oct-1.","method":"X-ray crystallography (2.3 Å resolution)","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution crystal structure with functional context","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 at the U6 promoter as part of mini-SNAPc (SNAP43 + SNAP50 + N-terminal SNAP190); loss of this region can be compensated by TBP recruitment through Brf2, revealing redundant mechanisms for TBP recruitment to the U6 initiation complex.","method":"Truncation/mutagenesis analysis, cooperative DNA-binding assay, in vitro U6 transcription","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — domain dissection with in vitro transcription functional readout","pmids":["12391172"],"is_preprint":false},{"year":2003,"finding":"The SNAP190 (SNAPC4) Myb DNA-binding domain directly interacts with the TBP DNA-binding domain; truncated SNAP190 containing only the Myb domain is sufficient to recruit TBP to the U6 TATA box and to stimulate assembly with Brf2, defining a role for the Myb domain in RNA Pol III pre-initiation complex assembly at juxtaposed promoter elements.","method":"TBP recruitment assay, pulldown interaction assay, in vitro transcription","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — direct interaction assay plus functional transcription reconstitution with domain-sufficient truncation","pmids":["12621023"],"is_preprint":false},{"year":2006,"finding":"A partial SNAPc containing SNAP190 (residues 1–505), SNAP50, SNAP43, and SNAP19, co-expressed in E. coli, binds PSE specifically, recruits TBP to U6 promoter DNA, and supports reconstituted transcription of U1 and U6 snRNA genes by RNA Pol II and III respectively, confirming SNAP190 as the PSE-recognizing scaffold of the functional complex.","method":"Recombinant co-expression in E. coli, PSE-binding assay, TBP recruitment assay, in vitro transcription","journal":"Protein expression and purification","confidence":"High","confidence_rationale":"Tier 1 — biochemical reconstitution with dual-polymerase functional validation","pmids":["16603380"],"is_preprint":false},{"year":2007,"finding":"CK2 phosphorylates the N-terminal half of SNAP190 (SNAPC4) at two regions (amino acids 20–63 and 514–545) containing multiple CK2 consensus sites; this phosphorylation inhibits SNAPc DNA binding and U6 transcription activity, and mutational analyses support an allosteric inhibition of the SNAP190 Myb DNA-binding domain as the mechanism.","method":"In vitro kinase assay, phosphorylation site mapping, mutagenesis, DNA-binding assay, in vitro U6 transcription","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay + mutagenesis + functional transcription assay","pmids":["17670747"],"is_preprint":false},{"year":2008,"finding":"Down-regulation of SNAP190 (SNAPC4) by RNAi leads to accumulation of cells with G0/G1 DNA content, whereas down-regulation of SNAP45 causes G2/M arrest, indicating distinct cell-cycle roles for different SNAPc subunits; SNAP190 depletion phenotype is consistent with its role in driving snRNA transcription needed for S-phase entry.","method":"RNAi knockdown, flow cytometry cell-cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — clean KO with defined cell-cycle phenotype, single lab","pmids":["18356157"],"is_preprint":false},{"year":2012,"finding":"ChIP-seq with anti-SNAPC4 antibody showed that SNAPC4 occupancy is limited to snRNA gene loci genome-wide, while SNAPC1 extends to protein-coding genes, establishing SNAPC4 as an snRNA-gene-specific component of SNAPc in chromatin.","method":"Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq)","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide ChIP-seq localization with functional context, single lab","pmids":["22966203"],"is_preprint":false},{"year":2012,"finding":"Site-specific protein–DNA photo-cross-linking mapped the topological arrangement of all 4.5 Myb repeats of Drosophila SNAP190 (ortholog of SNAPC4) on a U1 snRNA gene PSE, showing each repeat contacts the DNA and revealing their spatial organization within the SNAPc–DNA complex.","method":"Site-specific protein–DNA photo-cross-linking assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct structural mapping with residue-level resolution in the orthologous protein","pmids":["23038247"],"is_preprint":false},{"year":2011,"finding":"In zebrafish, a truncating mutation in snapc4 that deletes the C-terminal domain responsible for interaction with Snapc2 (a vertebrate-specific SNAPc subunit) causes apoptosis of biliary epithelial cells and loss of the intrahepatic biliary network; snapc2 knockdown phenocopies this, and the mutant shows altered expression of a subset of snRNAs, linking the Snapc4–Snapc2 physical interaction to snRNA transcription and biliary cell survival.","method":"Zebrafish forward genetic screen, morpholino knockdown, co-immunoprecipitation (interaction domain mapping), snRNA quantification, apoptosis assay","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — genetic mutant + domain deletion + knockdown epistasis + molecular phenotype","pmids":["22222761"],"is_preprint":false},{"year":2012,"finding":"Whole-genome sequencing of a zebrafish ENU mutant (m1045) identified a nonsense mutation in snapc4; morpholino knockdown confirmed that loss of Snapc4 causes severe exocrine pancreas hypoplasia, establishing a developmental requirement for Snapc4 in exocrine pancreatic organogenesis.","method":"Whole-genome sequencing, homozygosity mapping, morpholino knockdown, histology","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — genetic identification plus morpholino rescue/phenocopy, single study","pmids":["22496837"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of human SNAPc (N-terminal domain of SNAP190/SNAPC4, SNAP50, and SNAP43) in complex with the U6-1 PSE at 3.49 Å revealed a 'wrap-around' DNA-binding mode; three SNAP50 motifs contact both major and minor grooves of the PSE in coordination with the SNAP190 Myb domain, explaining PSE sequence conservation and SNAPc assembly.","method":"Cryo-electron microscopy structure determination (3.49 Å overall resolution)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — near-atomic cryo-EM structure with mechanistic interpretation of DNA recognition","pmids":["36369505"],"is_preprint":false},{"year":2023,"finding":"Bi-allelic deleterious SNAPC4 variants in humans reduce SNAPC4 protein abundance, decrease snRNA expression levels, and cause global dysregulation of alternative splicing (shown in patient fibroblasts and CRISPR-depleted HeLa cells), leading to neuroregression and progressive spastic paraparesis.","method":"Human genetic analysis, CRISPR genomic editing/depletion in HeLa cells, snRNA quantification (RT-qPCR), transcriptome-wide splicing analysis in patient fibroblasts","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — patient genetics corroborated by CRISPR depletion with orthogonal molecular phenotypes (snRNA and splicing)","pmids":["36965478"],"is_preprint":false},{"year":2025,"finding":"SUMOylation-deficient SNAPC1 (2KR mutant) retains interaction with SNAPC3 but has impaired interaction with SNAPC4, and fails to sustain basal snRNA transcription, indicating that SNAPC1 SUMOylation is required for proper SNAPc complex assembly involving SNAPC4 and for snRNA transcriptional activity.","method":"CRISPR/dCas9-SENP1 promoter-targeted deSUMOylation, inducible degron depletion of SNAPC1, co-immunoprecipitation of tagged endogenous SNAPC3 and SNAPC4, snRNA transcription assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including endogenous tagging, degron depletion, and functional transcription assay","pmids":["40956881"],"is_preprint":false}],"current_model":"SNAPC4 (SNAP190) is the largest subunit of the five-subunit SNAPc complex; its 4.5-repeat Myb domain directly contacts the PSE at snRNA gene promoters (in a 'wrap-around' mode with SNAP50 and SNAP43 as established by cryo-EM), recruits TBP to the adjacent TATA box via direct interaction, serves as the docking site for the Oct-1 POU domain activator (through a region similar to OBF-1), is negatively regulated by CK2 phosphorylation at its N-terminal half to allosterically inhibit DNA binding, requires SUMOylation of the SNAPC1 subunit for proper complex assembly, and is essential for snRNA transcription such that its loss causes global alternative splicing dysregulation, cell-cycle G0/G1 arrest, and in vivo developmental defects (biliary and exocrine pancreatic hypoplasia in zebrafish; neuroregression and spastic paraparesis in humans)."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of SNAP190 as the largest SNAPc subunit and its Myb domain as the direct PSE-binding module resolved how the complex recognizes snRNA promoters, and full reconstitution of SNAPc from five recombinant subunits established SNAP190 as essential for both Pol II and Pol III snRNA transcription.","evidence":"cDNA cloning, recombinant PSE-binding assays, five-subunit reconstitution with in vitro transcription","pmids":["9418884","9732265"],"confidence":"High","gaps":["Full-length structural model of the Myb–PSE interaction not yet available","Mechanism distinguishing Pol II vs Pol III promoter specificity remained unclear"]},{"year":1998,"claim":"Demonstration that Oct-1 POU domain directly contacts a specific region of SNAP190 (similar to OBF-1) to cooperatively recruit SNAPc to the PSE explained how enhancer-bound activators stimulate snRNA transcription.","evidence":"Switched-specificity mutagenesis and in vitro transcription","pmids":["9832505"],"confidence":"High","gaps":["Structural basis of the Oct-1/SNAP190 interface not yet resolved at atomic level"]},{"year":2000,"claim":"Systematic mapping of subunit–subunit contacts within SNAPc defined which domains of SNAP190 mediate direct interactions with SNAP45 and SNAP43, establishing the internal architecture of the complex.","evidence":"Deletion mapping, pulldown assays, and PSE-binding with minimal domains","pmids":["11056176"],"confidence":"High","gaps":["Three-dimensional arrangement of subunits relative to DNA not known"]},{"year":2002,"claim":"Atomic-resolution crystal structure of the Oct-1 POU/octamer/SNAP190 peptide ternary complex, together with identification of a SNAP190 N-terminal region that recruits TBP, revealed dual mechanisms by which SNAP190 bridges activator and basal machinery to snRNA promoters.","evidence":"X-ray crystallography at 2.3 Å; truncation/mutagenesis with cooperative DNA-binding and in vitro U6 transcription","pmids":["12414730","12391172"],"confidence":"High","gaps":["Redundancy between SNAP190-mediated and Brf2-mediated TBP recruitment not fully dissected in vivo"]},{"year":2003,"claim":"Showing that the SNAP190 Myb domain alone suffices to recruit TBP to the U6 TATA box established that PSE recognition and TBP recruitment are mechanistically coupled through the same structural domain.","evidence":"TBP recruitment assay, pulldown, in vitro transcription with domain truncations","pmids":["12621023"],"confidence":"High","gaps":["Role of full-length SNAP190 C-terminal regions in TBP-dependent complex assembly not addressed"]},{"year":2007,"claim":"Discovery that CK2 phosphorylates two N-terminal regions of SNAP190 to allosterically inhibit its Myb DNA-binding domain provided the first post-translational regulatory mechanism controlling SNAPc activity.","evidence":"In vitro kinase assay, phosphosite mutagenesis, DNA-binding and U6 transcription assays","pmids":["17670747"],"confidence":"High","gaps":["In vivo regulation by CK2 not demonstrated","Conditions or signals triggering CK2-mediated inhibition unknown"]},{"year":2008,"claim":"RNAi depletion of SNAP190 caused G0/G1 cell-cycle arrest, distinct from the G2/M arrest seen with SNAP45 depletion, revealing subunit-specific cell-cycle consequences of SNAPc disruption.","evidence":"RNAi knockdown in human cells, flow cytometry","pmids":["18356157"],"confidence":"Medium","gaps":["Mechanism linking snRNA deficiency specifically to G0/G1 arrest not resolved","Single lab result"]},{"year":2012,"claim":"ChIP-seq showed SNAPC4 occupancy is restricted to snRNA gene loci genome-wide, and photo-cross-linking mapped the topological arrangement of all 4.5 Myb repeats on the PSE, together defining SNAPC4 as an snRNA-gene-specific DNA-recognition module.","evidence":"ChIP-seq in human cells; site-specific protein–DNA photo-cross-linking with Drosophila SNAP190","pmids":["22966203","23038247"],"confidence":"High","gaps":["Whether the Drosophila Myb–PSE arrangement is conserved in the human complex"]},{"year":2011,"claim":"Zebrafish genetic studies revealed that truncating snapc4 mutations and loss of its vertebrate-specific interaction with Snapc2 cause biliary and exocrine pancreatic hypoplasia through altered snRNA expression and apoptosis, establishing developmental requirements for SNAPC4.","evidence":"Zebrafish forward genetic screen, morpholino knockdown, co-IP, snRNA quantification, whole-genome sequencing of ENU mutant","pmids":["22222761","22496837"],"confidence":"High","gaps":["Specific snRNA targets responsible for tissue-selective phenotypes not identified","Whether biliary and pancreatic phenotypes share a common snRNA deficiency mechanism"]},{"year":2022,"claim":"Cryo-EM structure of human SNAPc bound to the U6-1 PSE at 3.49 Å resolved the wrap-around DNA-binding mode in which SNAP190 Myb repeats and SNAP50 jointly encircle the PSE, explaining the sequence conservation of PSE motifs.","evidence":"Cryo-EM structure determination","pmids":["36369505"],"confidence":"High","gaps":["Full-length SNAP190 including C-terminal Oct-1 interaction and TBP-recruitment domains not resolved","No structure of the complete five-subunit complex on DNA"]},{"year":2023,"claim":"Identification of bi-allelic SNAPC4 variants in patients with neuroregression and spastic paraparesis, corroborated by CRISPR depletion showing decreased snRNA levels and global splicing dysregulation, established SNAPC4 deficiency as a human Mendelian neurodegenerative disorder.","evidence":"Human genetics, CRISPR depletion in HeLa, RT-qPCR of snRNAs, transcriptome-wide splicing analysis in patient fibroblasts","pmids":["36965478"],"confidence":"High","gaps":["Which specific snRNAs and mis-spliced transcripts are pathogenic","Cell-type-specific vulnerability of neurons to SNAPC4 deficiency not mechanistically explained"]},{"year":2025,"claim":"Demonstrating that SUMOylation of SNAPC1 is required for its interaction with SNAPC4 and for basal snRNA transcription revealed a new layer of post-translational control over SNAPc complex integrity.","evidence":"CRISPR/dCas9-SENP1 promoter-targeted deSUMOylation, inducible degron depletion, co-IP of endogenous tagged subunits, snRNA transcription assay","pmids":["40956881"],"confidence":"High","gaps":["Whether SNAPC4 itself is SUMOylated","Signals that regulate SNAPC1 SUMOylation status in vivo"]},{"year":null,"claim":"A complete structural model of the full five-subunit SNAPc in the context of a Pol II or Pol III pre-initiation complex, and the identity of specific snRNA targets whose deficiency underlies tissue-selective developmental and neurodegenerative phenotypes, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length five-subunit SNAPc structure on DNA","Mechanism of Pol II versus Pol III promoter discrimination by SNAPC4-containing complexes not resolved","Pathogenic snRNA and splicing targets in human SNAPC4-deficient disease not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,7,11,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,7,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,7,8,15,16]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[15,16]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9]}],"complexes":["SNAPc (snRNA-activating protein complex)"],"partners":["SNAPC1","SNAPC2","SNAPC3","SNAPC5","TBP","POU2F1","CSNK2A1"],"other_free_text":[]},"mechanistic_narrative":"SNAPC4 (SNAP190) is the largest subunit of the five-subunit SNAPc complex and serves as the central scaffold for snRNA gene transcription by both RNA polymerase II and III. Its 4.5-repeat Myb DNA-binding domain directly recognizes the proximal sequence element (PSE) of snRNA promoters in a wrap-around mode together with SNAP50 and SNAP43, while also recruiting TBP to the adjacent TATA box and providing the docking surface for cooperative activation by the Oct-1 POU domain [PMID:9418884, PMID:36369505, PMID:12414730, PMID:12391172]. CK2 phosphorylation of the SNAP190 N-terminal region allosterically inhibits its DNA-binding activity, and proper complex assembly depends on SUMOylation of the SNAPC1 subunit to maintain the SNAPC1–SNAPC4 interaction [PMID:17670747, PMID:40956881]. Bi-allelic loss-of-function SNAPC4 variants in humans cause reduced snRNA levels, global alternative splicing dysregulation, and a neurodegenerative disorder featuring neuroregression and progressive spastic paraparesis [PMID:36965478]."},"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":"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":"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":"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":15380,"output_tokens":4023,"usd":0.053242},"stage2":{"model":"claude-opus-4-6","input_tokens":7514,"output_tokens":2921,"usd":0.165892},"total_usd":0.219134,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"SNAP190 (SNAPC4) is the largest subunit of SNAPc and contains an unusual Myb DNA-binding domain with four complete repeats (Ra–Rd) and a half repeat (Rh); a truncated protein with only repeats Rc and Rd can bind the PSE, demonstrating that the SNAP190 Myb domain directly contacts the PSE. SNAP190 also interacts with SNAP45 and with Oct-1.\",\n      \"method\": \"cDNA cloning, recombinant protein PSE-binding assay, protein–protein interaction assays (co-immunoprecipitation/pulldown)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (DNA-binding assays, interaction assays, transcription reconstitution) in foundational paper\",\n      \"pmids\": [\"9418884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SNAPc can be reconstituted from five recombinant subunits (SNAP43, SNAP45, SNAP50, SNAP190, and the newly identified SNAP19) to form a complex that binds specifically to the PSE and directs both RNA polymerase II and III snRNA gene transcription, establishing SNAP190 as an essential core component.\",\n      \"method\": \"Recombinant protein co-expression and reconstitution, PSE-binding assay, in vitro transcription\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — full reconstitution of complex with functional validation of transcription\",\n      \"pmids\": [\"9732265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The Oct-1 POU domain directly contacts a specific small region of SNAP190 (SNAPC4) to cooperatively recruit SNAPc to the PSE and activate snRNA transcription; a switched-specificity SNAP190 mutant that interacts with Oct-1 POU E7R but not wild-type Oct-1 POU confirmed the direct protein–protein contact. The SNAP190 interacting region is similar to the OBF-1/OCA-B Oct-1 coactivator region.\",\n      \"method\": \"Protein–protein interaction assay, switched-specificity mutagenesis, in vitro transcription\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with switched-specificity control plus functional transcription assay\",\n      \"pmids\": [\"9832505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A detailed map of subunit–subunit contacts within SNAPc was established: SNAP190 (SNAPC4) directly contacts SNAP45 and SNAP43; specific domains required for each pairwise contact were defined, and complexes containing only these minimal interaction domains retain specific PSE-binding activity.\",\n      \"method\": \"Deletion mapping, pulldown/co-immunoprecipitation, PSE-binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic deletion mapping with multiple interaction pairs validated by PSE binding\",\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 protein contacts with the Oct-1 POU-specific domain and with DNA phosphate backbone within the enhancer, mechanistically explaining cooperative recruitment of SNAPc by Oct-1.\",\n      \"method\": \"X-ray crystallography (2.3 Å resolution)\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution crystal structure with functional context\",\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 at the U6 promoter as part of mini-SNAPc (SNAP43 + SNAP50 + N-terminal SNAP190); loss of this region can be compensated by TBP recruitment through Brf2, revealing redundant mechanisms for TBP recruitment to the U6 initiation complex.\",\n      \"method\": \"Truncation/mutagenesis analysis, cooperative DNA-binding assay, in vitro U6 transcription\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — domain dissection with in vitro transcription functional readout\",\n      \"pmids\": [\"12391172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The SNAP190 (SNAPC4) Myb DNA-binding domain directly interacts with the TBP DNA-binding domain; truncated SNAP190 containing only the Myb domain is sufficient to recruit TBP to the U6 TATA box and to stimulate assembly with Brf2, defining a role for the Myb domain in RNA Pol III pre-initiation complex assembly at juxtaposed promoter elements.\",\n      \"method\": \"TBP recruitment assay, pulldown interaction assay, in vitro transcription\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct interaction assay plus functional transcription reconstitution with domain-sufficient truncation\",\n      \"pmids\": [\"12621023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A partial SNAPc containing SNAP190 (residues 1–505), SNAP50, SNAP43, and SNAP19, co-expressed in E. coli, binds PSE specifically, recruits TBP to U6 promoter DNA, and supports reconstituted transcription of U1 and U6 snRNA genes by RNA Pol II and III respectively, confirming SNAP190 as the PSE-recognizing scaffold of the functional complex.\",\n      \"method\": \"Recombinant co-expression in E. coli, PSE-binding assay, TBP recruitment assay, in vitro transcription\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical reconstitution with dual-polymerase functional validation\",\n      \"pmids\": [\"16603380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CK2 phosphorylates the N-terminal half of SNAP190 (SNAPC4) at two regions (amino acids 20–63 and 514–545) containing multiple CK2 consensus sites; this phosphorylation inhibits SNAPc DNA binding and U6 transcription activity, and mutational analyses support an allosteric inhibition of the SNAP190 Myb DNA-binding domain as the mechanism.\",\n      \"method\": \"In vitro kinase assay, phosphorylation site mapping, mutagenesis, DNA-binding assay, in vitro U6 transcription\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay + mutagenesis + functional transcription assay\",\n      \"pmids\": [\"17670747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Down-regulation of SNAP190 (SNAPC4) by RNAi leads to accumulation of cells with G0/G1 DNA content, whereas down-regulation of SNAP45 causes G2/M arrest, indicating distinct cell-cycle roles for different SNAPc subunits; SNAP190 depletion phenotype is consistent with its role in driving snRNA transcription needed for S-phase entry.\",\n      \"method\": \"RNAi knockdown, flow cytometry cell-cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — clean KO with defined cell-cycle phenotype, single lab\",\n      \"pmids\": [\"18356157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ChIP-seq with anti-SNAPC4 antibody showed that SNAPC4 occupancy is limited to snRNA gene loci genome-wide, while SNAPC1 extends to protein-coding genes, establishing SNAPC4 as an snRNA-gene-specific component of SNAPc in chromatin.\",\n      \"method\": \"Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq localization with functional context, single lab\",\n      \"pmids\": [\"22966203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Site-specific protein–DNA photo-cross-linking mapped the topological arrangement of all 4.5 Myb repeats of Drosophila SNAP190 (ortholog of SNAPC4) on a U1 snRNA gene PSE, showing each repeat contacts the DNA and revealing their spatial organization within the SNAPc–DNA complex.\",\n      \"method\": \"Site-specific protein–DNA photo-cross-linking assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct structural mapping with residue-level resolution in the orthologous protein\",\n      \"pmids\": [\"23038247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In zebrafish, a truncating mutation in snapc4 that deletes the C-terminal domain responsible for interaction with Snapc2 (a vertebrate-specific SNAPc subunit) causes apoptosis of biliary epithelial cells and loss of the intrahepatic biliary network; snapc2 knockdown phenocopies this, and the mutant shows altered expression of a subset of snRNAs, linking the Snapc4–Snapc2 physical interaction to snRNA transcription and biliary cell survival.\",\n      \"method\": \"Zebrafish forward genetic screen, morpholino knockdown, co-immunoprecipitation (interaction domain mapping), snRNA quantification, apoptosis assay\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mutant + domain deletion + knockdown epistasis + molecular phenotype\",\n      \"pmids\": [\"22222761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Whole-genome sequencing of a zebrafish ENU mutant (m1045) identified a nonsense mutation in snapc4; morpholino knockdown confirmed that loss of Snapc4 causes severe exocrine pancreas hypoplasia, establishing a developmental requirement for Snapc4 in exocrine pancreatic organogenesis.\",\n      \"method\": \"Whole-genome sequencing, homozygosity mapping, morpholino knockdown, histology\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic identification plus morpholino rescue/phenocopy, single study\",\n      \"pmids\": [\"22496837\"],\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) in complex with the U6-1 PSE at 3.49 Å revealed a 'wrap-around' DNA-binding mode; three SNAP50 motifs contact both major and minor grooves of the PSE in coordination with the SNAP190 Myb domain, explaining PSE sequence conservation and SNAPc assembly.\",\n      \"method\": \"Cryo-electron microscopy structure determination (3.49 Å overall resolution)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — near-atomic cryo-EM structure with mechanistic interpretation of DNA recognition\",\n      \"pmids\": [\"36369505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Bi-allelic deleterious SNAPC4 variants in humans reduce SNAPC4 protein abundance, decrease snRNA expression levels, and cause global dysregulation of alternative splicing (shown in patient fibroblasts and CRISPR-depleted HeLa cells), leading to neuroregression and progressive spastic paraparesis.\",\n      \"method\": \"Human genetic analysis, CRISPR genomic editing/depletion in HeLa cells, snRNA quantification (RT-qPCR), transcriptome-wide splicing analysis in patient fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient genetics corroborated by CRISPR depletion with orthogonal molecular phenotypes (snRNA and splicing)\",\n      \"pmids\": [\"36965478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SUMOylation-deficient SNAPC1 (2KR mutant) retains interaction with SNAPC3 but has impaired interaction with SNAPC4, and fails to sustain basal snRNA transcription, indicating that SNAPC1 SUMOylation is required for proper SNAPc complex assembly involving SNAPC4 and for snRNA transcriptional activity.\",\n      \"method\": \"CRISPR/dCas9-SENP1 promoter-targeted deSUMOylation, inducible degron depletion of SNAPC1, co-immunoprecipitation of tagged endogenous SNAPC3 and SNAPC4, snRNA transcription assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including endogenous tagging, degron depletion, and functional transcription assay\",\n      \"pmids\": [\"40956881\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNAPC4 (SNAP190) is the largest subunit of the five-subunit SNAPc complex; its 4.5-repeat Myb domain directly contacts the PSE at snRNA gene promoters (in a 'wrap-around' mode with SNAP50 and SNAP43 as established by cryo-EM), recruits TBP to the adjacent TATA box via direct interaction, serves as the docking site for the Oct-1 POU domain activator (through a region similar to OBF-1), is negatively regulated by CK2 phosphorylation at its N-terminal half to allosterically inhibit DNA binding, requires SUMOylation of the SNAPC1 subunit for proper complex assembly, and is essential for snRNA transcription such that its loss causes global alternative splicing dysregulation, cell-cycle G0/G1 arrest, and in vivo developmental defects (biliary and exocrine pancreatic hypoplasia in zebrafish; neuroregression and spastic paraparesis in humans).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SNAPC4 (SNAP190) is the largest subunit of the five-subunit SNAPc complex and serves as the central scaffold for snRNA gene transcription by both RNA polymerase II and III. Its 4.5-repeat Myb DNA-binding domain directly recognizes the proximal sequence element (PSE) of snRNA promoters in a wrap-around mode together with SNAP50 and SNAP43, while also recruiting TBP to the adjacent TATA box and providing the docking surface for cooperative activation by the Oct-1 POU domain [PMID:9418884, PMID:36369505, PMID:12414730, PMID:12391172]. CK2 phosphorylation of the SNAP190 N-terminal region allosterically inhibits its DNA-binding activity, and proper complex assembly depends on SUMOylation of the SNAPC1 subunit to maintain the SNAPC1–SNAPC4 interaction [PMID:17670747, PMID:40956881]. Bi-allelic loss-of-function SNAPC4 variants in humans cause reduced snRNA levels, global alternative splicing dysregulation, and a neurodegenerative disorder featuring neuroregression and progressive spastic paraparesis [PMID:36965478].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of SNAP190 as the largest SNAPc subunit and its Myb domain as the direct PSE-binding module resolved how the complex recognizes snRNA promoters, and full reconstitution of SNAPc from five recombinant subunits established SNAP190 as essential for both Pol II and Pol III snRNA transcription.\",\n      \"evidence\": \"cDNA cloning, recombinant PSE-binding assays, five-subunit reconstitution with in vitro transcription\",\n      \"pmids\": [\"9418884\", \"9732265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length structural model of the Myb–PSE interaction not yet available\", \"Mechanism distinguishing Pol II vs Pol III promoter specificity remained unclear\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that Oct-1 POU domain directly contacts a specific region of SNAP190 (similar to OBF-1) to cooperatively recruit SNAPc to the PSE explained how enhancer-bound activators stimulate snRNA transcription.\",\n      \"evidence\": \"Switched-specificity mutagenesis and in vitro transcription\",\n      \"pmids\": [\"9832505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Oct-1/SNAP190 interface not yet resolved at atomic level\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Systematic mapping of subunit–subunit contacts within SNAPc defined which domains of SNAP190 mediate direct interactions with SNAP45 and SNAP43, establishing the internal architecture of the complex.\",\n      \"evidence\": \"Deletion mapping, pulldown assays, and PSE-binding with minimal domains\",\n      \"pmids\": [\"11056176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Three-dimensional arrangement of subunits relative to DNA not known\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Atomic-resolution crystal structure of the Oct-1 POU/octamer/SNAP190 peptide ternary complex, together with identification of a SNAP190 N-terminal region that recruits TBP, revealed dual mechanisms by which SNAP190 bridges activator and basal machinery to snRNA promoters.\",\n      \"evidence\": \"X-ray crystallography at 2.3 Å; truncation/mutagenesis with cooperative DNA-binding and in vitro U6 transcription\",\n      \"pmids\": [\"12414730\", \"12391172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy between SNAP190-mediated and Brf2-mediated TBP recruitment not fully dissected in vivo\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing that the SNAP190 Myb domain alone suffices to recruit TBP to the U6 TATA box established that PSE recognition and TBP recruitment are mechanistically coupled through the same structural domain.\",\n      \"evidence\": \"TBP recruitment assay, pulldown, in vitro transcription with domain truncations\",\n      \"pmids\": [\"12621023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of full-length SNAP190 C-terminal regions in TBP-dependent complex assembly not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that CK2 phosphorylates two N-terminal regions of SNAP190 to allosterically inhibit its Myb DNA-binding domain provided the first post-translational regulatory mechanism controlling SNAPc activity.\",\n      \"evidence\": \"In vitro kinase assay, phosphosite mutagenesis, DNA-binding and U6 transcription assays\",\n      \"pmids\": [\"17670747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo regulation by CK2 not demonstrated\", \"Conditions or signals triggering CK2-mediated inhibition unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"RNAi depletion of SNAP190 caused G0/G1 cell-cycle arrest, distinct from the G2/M arrest seen with SNAP45 depletion, revealing subunit-specific cell-cycle consequences of SNAPc disruption.\",\n      \"evidence\": \"RNAi knockdown in human cells, flow cytometry\",\n      \"pmids\": [\"18356157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking snRNA deficiency specifically to G0/G1 arrest not resolved\", \"Single lab result\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"ChIP-seq showed SNAPC4 occupancy is restricted to snRNA gene loci genome-wide, and photo-cross-linking mapped the topological arrangement of all 4.5 Myb repeats on the PSE, together defining SNAPC4 as an snRNA-gene-specific DNA-recognition module.\",\n      \"evidence\": \"ChIP-seq in human cells; site-specific protein–DNA photo-cross-linking with Drosophila SNAP190\",\n      \"pmids\": [\"22966203\", \"23038247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the Drosophila Myb–PSE arrangement is conserved in the human complex\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Zebrafish genetic studies revealed that truncating snapc4 mutations and loss of its vertebrate-specific interaction with Snapc2 cause biliary and exocrine pancreatic hypoplasia through altered snRNA expression and apoptosis, establishing developmental requirements for SNAPC4.\",\n      \"evidence\": \"Zebrafish forward genetic screen, morpholino knockdown, co-IP, snRNA quantification, whole-genome sequencing of ENU mutant\",\n      \"pmids\": [\"22222761\", \"22496837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific snRNA targets responsible for tissue-selective phenotypes not identified\", \"Whether biliary and pancreatic phenotypes share a common snRNA deficiency mechanism\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Cryo-EM structure of human SNAPc bound to the U6-1 PSE at 3.49 Å resolved the wrap-around DNA-binding mode in which SNAP190 Myb repeats and SNAP50 jointly encircle the PSE, explaining the sequence conservation of PSE motifs.\",\n      \"evidence\": \"Cryo-EM structure determination\",\n      \"pmids\": [\"36369505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length SNAP190 including C-terminal Oct-1 interaction and TBP-recruitment domains not resolved\", \"No structure of the complete five-subunit complex on DNA\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of bi-allelic SNAPC4 variants in patients with neuroregression and spastic paraparesis, corroborated by CRISPR depletion showing decreased snRNA levels and global splicing dysregulation, established SNAPC4 deficiency as a human Mendelian neurodegenerative disorder.\",\n      \"evidence\": \"Human genetics, CRISPR depletion in HeLa, RT-qPCR of snRNAs, transcriptome-wide splicing analysis in patient fibroblasts\",\n      \"pmids\": [\"36965478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific snRNAs and mis-spliced transcripts are pathogenic\", \"Cell-type-specific vulnerability of neurons to SNAPC4 deficiency not mechanistically explained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that SUMOylation of SNAPC1 is required for its interaction with SNAPC4 and for basal snRNA transcription revealed a new layer of post-translational control over SNAPc complex integrity.\",\n      \"evidence\": \"CRISPR/dCas9-SENP1 promoter-targeted deSUMOylation, inducible degron depletion, co-IP of endogenous tagged subunits, snRNA transcription assay\",\n      \"pmids\": [\"40956881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SNAPC4 itself is SUMOylated\", \"Signals that regulate SNAPC1 SUMOylation status in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A complete structural model of the full five-subunit SNAPc in the context of a Pol II or Pol III pre-initiation complex, and the identity of specific snRNA targets whose deficiency underlies tissue-selective developmental and neurodegenerative phenotypes, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length five-subunit SNAPc structure on DNA\", \"Mechanism of Pol II versus Pol III promoter discrimination by SNAPC4-containing complexes not resolved\", \"Pathogenic snRNA and splicing targets in human SNAPC4-deficient disease not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 7, 11, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 7, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 7, 8, 15, 16]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [15, 16]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"SNAPc (snRNA-activating protein complex)\"\n    ],\n    \"partners\": [\n      \"SNAPC1\",\n      \"SNAPC2\",\n      \"SNAPC3\",\n      \"SNAPC5\",\n      \"TBP\",\n      \"POU2F1\",\n      \"CSNK2A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}