{"gene":"SNRPC","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":1991,"finding":"The N-terminal zinc finger-like (CC-HH type) structure of U1-C is essential for binding to U1 snRNP particles. Deletion analysis showed the N-terminal 45 amino acids are sufficient for binding; modification of cysteine residues with N-ethylmaleimide or single point mutations of the cysteines and histidines abolished binding. U1-C does not bind naked U1 snRNA alone, and requires both U1 snRNA and one or more U1 snRNP proteins for association.","method":"Deletion mutagenesis, site-directed mutagenesis of zinc-coordinating residues, chemical modification (N-ethylmaleimide), immunoprecipitation binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (deletion analysis, point mutagenesis, chemical modification) all converging on the same conclusion in a single focused study","pmids":["1826349"],"is_preprint":false},{"year":1994,"finding":"U1-C does not bind naked U1 snRNA directly but requires the common Sm proteins and the N-terminal domain of U1-70K for its association with U1 snRNP. The N-terminal domain of U1-70K is necessary and sufficient for recruiting U1-C to core U1 snRNP. Chemical crosslinking of purified U1 snRNPs detected a direct crosslink between U1-C and the Sm B'/B protein.","method":"Immunoprecipitation of complexes formed with in vitro translated proteins and core snRNPs, binding studies with U1-70K deletion mutants, chemical crosslinking of purified U1 snRNPs","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal binding assays with defined mutants plus chemical crosslinking, multiple orthogonal approaches in one study","pmids":["8076607"],"is_preprint":false},{"year":1996,"finding":"The U1-C protein (but not U1-A) is required for the formation and/or stabilization of early (E) spliceosomal complexes in mammalian splicing. Reconstituted U1 snRNPs lacking U1-C failed to complement E complex formation, and the N-terminal domain of U1-C was necessary and sufficient for this stimulatory activity.","method":"In vitro reconstitution of U1 snRNPs from purified components, splicing complementation assays in U1-depleted HeLa extracts, E complex formation assays with recombinant U1-C mutants","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined mutants, single lab but multiple complementary functional assays","pmids":["8972845"],"is_preprint":false},{"year":1996,"finding":"U1-C protein makes direct contacts with the 5' splice site RNA oligonucleotide: UV crosslinking showed U1-C becomes crosslinked to the 5'SS RNA upon UV irradiation of purified U1 snRNP/5'SS RNA complexes. Kinetic studies also showed that the 5'SS–U1 snRNP interaction does not require base pairing for initial association (RNase H cleavage of U1 snRNA 5' end did not affect association rate) but base pairing is required for stability, indicating U1-C and other proteins are critical for initial 5'SS recognition.","method":"Purified U1 snRNP/RNA oligonucleotide binding kinetics, RNase H cleavage, UV crosslinking","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct UV crosslinking with purified components plus kinetic analysis, single lab with two orthogonal methods","pmids":["8798632"],"is_preprint":false},{"year":2001,"finding":"Specific mutations in U1-C (or in U1 snRNA) can bypass the otherwise essential requirement for the DEAD-box ATPase Prp28p in yeast. The conserved L13 residue of U1-C makes specific contact that stabilizes the U1 snRNA/5' splice site duplex in the prespliceosome; Prp28p functions to counteract this stabilizing effect of U1-C, promoting U1 snRNP dissociation from the 5' splice site.","method":"Genetic epistasis (suppressor mutations), yeast mutant growth assays, structure-function analysis of U1-C mutations","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple bypass mutations in yeast, replicated conceptually by subsequent structural and genetic studies","pmids":["11172727"],"is_preprint":false},{"year":2002,"finding":"The splicing regulator TIA-1 directly and specifically interacts with the N-terminal region of U1-C via its C-terminal glutamine-rich (Q) domain (enhanced by RRM1), and this interaction promotes U1 snRNP recruitment to weak 5' splice sites. Co-precipitation experiments established the direct U1-C/TIA-1 interaction.","method":"Co-precipitation/pulldown experiments with recombinant protein fragments, RNA recognition motif deletion analysis, splicing assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction mapped with deletion constructs, functional consequences tested in splicing assays, replicated in subsequent structural study (PMID:22154808)","pmids":["12486009"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of human U1 snRNP at 5.5 Å resolution, with site-specific labelling used to place U1-C and other proteins. U1-C is positioned such that the N-terminal polypeptide of U1-70K wraps around the Sm core and makes contact with U1-C, suggesting U1-C is crucial for 5' splice site recognition and revealing a hierarchical network of protein–protein and RNA–protein interactions.","method":"X-ray crystallography at 5.5 Å, site-specific protein labelling for subunit placement","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with site-specific labelling, replicated and extended by subsequent higher-resolution structure (PMID:25555158)","pmids":["19325628"],"is_preprint":false},{"year":2009,"finding":"Mass spectrometry analysis of native human U1 snRNP revealed that U1-C undergoes dynamic interactions with the complex; its unstructured, post-translationally modified C-terminal tail is responsible for its dynamic exchange, and this interaction is controlled by binding to different U1-70K isoforms and their phosphorylation status in vivo.","method":"Native mass spectrometry of purified U1 snRNP, comparison of native vs. recombinant complexes","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — native MS with defined subcomplexes, single lab, mechanistic inference from composition data","pmids":["19784376"],"is_preprint":false},{"year":2014,"finding":"Mutational analysis of yeast Yhc1 (U1-C ortholog) identified that Arg21 and other surface residues stabilize the U1–5'SS complex. Yhc1-R21A is synthetically lethal without Mud2 and bypasses the essentiality of Prp28, consistent with destabilization of U1•5'SS interaction. Yhc1 Arg21 fortifies the U1•5'SS complex via contacts with SmD3 residues Glu37/Asp38.","method":"Alanine-scanning mutagenesis, yeast genetic interaction screens (synthetic lethality, bypass suppression), growth assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic mutagenesis combined with multiple genetic interaction tests, guided by structural data, convergent with prior mechanistic findings","pmids":["24497193"],"is_preprint":false},{"year":2015,"finding":"Atomic-resolution crystal structures of engineered human U1 sub-structures showed that the zinc finger of U1-C interacts with the RNA duplex formed between the pre-mRNA 5' splice site and U1 snRNA, stabilizing it through hydrogen bonds and electrostatic interactions with the RNA backbone. U1-C makes no base-specific contacts with pre-mRNA; 5'SS selection is achieved predominantly through base pairing with U1 snRNA, while U1-C fine-tunes relative affinities for mismatched 5'SS.","method":"X-ray crystallography (atomic resolution), RNA binding assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structures combined with RNA binding assays, extends and refines earlier lower-resolution structure","pmids":["25555158"],"is_preprint":false},{"year":2015,"finding":"Extended genetic analysis in yeast confirmed that Yhc1 Val20 and Ser19 at the RNA interface are important for U1•5'SS complex stability; mutations V20A and S19A bypassed the essentiality of Prp28, consistent with destabilization of U1•5'SS interaction. Yhc1 interface mutations with SmD3, SmB, and U1-70K/Snp1 elicited synthetic defects in the absence of U1 subunit Mud1.","method":"Alanine-scanning mutagenesis, yeast genetic interaction assays (synthetic lethality, bypass of Prp28 essentiality)","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with mutagenesis, single lab, consistent with prior structural and genetic data","pmids":["25897024"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structures of the yeast pre-B and B spliceosomal complexes showed that in the pre-B complex, the duplex between the 5' splice site and U1 snRNA is recognized by Yhc1 (U1-C ortholog), Luc7, and the Sm ring. In the B complex, U1 snRNP is dissociated from the 5'SS.","method":"Cryo-electron microscopy at 3.3–4.6 Å resolution","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM of native spliceosomal complexes, reveals direct structural role of Yhc1 at the 5'SS","pmids":["29794219"],"is_preprint":false},{"year":2022,"finding":"Knockdown or overexpression of SNRPC (along with other free U1 snRNP proteins SNRPA, SNRNP70, SNRPD2) promotes usage of proximal alternative polyadenylation (APA) sites at the transcriptome level. SNRNP70 (but not SNRPC specifically) was shown to interact with CPSF6 to promote proximal APA; the mechanism for SNRPC in APA was not individually resolved beyond the transcriptome-level effect.","method":"siRNA knockdown, overexpression, transcriptome-level APA analysis","journal":"Journal of molecular cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown/overexpression with transcriptome readout, SNRPC-specific mechanism not individually resolved, single lab","pmids":["36073763"],"is_preprint":false},{"year":2023,"finding":"SNRPC is essential for the stability of U1 snRNP and contributes to RNA Pol II-controlled transcription of oncogenes. SNRPC ablation (CRISPR) decreased RNA Pol II enrichment on a subset of oncogenes (TNFAIP2, E2F2, CDK4) and reduced their expression. SNRPC deletion inhibited TNBC progression partially through regulation of the TNFAIP2-Rac1-β-catenin signaling pathway.","method":"In vivo CRISPR screen, CRISPR knockout, RNA Pol II ChIP, functional cell assays (proliferation, migration, invasion), in vivo tumor models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with ChIP and in vivo validation, single lab, multiple orthogonal readouts","pmids":["37057875"],"is_preprint":false},{"year":2024,"finding":"Single-molecule and ensemble kinetic studies established that U1-C protein binds reversibly to U1 snRNP (it is a dynamic subunit), and the small-molecule splicing modulator branaplam binds to the U1 snRNP/U1-C complex only after the complex has engaged with a -1A bulged 5' splice site. This obligate sequential binding explains how branaplam stabilizes long-lived U1 snRNP/5'SS complexes.","method":"Colocalization single-molecule spectroscopy (CoSMoS), ensemble kinetic measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — single-molecule and ensemble methods used orthogonally, mechanistic model validated by kinetic measurements, peer-reviewed publication","pmids":["39389991"],"is_preprint":false},{"year":2011,"finding":"TIA-1 RRM1 enhances the interaction of TIA-1's C-terminal Q-rich domain with U1-C, despite linear separation of the domains. SAXS showed TIA-1 adopts a 'V' shape that brings N- and C-termini to the same side, structurally rationalizing how RRM1 can facilitate U1-C contact.","method":"Isothermal titration calorimetry, small-angle X-ray scattering (SAXS), RNA binding assays with TIA-1 deletion variants","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — ITC and SAXS with deletion variants, single lab, extends prior TIA-1/U1-C interaction finding","pmids":["22154808"],"is_preprint":false},{"year":1997,"finding":"The U1-C protein (Yhc1) was identified as a component of yeast U1 snRNP by mass spectrometry peptide sequencing of a purified yeast U1 snRNP complex, establishing its presence as a U1-specific protein in Saccharomyces cerevisiae.","method":"Anti-m3G cap immunoaffinity purification, glycerol gradient centrifugation, nanoelectrospray mass spectrometry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct MS identification from purified complex, first demonstration of the yeast ortholog in the U1 snRNP","pmids":["9012791"],"is_preprint":false}],"current_model":"SNRPC (U1-C) is an essential subunit of the U1 snRNP that uses its N-terminal CC-HH zinc finger domain to stabilize the RNA duplex formed between the pre-mRNA 5' splice site and U1 snRNA through backbone contacts (but no base-specific contacts), thereby fine-tuning splice site selection; it is recruited to U1 snRNP via the N-terminal domain of U1-70K and the Sm core proteins rather than by direct RNA binding, binds reversibly and dynamically to U1 snRNP, and is displaced from the 5'SS by the DEAD-box ATPase Prp28 to allow spliceosome progression; U1-C also directly interacts with the splicing regulator TIA-1 to promote U1 snRNP recruitment to weak 5' splice sites, contributes to RNA Pol II-controlled transcription of oncogenes by stabilizing U1 snRNP, and its reversible association is the mechanistic basis through which small-molecule splicing modulators (e.g., branaplam) stabilize U1 snRNP at specific 5' splice sites."},"narrative":{"mechanistic_narrative":"SNRPC (U1-C) is an integral, splice-site-recognition subunit of the U1 snRNP that fine-tunes 5' splice site selection during the earliest steps of pre-mRNA splicing [PMID:8972845, PMID:25555158]. Its N-terminal CC-HH zinc finger is necessary and sufficient for incorporation into the particle, but U1-C does not bind naked U1 snRNA; instead it is recruited through the Sm core proteins (including a direct contact with Sm B'/B) and the N-terminal domain of U1-70K [PMID:1826349, PMID:8076607, PMID:19325628]. Once incorporated, U1-C contacts the RNA duplex formed between the pre-mRNA 5' splice site and U1 snRNA, stabilizing it through hydrogen bonds and electrostatic contacts to the RNA backbone without making base-specific contacts, so that base pairing with U1 snRNA dictates selection while U1-C tunes relative affinity for imperfect 5' splice sites [PMID:25555158, PMID:29794219]. This stabilizing activity is required to form and stabilize the early (E) spliceosomal complex and is directly counteracted by the DEAD-box ATPase Prp28, which displaces U1 snRNP from the 5'SS to permit spliceosome progression; mutations that weaken the U1-C/5'SS interface bypass the otherwise essential requirement for Prp28 [PMID:8972845, PMID:11172727, PMID:24497193]. U1-C associates reversibly and dynamically with U1 snRNP, and this reversible engagement is the mechanistic basis through which the small-molecule modulator branaplam stabilizes long-lived U1 snRNP/5'SS complexes at bulged 5' splice sites [PMID:19784376, PMID:39389991]. U1-C also binds the splicing regulator TIA-1 to recruit U1 snRNP to weak 5' splice sites and contributes to RNA Pol II-controlled transcription of oncogenes by maintaining U1 snRNP stability [PMID:12486009, PMID:37057875].","teleology":[{"year":1991,"claim":"Established the structural determinant by which U1-C joins the U1 snRNP, defining its zinc finger as the assembly module rather than an RNA-binding domain.","evidence":"Deletion and zinc-coordinating-residue mutagenesis with chemical modification and IP binding assays","pmids":["1826349"],"confidence":"High","gaps":["Did not identify the specific U1 snRNP protein(s) mediating recruitment","No structural model of the zinc finger fold"]},{"year":1994,"claim":"Resolved how U1-C is recruited, showing it depends on Sm proteins and the U1-70K N-terminal domain rather than direct snRNA binding.","evidence":"IP of in vitro translated proteins with core snRNPs, U1-70K deletion mapping, chemical crosslinking of purified U1 snRNP","pmids":["8076607"],"confidence":"High","gaps":["Stoichiometry and spatial arrangement of contacts not defined","Did not address function at the 5'SS"]},{"year":1996,"claim":"Demonstrated a functional requirement for U1-C in early spliceosome assembly, distinguishing it from U1-A.","evidence":"In vitro reconstitution of U1 snRNP from purified components and E-complex complementation in U1-depleted HeLa extracts","pmids":["8972845"],"confidence":"High","gaps":["Did not show how U1-C contacts the 5'SS RNA","Mechanism of stimulation at atomic level unresolved"]},{"year":1996,"claim":"Showed U1-C directly contacts 5'SS RNA and that initial recognition does not require base pairing, implicating protein contacts in early 5'SS engagement.","evidence":"UV crosslinking and binding kinetics of purified U1 snRNP with 5'SS oligonucleotides, RNase H cleavage","pmids":["8798632"],"confidence":"Medium","gaps":["Single lab, crosslinking does not localize the contact at residue level","Relative contributions of U1-C versus other proteins not separated"]},{"year":2001,"claim":"Placed U1-C in the dynamic splicing pathway, showing it stabilizes the U1/5'SS duplex and that Prp28 acts to counteract this stabilization.","evidence":"Genetic epistasis and suppressor mutations in yeast U1-C, growth assays","pmids":["11172727"],"confidence":"High","gaps":["Structural basis of the L13 contact inferred genetically, not visualized","Mechanism of Prp28-driven displacement not detailed"]},{"year":2002,"claim":"Identified TIA-1 as a direct U1-C partner that recruits U1 snRNP to weak 5' splice sites, extending U1-C function into regulated splice-site selection.","evidence":"Co-precipitation with recombinant protein fragments, RRM deletion analysis, splicing assays","pmids":["12486009"],"confidence":"High","gaps":["Interface residues on U1-C not mapped","In vivo target sites of TIA-1/U1-C cooperation not enumerated"]},{"year":2009,"claim":"Provided the first structural placement of U1-C within the intact particle, showing the U1-70K N-terminus wraps the Sm core to contact U1-C.","evidence":"X-ray crystallography at 5.5 Å with site-specific labelling","pmids":["19325628"],"confidence":"High","gaps":["Resolution insufficient for atomic contacts","5'SS RNA not present in the structure"]},{"year":2009,"claim":"Revealed that U1-C is a dynamically exchanging subunit whose C-terminal tail and U1-70K isoform/phosphorylation state control its association.","evidence":"Native mass spectrometry of purified U1 snRNP comparing native and recombinant complexes","pmids":["19784376"],"confidence":"Medium","gaps":["Mechanistic inference from composition data, not direct kinetics","Functional consequence of dynamic exchange not tested"]},{"year":2011,"claim":"Structurally rationalized the TIA-1/U1-C interaction by showing TIA-1 folds into a 'V' that juxtaposes its RRM1 and Q-domain to contact U1-C.","evidence":"ITC, SAXS, and RNA binding assays with TIA-1 deletion variants","pmids":["22154808"],"confidence":"Medium","gaps":["No co-structure of the TIA-1/U1-C complex","U1-C residues engaged not defined"]},{"year":2014,"claim":"Mapped specific U1-C surface residues that fortify the U1/5'SS complex through contacts with the Sm core, linking the interface to Prp28 bypass.","evidence":"Alanine-scanning mutagenesis and yeast genetic interaction screens in Yhc1","pmids":["24497193"],"confidence":"High","gaps":["Yeast ortholog data; human residue equivalence inferred","Direct biochemical affinity changes not quantified"]},{"year":2015,"claim":"Defined at atomic resolution that U1-C stabilizes the U1 snRNA/5'SS duplex via backbone contacts without base-specific recognition, settling how it tunes splice-site affinity.","evidence":"Atomic-resolution X-ray crystallography with RNA binding assays; extended by yeast interface mutagenesis","pmids":["25555158","25897024"],"confidence":"High","gaps":["Engineered sub-structures rather than full native particle","Dynamics of duplex stabilization not captured in static structure"]},{"year":2018,"claim":"Visualized U1-C's role within native spliceosomes, showing it recognizes the 5'SS/U1 duplex in pre-B and is released as U1 snRNP dissociates in the B complex.","evidence":"Cryo-EM of yeast pre-B and B spliceosomal complexes at 3.3–4.6 Å","pmids":["29794219"],"confidence":"High","gaps":["Yeast complexes; human spliceosome transitions inferred","Does not resolve the Prp28-catalyzed displacement intermediate"]},{"year":2022,"claim":"Linked SNRPC dosage to alternative polyadenylation site usage at the transcriptome level.","evidence":"siRNA knockdown, overexpression, and transcriptome-level APA analysis","pmids":["36073763"],"confidence":"Low","gaps":["SNRPC-specific mechanism in APA not individually resolved","Effect inferred from transcriptome readout, not direct binding","Single lab"]},{"year":2023,"claim":"Connected U1 snRNP stability via SNRPC to RNA Pol II-controlled oncogene transcription and tumor progression.","evidence":"In vivo CRISPR screen, CRISPR knockout, RNA Pol II ChIP, and in vivo TNBC tumor models","pmids":["37057875"],"confidence":"Medium","gaps":["Mechanistic link between U1 snRNP stability and Pol II enrichment not fully resolved","Single lab","Generality beyond TNBC oncogenes untested"]},{"year":2024,"claim":"Established the kinetic mechanism by which U1-C's reversible binding enables small-molecule modulation, with branaplam binding only after the complex engages a bulged 5'SS.","evidence":"Colocalization single-molecule spectroscopy (CoSMoS) and ensemble kinetic measurements","pmids":["39389991"],"confidence":"High","gaps":["Structural basis of branaplam binding to the U1-C/5'SS complex not solved","Generality across other splice-site sequences not exhaustively mapped"]},{"year":null,"claim":"How U1-C's dynamic exchange and post-translational modification are regulated in vivo, and how its U1 snRNP-stabilizing role couples to transcription and 3'-end processing, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mechanistic account of SNRPC-specific contribution to APA","Signaling/PTM control of U1-C exchange not defined in cells"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,9,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,9,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[13]}],"complexes":["U1 snRNP","spliceosomal E complex","pre-B spliceosome"],"partners":["SNRNP70","SNRPB","TIA1","SNRPD3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P09234","full_name":"U1 small nuclear ribonucleoprotein C","aliases":[],"length_aa":159,"mass_kda":17.4,"function":"Component of the spliceosomal U1 snRNP, which is essential for recognition of the pre-mRNA 5' splice-site and the subsequent assembly of the spliceosome. SNRPC/U1-C is directly involved in initial 5' splice-site recognition for both constitutive and regulated alternative splicing. The interaction with the 5' splice-site seems to precede base-pairing between the pre-mRNA and the U1 snRNA. Stimulates commitment or early (E) complex formation by stabilizing the base pairing of the 5' end of the U1 snRNA and the 5' splice-site region","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P09234/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SNRPC","classification":"Common Essential","n_dependent_lines":1182,"n_total_lines":1208,"dependency_fraction":0.9784768211920529},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000124562","cell_line_id":"CID001457","localizations":[{"compartment":"chromatin","grade":3},{"compartment":"nuclear_punctae","grade":3}],"interactors":[{"gene":"FUS","stoichiometry":10.0},{"gene":"SNRPA","stoichiometry":10.0},{"gene":"SNRPB","stoichiometry":10.0},{"gene":"SRSF1","stoichiometry":10.0},{"gene":"SNRPB;SNRPN","stoichiometry":10.0},{"gene":"TXN","stoichiometry":10.0},{"gene":"SNRNP70","stoichiometry":10.0},{"gene":"SNRPF","stoichiometry":10.0},{"gene":"HNRNPA1;HNRNPA1L2","stoichiometry":10.0},{"gene":"RBMX;RBMXL2","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001457","total_profiled":1310},"omim":[{"mim_id":"603934","title":"COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1; CARM1","url":"https://www.omim.org/entry/603934"},{"mim_id":"603522","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE C; SNRPC","url":"https://www.omim.org/entry/603522"},{"mim_id":"182285","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE A; SNRPA","url":"https://www.omim.org/entry/182285"},{"mim_id":"180740","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN, U1 SUBUNIT, 70-KD; SNRNP70","url":"https://www.omim.org/entry/180740"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNRPC"},"hgnc":{"alias_symbol":["U1-C","Yhc1"],"prev_symbol":[]},"alphafold":{"accession":"P09234","domains":[{"cath_id":"3.30.160","chopping":"4-58","consensus_level":"high","plddt":91.5989,"start":4,"end":58}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09234","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09234-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09234-F1-predicted_aligned_error_v6.png","plddt_mean":70.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNRPC","jax_strain_url":"https://www.jax.org/strain/search?query=SNRPC"},"sequence":{"accession":"P09234","fasta_url":"https://rest.uniprot.org/uniprotkb/P09234.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09234/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09234"}},"corpus_meta":[{"pmid":"19325628","id":"PMC_19325628","title":"Crystal structure of human spliceosomal U1 snRNP at 5.5 A resolution.","date":"2009","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/19325628","citation_count":282,"is_preprint":false},{"pmid":"25555158","id":"PMC_25555158","title":"Crystal structure of human U1 snRNP, a small nuclear ribonucleoprotein particle, reveals the mechanism of 5' splice site recognition.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25555158","citation_count":220,"is_preprint":false},{"pmid":"12486009","id":"PMC_12486009","title":"The splicing regulator TIA-1 interacts with U1-C to promote U1 snRNP recruitment to 5' splice sites.","date":"2002","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12486009","citation_count":189,"is_preprint":false},{"pmid":"11172727","id":"PMC_11172727","title":"Specific alterations of U1-C protein or U1 small nuclear RNA can eliminate the requirement of Prp28p, an essential DEAD box splicing factor.","date":"2001","source":"Molecular 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Deletion analysis showed the N-terminal 45 amino acids are sufficient for binding; modification of cysteine residues with N-ethylmaleimide or single point mutations of the cysteines and histidines abolished binding. U1-C does not bind naked U1 snRNA alone, and requires both U1 snRNA and one or more U1 snRNP proteins for association.\",\n      \"method\": \"Deletion mutagenesis, site-directed mutagenesis of zinc-coordinating residues, chemical modification (N-ethylmaleimide), immunoprecipitation binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (deletion analysis, point mutagenesis, chemical modification) all converging on the same conclusion in a single focused study\",\n      \"pmids\": [\"1826349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"U1-C does not bind naked U1 snRNA directly but requires the common Sm proteins and the N-terminal domain of U1-70K for its association with U1 snRNP. The N-terminal domain of U1-70K is necessary and sufficient for recruiting U1-C to core U1 snRNP. Chemical crosslinking of purified U1 snRNPs detected a direct crosslink between U1-C and the Sm B'/B protein.\",\n      \"method\": \"Immunoprecipitation of complexes formed with in vitro translated proteins and core snRNPs, binding studies with U1-70K deletion mutants, chemical crosslinking of purified U1 snRNPs\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal binding assays with defined mutants plus chemical crosslinking, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"8076607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The U1-C protein (but not U1-A) is required for the formation and/or stabilization of early (E) spliceosomal complexes in mammalian splicing. Reconstituted U1 snRNPs lacking U1-C failed to complement E complex formation, and the N-terminal domain of U1-C was necessary and sufficient for this stimulatory activity.\",\n      \"method\": \"In vitro reconstitution of U1 snRNPs from purified components, splicing complementation assays in U1-depleted HeLa extracts, E complex formation assays with recombinant U1-C mutants\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined mutants, single lab but multiple complementary functional assays\",\n      \"pmids\": [\"8972845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"U1-C protein makes direct contacts with the 5' splice site RNA oligonucleotide: UV crosslinking showed U1-C becomes crosslinked to the 5'SS RNA upon UV irradiation of purified U1 snRNP/5'SS RNA complexes. Kinetic studies also showed that the 5'SS–U1 snRNP interaction does not require base pairing for initial association (RNase H cleavage of U1 snRNA 5' end did not affect association rate) but base pairing is required for stability, indicating U1-C and other proteins are critical for initial 5'SS recognition.\",\n      \"method\": \"Purified U1 snRNP/RNA oligonucleotide binding kinetics, RNase H cleavage, UV crosslinking\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct UV crosslinking with purified components plus kinetic analysis, single lab with two orthogonal methods\",\n      \"pmids\": [\"8798632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Specific mutations in U1-C (or in U1 snRNA) can bypass the otherwise essential requirement for the DEAD-box ATPase Prp28p in yeast. The conserved L13 residue of U1-C makes specific contact that stabilizes the U1 snRNA/5' splice site duplex in the prespliceosome; Prp28p functions to counteract this stabilizing effect of U1-C, promoting U1 snRNP dissociation from the 5' splice site.\",\n      \"method\": \"Genetic epistasis (suppressor mutations), yeast mutant growth assays, structure-function analysis of U1-C mutations\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple bypass mutations in yeast, replicated conceptually by subsequent structural and genetic studies\",\n      \"pmids\": [\"11172727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The splicing regulator TIA-1 directly and specifically interacts with the N-terminal region of U1-C via its C-terminal glutamine-rich (Q) domain (enhanced by RRM1), and this interaction promotes U1 snRNP recruitment to weak 5' splice sites. Co-precipitation experiments established the direct U1-C/TIA-1 interaction.\",\n      \"method\": \"Co-precipitation/pulldown experiments with recombinant protein fragments, RNA recognition motif deletion analysis, splicing assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction mapped with deletion constructs, functional consequences tested in splicing assays, replicated in subsequent structural study (PMID:22154808)\",\n      \"pmids\": [\"12486009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of human U1 snRNP at 5.5 Å resolution, with site-specific labelling used to place U1-C and other proteins. U1-C is positioned such that the N-terminal polypeptide of U1-70K wraps around the Sm core and makes contact with U1-C, suggesting U1-C is crucial for 5' splice site recognition and revealing a hierarchical network of protein–protein and RNA–protein interactions.\",\n      \"method\": \"X-ray crystallography at 5.5 Å, site-specific protein labelling for subunit placement\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with site-specific labelling, replicated and extended by subsequent higher-resolution structure (PMID:25555158)\",\n      \"pmids\": [\"19325628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mass spectrometry analysis of native human U1 snRNP revealed that U1-C undergoes dynamic interactions with the complex; its unstructured, post-translationally modified C-terminal tail is responsible for its dynamic exchange, and this interaction is controlled by binding to different U1-70K isoforms and their phosphorylation status in vivo.\",\n      \"method\": \"Native mass spectrometry of purified U1 snRNP, comparison of native vs. recombinant complexes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — native MS with defined subcomplexes, single lab, mechanistic inference from composition data\",\n      \"pmids\": [\"19784376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mutational analysis of yeast Yhc1 (U1-C ortholog) identified that Arg21 and other surface residues stabilize the U1–5'SS complex. Yhc1-R21A is synthetically lethal without Mud2 and bypasses the essentiality of Prp28, consistent with destabilization of U1•5'SS interaction. Yhc1 Arg21 fortifies the U1•5'SS complex via contacts with SmD3 residues Glu37/Asp38.\",\n      \"method\": \"Alanine-scanning mutagenesis, yeast genetic interaction screens (synthetic lethality, bypass suppression), growth assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic mutagenesis combined with multiple genetic interaction tests, guided by structural data, convergent with prior mechanistic findings\",\n      \"pmids\": [\"24497193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Atomic-resolution crystal structures of engineered human U1 sub-structures showed that the zinc finger of U1-C interacts with the RNA duplex formed between the pre-mRNA 5' splice site and U1 snRNA, stabilizing it through hydrogen bonds and electrostatic interactions with the RNA backbone. U1-C makes no base-specific contacts with pre-mRNA; 5'SS selection is achieved predominantly through base pairing with U1 snRNA, while U1-C fine-tunes relative affinities for mismatched 5'SS.\",\n      \"method\": \"X-ray crystallography (atomic resolution), RNA binding assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structures combined with RNA binding assays, extends and refines earlier lower-resolution structure\",\n      \"pmids\": [\"25555158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Extended genetic analysis in yeast confirmed that Yhc1 Val20 and Ser19 at the RNA interface are important for U1•5'SS complex stability; mutations V20A and S19A bypassed the essentiality of Prp28, consistent with destabilization of U1•5'SS interaction. Yhc1 interface mutations with SmD3, SmB, and U1-70K/Snp1 elicited synthetic defects in the absence of U1 subunit Mud1.\",\n      \"method\": \"Alanine-scanning mutagenesis, yeast genetic interaction assays (synthetic lethality, bypass of Prp28 essentiality)\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with mutagenesis, single lab, consistent with prior structural and genetic data\",\n      \"pmids\": [\"25897024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structures of the yeast pre-B and B spliceosomal complexes showed that in the pre-B complex, the duplex between the 5' splice site and U1 snRNA is recognized by Yhc1 (U1-C ortholog), Luc7, and the Sm ring. In the B complex, U1 snRNP is dissociated from the 5'SS.\",\n      \"method\": \"Cryo-electron microscopy at 3.3–4.6 Å resolution\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM of native spliceosomal complexes, reveals direct structural role of Yhc1 at the 5'SS\",\n      \"pmids\": [\"29794219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown or overexpression of SNRPC (along with other free U1 snRNP proteins SNRPA, SNRNP70, SNRPD2) promotes usage of proximal alternative polyadenylation (APA) sites at the transcriptome level. SNRNP70 (but not SNRPC specifically) was shown to interact with CPSF6 to promote proximal APA; the mechanism for SNRPC in APA was not individually resolved beyond the transcriptome-level effect.\",\n      \"method\": \"siRNA knockdown, overexpression, transcriptome-level APA analysis\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown/overexpression with transcriptome readout, SNRPC-specific mechanism not individually resolved, single lab\",\n      \"pmids\": [\"36073763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SNRPC is essential for the stability of U1 snRNP and contributes to RNA Pol II-controlled transcription of oncogenes. SNRPC ablation (CRISPR) decreased RNA Pol II enrichment on a subset of oncogenes (TNFAIP2, E2F2, CDK4) and reduced their expression. SNRPC deletion inhibited TNBC progression partially through regulation of the TNFAIP2-Rac1-β-catenin signaling pathway.\",\n      \"method\": \"In vivo CRISPR screen, CRISPR knockout, RNA Pol II ChIP, functional cell assays (proliferation, migration, invasion), in vivo tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with ChIP and in vivo validation, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"37057875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Single-molecule and ensemble kinetic studies established that U1-C protein binds reversibly to U1 snRNP (it is a dynamic subunit), and the small-molecule splicing modulator branaplam binds to the U1 snRNP/U1-C complex only after the complex has engaged with a -1A bulged 5' splice site. This obligate sequential binding explains how branaplam stabilizes long-lived U1 snRNP/5'SS complexes.\",\n      \"method\": \"Colocalization single-molecule spectroscopy (CoSMoS), ensemble kinetic measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — single-molecule and ensemble methods used orthogonally, mechanistic model validated by kinetic measurements, peer-reviewed publication\",\n      \"pmids\": [\"39389991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIA-1 RRM1 enhances the interaction of TIA-1's C-terminal Q-rich domain with U1-C, despite linear separation of the domains. SAXS showed TIA-1 adopts a 'V' shape that brings N- and C-termini to the same side, structurally rationalizing how RRM1 can facilitate U1-C contact.\",\n      \"method\": \"Isothermal titration calorimetry, small-angle X-ray scattering (SAXS), RNA binding assays with TIA-1 deletion variants\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ITC and SAXS with deletion variants, single lab, extends prior TIA-1/U1-C interaction finding\",\n      \"pmids\": [\"22154808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The U1-C protein (Yhc1) was identified as a component of yeast U1 snRNP by mass spectrometry peptide sequencing of a purified yeast U1 snRNP complex, establishing its presence as a U1-specific protein in Saccharomyces cerevisiae.\",\n      \"method\": \"Anti-m3G cap immunoaffinity purification, glycerol gradient centrifugation, nanoelectrospray mass spectrometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct MS identification from purified complex, first demonstration of the yeast ortholog in the U1 snRNP\",\n      \"pmids\": [\"9012791\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNRPC (U1-C) is an essential subunit of the U1 snRNP that uses its N-terminal CC-HH zinc finger domain to stabilize the RNA duplex formed between the pre-mRNA 5' splice site and U1 snRNA through backbone contacts (but no base-specific contacts), thereby fine-tuning splice site selection; it is recruited to U1 snRNP via the N-terminal domain of U1-70K and the Sm core proteins rather than by direct RNA binding, binds reversibly and dynamically to U1 snRNP, and is displaced from the 5'SS by the DEAD-box ATPase Prp28 to allow spliceosome progression; U1-C also directly interacts with the splicing regulator TIA-1 to promote U1 snRNP recruitment to weak 5' splice sites, contributes to RNA Pol II-controlled transcription of oncogenes by stabilizing U1 snRNP, and its reversible association is the mechanistic basis through which small-molecule splicing modulators (e.g., branaplam) stabilize U1 snRNP at specific 5' splice sites.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNRPC (U1-C) is an integral, splice-site-recognition subunit of the U1 snRNP that fine-tunes 5' splice site selection during the earliest steps of pre-mRNA splicing [#2, #9]. Its N-terminal CC-HH zinc finger is necessary and sufficient for incorporation into the particle, but U1-C does not bind naked U1 snRNA; instead it is recruited through the Sm core proteins (including a direct contact with Sm B'/B) and the N-terminal domain of U1-70K [#0, #1, #6]. Once incorporated, U1-C contacts the RNA duplex formed between the pre-mRNA 5' splice site and U1 snRNA, stabilizing it through hydrogen bonds and electrostatic contacts to the RNA backbone without making base-specific contacts, so that base pairing with U1 snRNA dictates selection while U1-C tunes relative affinity for imperfect 5' splice sites [#9, #11]. This stabilizing activity is required to form and stabilize the early (E) spliceosomal complex and is directly counteracted by the DEAD-box ATPase Prp28, which displaces U1 snRNP from the 5'SS to permit spliceosome progression; mutations that weaken the U1-C/5'SS interface bypass the otherwise essential requirement for Prp28 [#2, #4, #8]. U1-C associates reversibly and dynamically with U1 snRNP, and this reversible engagement is the mechanistic basis through which the small-molecule modulator branaplam stabilizes long-lived U1 snRNP/5'SS complexes at bulged 5' splice sites [#7, #14]. U1-C also binds the splicing regulator TIA-1 to recruit U1 snRNP to weak 5' splice sites and contributes to RNA Pol II-controlled transcription of oncogenes by maintaining U1 snRNP stability [#5, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established the structural determinant by which U1-C joins the U1 snRNP, defining its zinc finger as the assembly module rather than an RNA-binding domain.\",\n      \"evidence\": \"Deletion and zinc-coordinating-residue mutagenesis with chemical modification and IP binding assays\",\n      \"pmids\": [\"1826349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the specific U1 snRNP protein(s) mediating recruitment\", \"No structural model of the zinc finger fold\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Resolved how U1-C is recruited, showing it depends on Sm proteins and the U1-70K N-terminal domain rather than direct snRNA binding.\",\n      \"evidence\": \"IP of in vitro translated proteins with core snRNPs, U1-70K deletion mapping, chemical crosslinking of purified U1 snRNP\",\n      \"pmids\": [\"8076607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and spatial arrangement of contacts not defined\", \"Did not address function at the 5'SS\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrated a functional requirement for U1-C in early spliceosome assembly, distinguishing it from U1-A.\",\n      \"evidence\": \"In vitro reconstitution of U1 snRNP from purified components and E-complex complementation in U1-depleted HeLa extracts\",\n      \"pmids\": [\"8972845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show how U1-C contacts the 5'SS RNA\", \"Mechanism of stimulation at atomic level unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Showed U1-C directly contacts 5'SS RNA and that initial recognition does not require base pairing, implicating protein contacts in early 5'SS engagement.\",\n      \"evidence\": \"UV crosslinking and binding kinetics of purified U1 snRNP with 5'SS oligonucleotides, RNase H cleavage\",\n      \"pmids\": [\"8798632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, crosslinking does not localize the contact at residue level\", \"Relative contributions of U1-C versus other proteins not separated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Placed U1-C in the dynamic splicing pathway, showing it stabilizes the U1/5'SS duplex and that Prp28 acts to counteract this stabilization.\",\n      \"evidence\": \"Genetic epistasis and suppressor mutations in yeast U1-C, growth assays\",\n      \"pmids\": [\"11172727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the L13 contact inferred genetically, not visualized\", \"Mechanism of Prp28-driven displacement not detailed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified TIA-1 as a direct U1-C partner that recruits U1 snRNP to weak 5' splice sites, extending U1-C function into regulated splice-site selection.\",\n      \"evidence\": \"Co-precipitation with recombinant protein fragments, RRM deletion analysis, splicing assays\",\n      \"pmids\": [\"12486009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interface residues on U1-C not mapped\", \"In vivo target sites of TIA-1/U1-C cooperation not enumerated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided the first structural placement of U1-C within the intact particle, showing the U1-70K N-terminus wraps the Sm core to contact U1-C.\",\n      \"evidence\": \"X-ray crystallography at 5.5 Å with site-specific labelling\",\n      \"pmids\": [\"19325628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Resolution insufficient for atomic contacts\", \"5'SS RNA not present in the structure\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed that U1-C is a dynamically exchanging subunit whose C-terminal tail and U1-70K isoform/phosphorylation state control its association.\",\n      \"evidence\": \"Native mass spectrometry of purified U1 snRNP comparing native and recombinant complexes\",\n      \"pmids\": [\"19784376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic inference from composition data, not direct kinetics\", \"Functional consequence of dynamic exchange not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Structurally rationalized the TIA-1/U1-C interaction by showing TIA-1 folds into a 'V' that juxtaposes its RRM1 and Q-domain to contact U1-C.\",\n      \"evidence\": \"ITC, SAXS, and RNA binding assays with TIA-1 deletion variants\",\n      \"pmids\": [\"22154808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-structure of the TIA-1/U1-C complex\", \"U1-C residues engaged not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped specific U1-C surface residues that fortify the U1/5'SS complex through contacts with the Sm core, linking the interface to Prp28 bypass.\",\n      \"evidence\": \"Alanine-scanning mutagenesis and yeast genetic interaction screens in Yhc1\",\n      \"pmids\": [\"24497193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast ortholog data; human residue equivalence inferred\", \"Direct biochemical affinity changes not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined at atomic resolution that U1-C stabilizes the U1 snRNA/5'SS duplex via backbone contacts without base-specific recognition, settling how it tunes splice-site affinity.\",\n      \"evidence\": \"Atomic-resolution X-ray crystallography with RNA binding assays; extended by yeast interface mutagenesis\",\n      \"pmids\": [\"25555158\", \"25897024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Engineered sub-structures rather than full native particle\", \"Dynamics of duplex stabilization not captured in static structure\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Visualized U1-C's role within native spliceosomes, showing it recognizes the 5'SS/U1 duplex in pre-B and is released as U1 snRNP dissociates in the B complex.\",\n      \"evidence\": \"Cryo-EM of yeast pre-B and B spliceosomal complexes at 3.3–4.6 Å\",\n      \"pmids\": [\"29794219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast complexes; human spliceosome transitions inferred\", \"Does not resolve the Prp28-catalyzed displacement intermediate\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked SNRPC dosage to alternative polyadenylation site usage at the transcriptome level.\",\n      \"evidence\": \"siRNA knockdown, overexpression, and transcriptome-level APA analysis\",\n      \"pmids\": [\"36073763\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"SNRPC-specific mechanism in APA not individually resolved\", \"Effect inferred from transcriptome readout, not direct binding\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected U1 snRNP stability via SNRPC to RNA Pol II-controlled oncogene transcription and tumor progression.\",\n      \"evidence\": \"In vivo CRISPR screen, CRISPR knockout, RNA Pol II ChIP, and in vivo TNBC tumor models\",\n      \"pmids\": [\"37057875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between U1 snRNP stability and Pol II enrichment not fully resolved\", \"Single lab\", \"Generality beyond TNBC oncogenes untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the kinetic mechanism by which U1-C's reversible binding enables small-molecule modulation, with branaplam binding only after the complex engages a bulged 5'SS.\",\n      \"evidence\": \"Colocalization single-molecule spectroscopy (CoSMoS) and ensemble kinetic measurements\",\n      \"pmids\": [\"39389991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of branaplam binding to the U1-C/5'SS complex not solved\", \"Generality across other splice-site sequences not exhaustively mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How U1-C's dynamic exchange and post-translational modification are regulated in vivo, and how its U1 snRNP-stabilizing role couples to transcription and 3'-end processing, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanistic account of SNRPC-specific contribution to APA\", \"Signaling/PTM control of U1-C exchange not defined in cells\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 9, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 9, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\n      \"U1 snRNP\",\n      \"spliceosomal E complex\",\n      \"pre-B spliceosome\"\n    ],\n    \"partners\": [\n      \"SNRNP70\",\n      \"SNRPB\",\n      \"TIA1\",\n      \"SNRPD3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}