{"gene":"SNRPA1","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":1998,"finding":"Crystal structure at 2.4 Å of the ternary U2B\"/U2A'/U2 snRNA hairpin-loop IV complex revealed that the concave surface of the leucine-rich-repeat (LRR) parallel beta-sheet of U2A' interacts with the RRM domain of U2B\" on the surface opposite its RNA-binding surface, while the basic C-terminal region of U2A' contacts the RNA stem. This protein-protein interaction is required for RNA-binding specificity of U2B\", explaining how U2B\" discriminates U2 hairpin IV from U1 hairpin II.","method":"X-ray crystallography (2.4 Å resolution) of recombinant ternary complex","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with direct structural interpretation of protein-protein and protein-RNA interfaces","pmids":["9716128"],"is_preprint":false},{"year":1991,"finding":"U2A' forms a weak but detectable direct interaction with U2 RNA and a stable protein-protein complex with U2B\"; the combined U2A'-U2B\" complex binds U2 RNA efficiently and specifically. Mutational analysis mapped the U2B\"-binding region of U2A' to amino acids 1-164, and mutation of residues 3-5 of U2A' reduced RNA binding, indicating U2A' contacts the stem of hairpin IV to stabilize the trimeric complex.","method":"RNA-protein and protein-protein binding assays with deletion/point mutants of U2A' and U2 RNA","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis of both protein and RNA, single lab but multiple orthogonal methods","pmids":["1826350"],"is_preprint":false},{"year":1998,"finding":"U2A' enables U2B\" to discriminate the loop sequence of U2hpIV from U1hpII but plays no role in stem sequence discrimination. U2A' binds U2B\" with ~500-fold higher affinity than U1A, and a single leucine residue (Leu-44) in U1A is critical for its intrinsic specificity for U1hpII over U2hpIV.","method":"In vitro RNA-binding and protein-protein interaction assays with point mutants; quantitative affinity measurements","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative in vitro binding assays with site-directed mutagenesis, single lab, multiple orthogonal readouts","pmids":["9814759"],"is_preprint":false},{"year":1998,"finding":"Yeast ortholog Lea1p (U2A') is a specific component of the yeast U2 snRNP. Lea1p directly interacts with Yib9p (U2B\" ortholog); in vivo association of Lea1p with U2 snRNA requires Yib9p, and reciprocally Yib9p requires Lea1p for U2 snRNA association in vivo. Strains lacking LEA1 and/or YIB9 have impaired pre-mRNA splicing, and in vitro spliceosome assembly is blocked prior to U2 snRNP addition; this defect is rescued by addition of recombinant protein(s).","method":"Genetic deletion (lea1Δ, yib9Δ), in vitro spliceosome assembly rescue with recombinant proteins, co-immunoprecipitation/co-purification with U2 snRNA","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis combined with in vitro reconstitution rescue and co-purification, single lab but multiple orthogonal methods","pmids":["9799242"],"is_preprint":false},{"year":2001,"finding":"Drosophila U2A' protein interacts with SNF (U2B\" ortholog) in vivo and is U2 snRNP-specific. Loss-of-function of U2A' causes lethality, demonstrating it is essential for U2 snRNP function. Importantly, U2A' does not require heterodimer formation with SNF for either its vital function or U2 snRNP assembly, indicating U2A' has an essential SNF/U2B\"-independent function.","method":"Genetic loss-of-function (null alleles), in vivo co-immunoprecipitation, domain interaction mapping","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic LOF with lethality phenotype, in vivo co-IP, domain mapping; single lab but multiple orthogonal methods","pmids":["11557816"],"is_preprint":false},{"year":2014,"finding":"U2A' binds U2B\" with nanomolar affinity but binds U1A with only micromolar affinity. There is RNA-dependent cooperativity (thermodynamic linkage) between protein-protein and protein-RNA binding in the U2A'/U2B\"/U2 snRNA complex formation. This combination of tight binding and cooperativity ensures that the U2A'/U2B\" complex is partitioned exclusively to the U2 snRNP.","method":"Fluorescence binding assays and isothermal titration calorimetry (ITC) measuring protein-protein and protein-RNA interactions","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative thermodynamic measurements by ITC and fluorescence, single lab, two orthogonal methods","pmids":["24866816"],"is_preprint":false},{"year":2015,"finding":"All three RNA-binding site mutations of SmD3 were lethal in cells lacking the U2 snRNP subunit Lea1 (yeast U2A'), and benign C-terminal truncations of SmD3 were also lethal in the absence of Lea1. Conversely, SMD3-E35A specifically suppressed the temperature-sensitivity of lea1Δ. These genetic interactions place Lea1/U2A' in an epistatic network with Sm proteins at the U1/U2 snRNP interface.","method":"Genetic epistasis analysis via double-mutant combinations (synthetic lethality and suppression) in yeast","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic genetic epistasis with multiple allele combinations, single lab","pmids":["25897024"],"is_preprint":false},{"year":2021,"finding":"SNRPA1 interacts with a structural splicing enhancer (RNA structural element) enriched near cassette exons to promote cassette exon inclusion in a non-canonical, context-dependent manner. SNRPA1-mediated regulation of PLEC alternative splicing promotes cancer cell invasion and metastatic lung colonization. This noncanonical splicing enhancer role was established by loss-of-function experiments and splicing modulating morpholinos.","method":"SNRPA1 loss-of-function, RNA structural analysis, splicing assays, invasion/metastasis functional assays, morpholino rescue","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNA structural mapping, LOF, splicing assays, morpholino rescue, in vivo metastasis), single lab","pmids":["33986153"],"is_preprint":false},{"year":2017,"finding":"SNRPA1 physically interacts with SNRPD1 and PNN in human pluripotent stem cells, co-localizing with hPS spliceosomes. SNRPA1 depletion causes loss of pluripotency and blocks hiPS generation, and reduces hPS spliceosome assembly, defining a role for SNRPA1 in pluripotency-specific spliceosome assembly.","method":"Co-immunoprecipitation, co-localization imaging, shRNA knockdown with pluripotency and spliceosome assembly readouts","journal":"Stem cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional KD with defined cellular phenotype, single lab, multiple readouts","pmids":["28595116"],"is_preprint":false},{"year":2020,"finding":"SNRPA1 expression in hepatocellular carcinoma cells is stimulated by mTOR activation. Knockdown of SNRPA1 inhibited HCC cell proliferation and xenograft tumorigenesis, induced apoptosis, and altered expression of FGF2, AFP, β-catenin, Ki-67, cyclin B1, caspase 3, p53, and p21.","method":"shRNA knockdown, mTOR activation/inhibition, xenograft mouse model, microarray gene profiling, qPCR","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mTOR-SNRPA1 regulatory link demonstrated by activation/knockdown, LOF phenotype in vitro and in vivo, single lab","pmids":["32420585"],"is_preprint":false},{"year":2026,"finding":"METTL3 and IGF2BP2 stabilize SNRPA1 mRNA through m6A methylation modification. SNRPA1 protein interacts with TWIST1 in NSCLC cells (Co-IP), and TWIST1 overexpression attenuates SNRPA1 knockdown-induced suppression of proliferation/migration/invasion. In vivo, SNRPA1 overexpression rescued the anti-tumor effects of METTL3 depletion.","method":"RIP assay, dual-luciferase reporter assay, actinomycin D mRNA stability assay, Co-IP, xenograft and lung metastasis models","journal":"Cytotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RIP, Co-IP, reporter assay, in vivo rescue), single lab","pmids":["41841152"],"is_preprint":false},{"year":2025,"finding":"lncRNA ENST00000458139 (lnc458) physically interacts with SNRPA1 protein (identified by biotin-labeled RNA pulldown + mass spectrometry). SNRPA1 mediates MYC transactivation downstream of lnc458, leading to upregulation of DDIT4 and mitochondrial dysfunction/apoptosis in podocytes.","method":"Biotin-labeled RNA pulldown followed by mass spectrometry, RNA-seq, gain/loss-of-function","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNA pulldown + MS identification of SNRPA1 as lnc458 binding partner, functional downstream pathway defined, single lab","pmids":["40680608"],"is_preprint":false},{"year":2026,"finding":"SNRPA1 and DHM (dihydromethysticin) regulate c-MYC expression through affecting c-MYC protein stability. Downregulation of SNRPA1 by DHM increases c-MYC protein degradation, inhibiting Cr(VI)-induced cell transformation and cancer stemness properties.","method":"Western blot for c-MYC stability (CHX chase implied), knockdown/overexpression, soft agar colony formation, xenograft tumorigenesis","journal":"Chemical research in toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — c-MYC protein stability regulation by SNRPA1 inferred from knockdown/expression data, single lab, mechanism not directly reconstituted","pmids":["42135982"],"is_preprint":false}],"current_model":"SNRPA1 (U2A') is a leucine-rich-repeat protein that forms a stable heterodimer with U2B\" via its concave LRR surface, enabling U2B\" to bind specifically to U2 snRNA hairpin IV with nanomolar affinity and RNA-dependent cooperativity, thereby assembling into the U2 snRNP and facilitating pre-spliceosome formation; beyond this canonical spliceosomal role, SNRPA1 also functions as a noncanonical splicing enhancer by binding structured RNA elements near cassette exons to regulate alternative splicing (including of PLEC) in a prometastatic context, and its expression is regulated post-transcriptionally by METTL3/IGF2BP2-mediated m6A methylation."},"narrative":{"mechanistic_narrative":"SNRPA1 (U2A') is a leucine-rich-repeat protein that defines the U2 small nuclear ribonucleoprotein (snRNP) by forming a stable heterodimer with U2B\" and conferring on it the specificity required for pre-spliceosome assembly [PMID:9716128, PMID:9799242]. Crystallographic analysis of the ternary U2B\"/U2A'/U2 snRNA hairpin-loop IV complex shows that the concave LRR beta-sheet of U2A' clamps the RRM of U2B\" on the face opposite its RNA-binding surface, while the basic C-terminal region of U2A' contacts the RNA stem; this protein-protein interface is what allows U2B\" to discriminate U2 hairpin IV from U1 hairpin II [PMID:9716128, PMID:9814759]. Thermodynamically, U2A' binds U2B\" with nanomolar affinity and exhibits RNA-dependent cooperativity, ensuring the U2A'/U2B\" module partitions exclusively into the U2 snRNP [PMID:24866816]. In yeast and Drosophila the orthologs are U2 snRNP-specific and essential, with reciprocal dependence between U2A' and U2B\" for U2 snRNA association and a spliceosome assembly block prior to U2 snRNP addition; notably, the Drosophila protein retains an essential function independent of heterodimerization [PMID:9799242, PMID:11557816]. Beyond this canonical role, SNRPA1 acts as a noncanonical splicing enhancer that binds structured RNA elements near cassette exons to promote exon inclusion, and through regulation of PLEC alternative splicing drives cancer cell invasion and metastatic lung colonization [PMID:33986153]. Its expression is controlled post-transcriptionally by METTL3/IGF2BP2-mediated m6A stabilization of SNRPA1 mRNA, and in tumor contexts SNRPA1 engages TWIST1 and modulates c-MYC-dependent transcription and proliferation [PMID:41841152]. SNRPA1 is also required for pluripotency-specific spliceosome assembly, physically associating with SNRPD1 and PNN [PMID:28595116].","teleology":[{"year":1991,"claim":"Established that U2A' is not a stand-alone RNA-binding protein but functions by forming a stable heterodimer with U2B\" that is required for efficient and specific U2 RNA recognition.","evidence":"In vitro RNA-protein and protein-protein binding assays with deletion/point mutants of U2A' and U2 RNA","pmids":["1826350"],"confidence":"High","gaps":["Structural basis of specificity not resolved","Affinity values not quantified"]},{"year":1998,"claim":"Defined the structural and thermodynamic logic of U2 snRNP assembly: the LRR concave surface of U2A' binds the U2B\" RRM and dictates loop discrimination between U2hpIV and U1hpII.","evidence":"2.4 Å crystal structure of the ternary complex plus quantitative in vitro binding with point mutants","pmids":["9716128","9814759"],"confidence":"High","gaps":["Does not address in vivo dynamics of complex assembly","Cooperativity not yet quantified thermodynamically"]},{"year":1998,"claim":"Demonstrated in vivo that the U2A' ortholog (Lea1p) is a U2 snRNP-specific component with reciprocal dependence on the U2B\" ortholog for snRNA association and is needed for spliceosome assembly prior to U2 addition.","evidence":"Yeast gene deletion, co-purification with U2 snRNA, and in vitro spliceosome assembly rescue with recombinant proteins","pmids":["9799242"],"confidence":"High","gaps":["Genetic redundancy with other factors unresolved","Mechanism of pre-U2 assembly block not detailed"]},{"year":2001,"claim":"Revealed that U2A' has an essential function that does not require heterodimerization with U2B\", separating its vital role from canonical complex formation.","evidence":"Drosophila null alleles, in vivo co-IP, and domain interaction mapping","pmids":["11557816"],"confidence":"High","gaps":["The identity of the heterodimer-independent function is not defined","Not validated in mammalian cells"]},{"year":2014,"claim":"Quantified the thermodynamic linkage explaining specificity: nanomolar U2A'/U2B\" binding plus RNA-dependent cooperativity partitions the module exclusively to U2 snRNP rather than U1.","evidence":"ITC and fluorescence binding measurements of protein-protein and protein-RNA interactions","pmids":["24866816"],"confidence":"High","gaps":["Cellular concentrations driving partitioning not measured","Does not address regulation in vivo"]},{"year":2015,"claim":"Placed U2A'/Lea1 in a genetic network with Sm proteins at the U1/U2 snRNP interface through synthetic lethal and suppression interactions.","evidence":"Yeast double-mutant epistasis analysis with SmD3 alleles","pmids":["25897024"],"confidence":"Medium","gaps":["Physical basis of the genetic interactions not shown","Yeast-specific; not tested in human cells"]},{"year":2017,"claim":"Extended SNRPA1 function to a cell-state-specific role, showing it is required for pluripotency-specific spliceosome assembly via physical association with SNRPD1 and PNN.","evidence":"Co-IP, co-localization imaging, and shRNA knockdown in human pluripotent stem cells","pmids":["28595116"],"confidence":"Medium","gaps":["Whether spliceosome role differs mechanistically from canonical U2 function unclear","Direct vs indirect interaction with PNN not resolved"]},{"year":2020,"claim":"Connected SNRPA1 to growth signaling and tumorigenesis by showing mTOR-driven expression and a proliferative/anti-apoptotic requirement in hepatocellular carcinoma.","evidence":"shRNA knockdown, mTOR modulation, xenograft model, and gene expression profiling","pmids":["32420585"],"confidence":"Medium","gaps":["Whether tumor phenotype reflects splicing activity not established","Direct targets among altered genes not defined"]},{"year":2021,"claim":"Defined a noncanonical, splicing-enhancer activity in which SNRPA1 binds structured RNA elements near cassette exons to promote inclusion, driving metastasis through PLEC.","evidence":"RNA structural mapping, loss-of-function, splicing assays, morpholino rescue, and in vivo metastasis assays","pmids":["33986153"],"confidence":"High","gaps":["Relationship between noncanonical and canonical U2 snRNP roles unclear","Full target repertoire beyond PLEC not mapped"]},{"year":2025,"claim":"Identified SNRPA1 as an effector of lncRNA signaling, mediating MYC transactivation downstream of lnc458 to drive DDIT4 expression and podocyte apoptosis.","evidence":"Biotin-RNA pulldown with mass spectrometry, RNA-seq, and gain/loss-of-function","pmids":["40680608"],"confidence":"Medium","gaps":["Mechanism by which SNRPA1 mediates MYC transactivation not resolved","Direct vs indirect lnc458 binding effect on MYC unclear"]},{"year":2026,"claim":"Mapped upstream control and downstream effectors of SNRPA1 in cancer: m6A stabilization of its mRNA by METTL3/IGF2BP2 and physical interaction with TWIST1, plus regulation of c-MYC protein stability.","evidence":"RIP, dual-luciferase, mRNA stability assay, Co-IP, and xenograft/metastasis rescue models","pmids":["41841152","42135982"],"confidence":"Medium","gaps":["Direct biochemical mechanism of c-MYC stability regulation not reconstituted","TWIST1 interaction interface undefined"]},{"year":null,"claim":"The molecular basis of SNRPA1's heterodimer-independent and noncanonical activities — and how these relate to its canonical U2 snRNP role — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model for SNRPA1 binding to noncanonical structured RNA elements","No defined molecular link between spliceosomal and transcriptional/oncogenic functions","Heterodimer-independent essential function still uncharacterized at the molecular level"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,5,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,8]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,7]}],"complexes":["U2 snRNP","spliceosome"],"partners":["SNRPB2","SNRPD1","PNN","TWIST1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P09661","full_name":"U2 small nuclear ribonucleoprotein A'","aliases":[],"length_aa":255,"mass_kda":28.4,"function":"Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:27035939, PubMed:28076346, PubMed:28502770, PubMed:28781166, PubMed:32494006). Associated with sn-RNP U2, where it contributes to the binding of stem loop IV of U2 snRNA (PubMed:27035939, PubMed:32494006, PubMed:9716128)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P09661/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SNRPA1","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PRPF4B","stoichiometry":10.0},{"gene":"RANBP2","stoichiometry":10.0},{"gene":"RBM17","stoichiometry":10.0},{"gene":"SF3A1","stoichiometry":10.0},{"gene":"SF3A2","stoichiometry":10.0},{"gene":"SF3A3","stoichiometry":10.0},{"gene":"SF3B1","stoichiometry":10.0},{"gene":"SF3B2","stoichiometry":10.0},{"gene":"SF3B3","stoichiometry":10.0},{"gene":"SF3B5","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/SNRPA1","total_profiled":1310},"omim":[{"mim_id":"603521","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE A-PRIME; SNRPA1","url":"https://www.omim.org/entry/603521"},{"mim_id":"603520","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE B-DOUBLE PRIME; SNRPB2","url":"https://www.omim.org/entry/603520"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNRPA1"},"hgnc":{"alias_symbol":["Lea1","U2A'"],"prev_symbol":[]},"alphafold":{"accession":"P09661","domains":[{"cath_id":"3.80.10.10","chopping":"5-174","consensus_level":"high","plddt":97.2639,"start":5,"end":174}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09661","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09661-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09661-F1-predicted_aligned_error_v6.png","plddt_mean":87.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNRPA1","jax_strain_url":"https://www.jax.org/strain/search?query=SNRPA1"},"sequence":{"accession":"P09661","fasta_url":"https://rest.uniprot.org/uniprotkb/P09661.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09661/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09661"}},"corpus_meta":[{"pmid":"9716128","id":"PMC_9716128","title":"Crystal structure of the spliceosomal U2B\"-U2A' protein complex bound to a fragment of U2 small nuclear RNA.","date":"1998","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9716128","citation_count":313,"is_preprint":false},{"pmid":"33986153","id":"PMC_33986153","title":"A prometastatic splicing program regulated by SNRPA1 interactions with structured RNA elements.","date":"2021","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/33986153","citation_count":59,"is_preprint":false},{"pmid":"9799242","id":"PMC_9799242","title":"The yeast U2A'/U2B complex is required for pre-spliceosome formation.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9799242","citation_count":48,"is_preprint":false},{"pmid":"1826350","id":"PMC_1826350","title":"A weak interaction between the U2A' protein and U2 snRNA helps to stabilize their complex with the U2B\" protein.","date":"1991","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1826350","citation_count":42,"is_preprint":false},{"pmid":"31203132","id":"PMC_31203132","title":"An oncogenic gene, SNRPA1, regulates PIK3R1, VEGFC, MKI67, CDK1 and other genes in colorectal cancer.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/31203132","citation_count":28,"is_preprint":false},{"pmid":"28595116","id":"PMC_28595116","title":"The unique spliceosome signature of human pluripotent stem cells is mediated by SNRPA1, SNRPD1, and PNN.","date":"2017","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/28595116","citation_count":26,"is_preprint":false},{"pmid":"35281041","id":"PMC_35281041","title":"Elevated SNRPA1, as a Promising Predictor Reflecting Severe Clinical Outcome via Effecting Tumor Immunity for ccRCC, Is Related to Cell Invasion, Metastasis, and Sunitinib Sensitivity.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35281041","citation_count":25,"is_preprint":false},{"pmid":"9814759","id":"PMC_9814759","title":"Target discrimination by RNA-binding proteins: role of the ancillary protein U2A' and a critical leucine residue in differentiating the RNA-binding specificity of spliceosomal proteins U1A and U2B\".","date":"1998","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9814759","citation_count":25,"is_preprint":false},{"pmid":"25897024","id":"PMC_25897024","title":"Structure-function analysis and genetic interactions of the Yhc1, SmD3, SmB, and Snp1 subunits of yeast U1 snRNP and genetic interactions of SmD3 with U2 snRNP subunit Lea1.","date":"2015","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/25897024","citation_count":17,"is_preprint":false},{"pmid":"11557816","id":"PMC_11557816","title":"The Drosophila U2 snRNP protein U2A' has an essential function that is SNF/U2B\" independent.","date":"2001","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/11557816","citation_count":15,"is_preprint":false},{"pmid":"24866816","id":"PMC_24866816","title":"Binding affinity and cooperativity control U2B″/snRNA/U2A' RNP formation.","date":"2014","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24866816","citation_count":13,"is_preprint":false},{"pmid":"8642844","id":"PMC_8642844","title":"Clinical significance of LEA-1 expression in adult acute myeloid leukemia.","date":"1996","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/8642844","citation_count":10,"is_preprint":false},{"pmid":"32420585","id":"PMC_32420585","title":"mTOR up-regulation of SNRPA1 contributes to hepatocellular carcinoma development.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32420585","citation_count":7,"is_preprint":false},{"pmid":"21455835","id":"PMC_21455835","title":"Polyproline II structure is critical for the enzyme protective function of soybean Em (LEA1) conserved domains.","date":"2011","source":"Biotechnology letters","url":"https://pubmed.ncbi.nlm.nih.gov/21455835","citation_count":6,"is_preprint":false},{"pmid":"34940917","id":"PMC_34940917","title":"Phylogeny and conservation of plant U2A/U2A', a core splicing component in U2 spliceosomal complex.","date":"2021","source":"Planta","url":"https://pubmed.ncbi.nlm.nih.gov/34940917","citation_count":5,"is_preprint":false},{"pmid":"35053361","id":"PMC_35053361","title":"Accumulation of Glycogen and Upregulation of LEA-1 in C. elegans daf-2(e1370) Support Stress Resistance, Not Longevity.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35053361","citation_count":5,"is_preprint":false},{"pmid":"20858208","id":"PMC_20858208","title":"Conformational variation revealed by the crystal structure of RNase U2A complexed with Ca ion and 2'-adenylic acid at 1.03 Å resolution.","date":"2010","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/20858208","citation_count":5,"is_preprint":false},{"pmid":"37806618","id":"PMC_37806618","title":"A U2 snRNP-specific protein, U2A', is involved in stress response and drug resistance in Cryptococcus deneoformans.","date":"2023","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/37806618","citation_count":2,"is_preprint":false},{"pmid":"41104127","id":"PMC_41104127","title":"TIGIT and SNRPA1 as novel diagnostic and predictive biomarkers in obstructive ventilatory dysfunction combined with pulmonary nontuberculous mycobacterial infection patients.","date":"2025","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41104127","citation_count":1,"is_preprint":false},{"pmid":"41841152","id":"PMC_41841152","title":"METTL3/IGF2BP2 mediates m6A methylation modification of SNRPA1 to promote tumor property of non-small cell lung cancer cells.","date":"2026","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/41841152","citation_count":1,"is_preprint":false},{"pmid":"40680608","id":"PMC_40680608","title":"Long noncoding RNA ENST00000458139 promotes mitochondrial dysfunction and apoptosis of podocytes in diabetic kidney disease through binding with SNRPA1.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40680608","citation_count":0,"is_preprint":false},{"pmid":"42135982","id":"PMC_42135982","title":"AB-Free Kava and Dihydromethysticin Inhibit Chronic Hexavalent Chromium Exposure-Induced Cell Malignant Transformation through Down-Regulating RNA Splicing Factor SNRPA1 Expression.","date":"2026","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/42135982","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12881,"output_tokens":3517,"usd":0.045699,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11072,"output_tokens":3574,"usd":0.072355,"stage2_stop_reason":"end_turn"},"total_usd":0.118054,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Crystal structure at 2.4 Å of the ternary U2B\\\"/U2A'/U2 snRNA hairpin-loop IV complex revealed that the concave surface of the leucine-rich-repeat (LRR) parallel beta-sheet of U2A' interacts with the RRM domain of U2B\\\" on the surface opposite its RNA-binding surface, while the basic C-terminal region of U2A' contacts the RNA stem. This protein-protein interaction is required for RNA-binding specificity of U2B\\\", explaining how U2B\\\" discriminates U2 hairpin IV from U1 hairpin II.\",\n      \"method\": \"X-ray crystallography (2.4 Å resolution) of recombinant ternary complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with direct structural interpretation of protein-protein and protein-RNA interfaces\",\n      \"pmids\": [\"9716128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"U2A' forms a weak but detectable direct interaction with U2 RNA and a stable protein-protein complex with U2B\\\"; the combined U2A'-U2B\\\" complex binds U2 RNA efficiently and specifically. Mutational analysis mapped the U2B\\\"-binding region of U2A' to amino acids 1-164, and mutation of residues 3-5 of U2A' reduced RNA binding, indicating U2A' contacts the stem of hairpin IV to stabilize the trimeric complex.\",\n      \"method\": \"RNA-protein and protein-protein binding assays with deletion/point mutants of U2A' and U2 RNA\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis of both protein and RNA, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"1826350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"U2A' enables U2B\\\" to discriminate the loop sequence of U2hpIV from U1hpII but plays no role in stem sequence discrimination. U2A' binds U2B\\\" with ~500-fold higher affinity than U1A, and a single leucine residue (Leu-44) in U1A is critical for its intrinsic specificity for U1hpII over U2hpIV.\",\n      \"method\": \"In vitro RNA-binding and protein-protein interaction assays with point mutants; quantitative affinity measurements\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative in vitro binding assays with site-directed mutagenesis, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"9814759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast ortholog Lea1p (U2A') is a specific component of the yeast U2 snRNP. Lea1p directly interacts with Yib9p (U2B\\\" ortholog); in vivo association of Lea1p with U2 snRNA requires Yib9p, and reciprocally Yib9p requires Lea1p for U2 snRNA association in vivo. Strains lacking LEA1 and/or YIB9 have impaired pre-mRNA splicing, and in vitro spliceosome assembly is blocked prior to U2 snRNP addition; this defect is rescued by addition of recombinant protein(s).\",\n      \"method\": \"Genetic deletion (lea1Δ, yib9Δ), in vitro spliceosome assembly rescue with recombinant proteins, co-immunoprecipitation/co-purification with U2 snRNA\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis combined with in vitro reconstitution rescue and co-purification, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"9799242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Drosophila U2A' protein interacts with SNF (U2B\\\" ortholog) in vivo and is U2 snRNP-specific. Loss-of-function of U2A' causes lethality, demonstrating it is essential for U2 snRNP function. Importantly, U2A' does not require heterodimer formation with SNF for either its vital function or U2 snRNP assembly, indicating U2A' has an essential SNF/U2B\\\"-independent function.\",\n      \"method\": \"Genetic loss-of-function (null alleles), in vivo co-immunoprecipitation, domain interaction mapping\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic LOF with lethality phenotype, in vivo co-IP, domain mapping; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"11557816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"U2A' binds U2B\\\" with nanomolar affinity but binds U1A with only micromolar affinity. There is RNA-dependent cooperativity (thermodynamic linkage) between protein-protein and protein-RNA binding in the U2A'/U2B\\\"/U2 snRNA complex formation. This combination of tight binding and cooperativity ensures that the U2A'/U2B\\\" complex is partitioned exclusively to the U2 snRNP.\",\n      \"method\": \"Fluorescence binding assays and isothermal titration calorimetry (ITC) measuring protein-protein and protein-RNA interactions\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative thermodynamic measurements by ITC and fluorescence, single lab, two orthogonal methods\",\n      \"pmids\": [\"24866816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"All three RNA-binding site mutations of SmD3 were lethal in cells lacking the U2 snRNP subunit Lea1 (yeast U2A'), and benign C-terminal truncations of SmD3 were also lethal in the absence of Lea1. Conversely, SMD3-E35A specifically suppressed the temperature-sensitivity of lea1Δ. These genetic interactions place Lea1/U2A' in an epistatic network with Sm proteins at the U1/U2 snRNP interface.\",\n      \"method\": \"Genetic epistasis analysis via double-mutant combinations (synthetic lethality and suppression) in yeast\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic genetic epistasis with multiple allele combinations, single lab\",\n      \"pmids\": [\"25897024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNRPA1 interacts with a structural splicing enhancer (RNA structural element) enriched near cassette exons to promote cassette exon inclusion in a non-canonical, context-dependent manner. SNRPA1-mediated regulation of PLEC alternative splicing promotes cancer cell invasion and metastatic lung colonization. This noncanonical splicing enhancer role was established by loss-of-function experiments and splicing modulating morpholinos.\",\n      \"method\": \"SNRPA1 loss-of-function, RNA structural analysis, splicing assays, invasion/metastasis functional assays, morpholino rescue\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNA structural mapping, LOF, splicing assays, morpholino rescue, in vivo metastasis), single lab\",\n      \"pmids\": [\"33986153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SNRPA1 physically interacts with SNRPD1 and PNN in human pluripotent stem cells, co-localizing with hPS spliceosomes. SNRPA1 depletion causes loss of pluripotency and blocks hiPS generation, and reduces hPS spliceosome assembly, defining a role for SNRPA1 in pluripotency-specific spliceosome assembly.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging, shRNA knockdown with pluripotency and spliceosome assembly readouts\",\n      \"journal\": \"Stem cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional KD with defined cellular phenotype, single lab, multiple readouts\",\n      \"pmids\": [\"28595116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SNRPA1 expression in hepatocellular carcinoma cells is stimulated by mTOR activation. Knockdown of SNRPA1 inhibited HCC cell proliferation and xenograft tumorigenesis, induced apoptosis, and altered expression of FGF2, AFP, β-catenin, Ki-67, cyclin B1, caspase 3, p53, and p21.\",\n      \"method\": \"shRNA knockdown, mTOR activation/inhibition, xenograft mouse model, microarray gene profiling, qPCR\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mTOR-SNRPA1 regulatory link demonstrated by activation/knockdown, LOF phenotype in vitro and in vivo, single lab\",\n      \"pmids\": [\"32420585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"METTL3 and IGF2BP2 stabilize SNRPA1 mRNA through m6A methylation modification. SNRPA1 protein interacts with TWIST1 in NSCLC cells (Co-IP), and TWIST1 overexpression attenuates SNRPA1 knockdown-induced suppression of proliferation/migration/invasion. In vivo, SNRPA1 overexpression rescued the anti-tumor effects of METTL3 depletion.\",\n      \"method\": \"RIP assay, dual-luciferase reporter assay, actinomycin D mRNA stability assay, Co-IP, xenograft and lung metastasis models\",\n      \"journal\": \"Cytotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RIP, Co-IP, reporter assay, in vivo rescue), single lab\",\n      \"pmids\": [\"41841152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"lncRNA ENST00000458139 (lnc458) physically interacts with SNRPA1 protein (identified by biotin-labeled RNA pulldown + mass spectrometry). SNRPA1 mediates MYC transactivation downstream of lnc458, leading to upregulation of DDIT4 and mitochondrial dysfunction/apoptosis in podocytes.\",\n      \"method\": \"Biotin-labeled RNA pulldown followed by mass spectrometry, RNA-seq, gain/loss-of-function\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNA pulldown + MS identification of SNRPA1 as lnc458 binding partner, functional downstream pathway defined, single lab\",\n      \"pmids\": [\"40680608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SNRPA1 and DHM (dihydromethysticin) regulate c-MYC expression through affecting c-MYC protein stability. Downregulation of SNRPA1 by DHM increases c-MYC protein degradation, inhibiting Cr(VI)-induced cell transformation and cancer stemness properties.\",\n      \"method\": \"Western blot for c-MYC stability (CHX chase implied), knockdown/overexpression, soft agar colony formation, xenograft tumorigenesis\",\n      \"journal\": \"Chemical research in toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — c-MYC protein stability regulation by SNRPA1 inferred from knockdown/expression data, single lab, mechanism not directly reconstituted\",\n      \"pmids\": [\"42135982\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNRPA1 (U2A') is a leucine-rich-repeat protein that forms a stable heterodimer with U2B\\\" via its concave LRR surface, enabling U2B\\\" to bind specifically to U2 snRNA hairpin IV with nanomolar affinity and RNA-dependent cooperativity, thereby assembling into the U2 snRNP and facilitating pre-spliceosome formation; beyond this canonical spliceosomal role, SNRPA1 also functions as a noncanonical splicing enhancer by binding structured RNA elements near cassette exons to regulate alternative splicing (including of PLEC) in a prometastatic context, and its expression is regulated post-transcriptionally by METTL3/IGF2BP2-mediated m6A methylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNRPA1 (U2A') is a leucine-rich-repeat protein that defines the U2 small nuclear ribonucleoprotein (snRNP) by forming a stable heterodimer with U2B\\\" and conferring on it the specificity required for pre-spliceosome assembly [#0, #3]. Crystallographic analysis of the ternary U2B\\\"/U2A'/U2 snRNA hairpin-loop IV complex shows that the concave LRR beta-sheet of U2A' clamps the RRM of U2B\\\" on the face opposite its RNA-binding surface, while the basic C-terminal region of U2A' contacts the RNA stem; this protein-protein interface is what allows U2B\\\" to discriminate U2 hairpin IV from U1 hairpin II [#0, #2]. Thermodynamically, U2A' binds U2B\\\" with nanomolar affinity and exhibits RNA-dependent cooperativity, ensuring the U2A'/U2B\\\" module partitions exclusively into the U2 snRNP [#5]. In yeast and Drosophila the orthologs are U2 snRNP-specific and essential, with reciprocal dependence between U2A' and U2B\\\" for U2 snRNA association and a spliceosome assembly block prior to U2 snRNP addition; notably, the Drosophila protein retains an essential function independent of heterodimerization [#3, #4]. Beyond this canonical role, SNRPA1 acts as a noncanonical splicing enhancer that binds structured RNA elements near cassette exons to promote exon inclusion, and through regulation of PLEC alternative splicing drives cancer cell invasion and metastatic lung colonization [#7]. Its expression is controlled post-transcriptionally by METTL3/IGF2BP2-mediated m6A stabilization of SNRPA1 mRNA, and in tumor contexts SNRPA1 engages TWIST1 and modulates c-MYC-dependent transcription and proliferation [#10]. SNRPA1 is also required for pluripotency-specific spliceosome assembly, physically associating with SNRPD1 and PNN [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established that U2A' is not a stand-alone RNA-binding protein but functions by forming a stable heterodimer with U2B\\\" that is required for efficient and specific U2 RNA recognition.\",\n      \"evidence\": \"In vitro RNA-protein and protein-protein binding assays with deletion/point mutants of U2A' and U2 RNA\",\n      \"pmids\": [\"1826350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of specificity not resolved\", \"Affinity values not quantified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the structural and thermodynamic logic of U2 snRNP assembly: the LRR concave surface of U2A' binds the U2B\\\" RRM and dictates loop discrimination between U2hpIV and U1hpII.\",\n      \"evidence\": \"2.4 Å crystal structure of the ternary complex plus quantitative in vitro binding with point mutants\",\n      \"pmids\": [\"9716128\", \"9814759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address in vivo dynamics of complex assembly\", \"Cooperativity not yet quantified thermodynamically\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated in vivo that the U2A' ortholog (Lea1p) is a U2 snRNP-specific component with reciprocal dependence on the U2B\\\" ortholog for snRNA association and is needed for spliceosome assembly prior to U2 addition.\",\n      \"evidence\": \"Yeast gene deletion, co-purification with U2 snRNA, and in vitro spliceosome assembly rescue with recombinant proteins\",\n      \"pmids\": [\"9799242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genetic redundancy with other factors unresolved\", \"Mechanism of pre-U2 assembly block not detailed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Revealed that U2A' has an essential function that does not require heterodimerization with U2B\\\", separating its vital role from canonical complex formation.\",\n      \"evidence\": \"Drosophila null alleles, in vivo co-IP, and domain interaction mapping\",\n      \"pmids\": [\"11557816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The identity of the heterodimer-independent function is not defined\", \"Not validated in mammalian cells\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Quantified the thermodynamic linkage explaining specificity: nanomolar U2A'/U2B\\\" binding plus RNA-dependent cooperativity partitions the module exclusively to U2 snRNP rather than U1.\",\n      \"evidence\": \"ITC and fluorescence binding measurements of protein-protein and protein-RNA interactions\",\n      \"pmids\": [\"24866816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular concentrations driving partitioning not measured\", \"Does not address regulation in vivo\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed U2A'/Lea1 in a genetic network with Sm proteins at the U1/U2 snRNP interface through synthetic lethal and suppression interactions.\",\n      \"evidence\": \"Yeast double-mutant epistasis analysis with SmD3 alleles\",\n      \"pmids\": [\"25897024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physical basis of the genetic interactions not shown\", \"Yeast-specific; not tested in human cells\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended SNRPA1 function to a cell-state-specific role, showing it is required for pluripotency-specific spliceosome assembly via physical association with SNRPD1 and PNN.\",\n      \"evidence\": \"Co-IP, co-localization imaging, and shRNA knockdown in human pluripotent stem cells\",\n      \"pmids\": [\"28595116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether spliceosome role differs mechanistically from canonical U2 function unclear\", \"Direct vs indirect interaction with PNN not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected SNRPA1 to growth signaling and tumorigenesis by showing mTOR-driven expression and a proliferative/anti-apoptotic requirement in hepatocellular carcinoma.\",\n      \"evidence\": \"shRNA knockdown, mTOR modulation, xenograft model, and gene expression profiling\",\n      \"pmids\": [\"32420585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether tumor phenotype reflects splicing activity not established\", \"Direct targets among altered genes not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a noncanonical, splicing-enhancer activity in which SNRPA1 binds structured RNA elements near cassette exons to promote inclusion, driving metastasis through PLEC.\",\n      \"evidence\": \"RNA structural mapping, loss-of-function, splicing assays, morpholino rescue, and in vivo metastasis assays\",\n      \"pmids\": [\"33986153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between noncanonical and canonical U2 snRNP roles unclear\", \"Full target repertoire beyond PLEC not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified SNRPA1 as an effector of lncRNA signaling, mediating MYC transactivation downstream of lnc458 to drive DDIT4 expression and podocyte apoptosis.\",\n      \"evidence\": \"Biotin-RNA pulldown with mass spectrometry, RNA-seq, and gain/loss-of-function\",\n      \"pmids\": [\"40680608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SNRPA1 mediates MYC transactivation not resolved\", \"Direct vs indirect lnc458 binding effect on MYC unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mapped upstream control and downstream effectors of SNRPA1 in cancer: m6A stabilization of its mRNA by METTL3/IGF2BP2 and physical interaction with TWIST1, plus regulation of c-MYC protein stability.\",\n      \"evidence\": \"RIP, dual-luciferase, mRNA stability assay, Co-IP, and xenograft/metastasis rescue models\",\n      \"pmids\": [\"41841152\", \"42135982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism of c-MYC stability regulation not reconstituted\", \"TWIST1 interaction interface undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis of SNRPA1's heterodimer-independent and noncanonical activities — and how these relate to its canonical U2 snRNP role — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model for SNRPA1 binding to noncanonical structured RNA elements\", \"No defined molecular link between spliceosomal and transcriptional/oncogenic functions\", \"Heterodimer-independent essential function still uncharacterized at the molecular level\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 5, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 7]}\n    ],\n    \"complexes\": [\"U2 snRNP\", \"spliceosome\"],\n    \"partners\": [\"SNRPB2\", \"SNRPD1\", \"PNN\", \"TWIST1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}