{"gene":"SF3B3","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2001,"finding":"S. pombe Prp12p (ortholog of human SF3B3/SAP130) is a subunit of the SF3b complex of U2 snRNP and is required for pre-mRNA splicing; genetic interaction with Prp10p (SAP155/SF3b155 ortholog) was demonstrated. Loss-of-function causes selective splicing defects and cell-cycle arrest (elongated cells, G2/M block), with the cdc phenotype attributable to failure to splice a limiting transcript required for G2/M transition. GFP-tagged Prp12p localizes uniformly in the nuclear DNA region.","method":"Temperature-sensitive mutant analysis, northern blot splicing kinetics, genetic interaction (prp12/prp10), GFP tagging and fluorescence microscopy in S. pombe","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic epistasis, splicing assays, localization), replicated across multiple prp mutants in same study","pmids":["11350031"],"is_preprint":false},{"year":1998,"finding":"S. cerevisiae RSE1 (ortholog of human SF3B3) is required for pre-mRNA splicing; rse1-1 mutants accumulate unspliced SAR1 pre-mRNA, causing a secondary ER-to-Golgi secretion defect that is rescued by increasing SAR1 dosage or deleting the SAR1 intron, placing RSE1 upstream of SAR1 splicing in the secretory pathway.","method":"Temperature-sensitive mutant screen, genetic suppression (SAR1 overexpression or intron deletion), accumulation of ER forms of invertase and CPY as secretion readout","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis confirmed by two independent suppression strategies, clean genetic placement of RSE1 in splicing upstream of SAR1","pmids":["9819400"],"is_preprint":false},{"year":2016,"finding":"SF3B3 stimulates inclusion of alternative exon 14 in EZH2 pre-mRNA in renal cancer cells, generating a dominant-negative EZH2Δ14 isoform that abrogates EZH2-mediated suppression of DAB2IP and HOXA9 and inhibits EZH2-driven tumorigenesis; SF3B3 knockdown reduces exon 14 inclusion and promotes tumor growth.","method":"RT-PCR splicing assay, siRNA knockdown, ectopic expression, xenograft tumor model, western blot","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (in vitro + in vivo xenograft), single lab, no in vitro reconstitution of splicing","pmids":["27879367"],"is_preprint":false},{"year":2021,"finding":"SF3B3 physically complexes with lncRNA LINC01348 in hepatocellular carcinoma cells; this complex modulates EZH2 pre-mRNA alternative splicing and alters JNK/c-Jun activity and Snail expression to control metastasis.","method":"Co-immunoprecipitation of SF3B3 with LINC01348, RT-PCR splicing assay, knockdown/overexpression in vitro and in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP demonstrating lncRNA-SF3B3 interaction, multiple downstream functional readouts, single lab","pmids":["34140643"],"is_preprint":false},{"year":2022,"finding":"SF3B3 binds directly to ZIKV NS5 protein (identified by affinity pull-down and LC-MS/MS); SF3B3 overexpression restricts ZIKV replication by promoting ISG expression and reducing GCH1 protein levels, whereas SF3B3 knockdown has the opposite effect.","method":"Affinity pull-down, LC-MS/MS, overexpression and siRNA knockdown, viral replication assay, ISG expression analysis, western blot","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down with MS identification of interaction, multiple functional assays, single lab","pmids":["36572150"],"is_preprint":false},{"year":2023,"finding":"Nuclear AGO3 directly interacts with SF3B3 (a U2 spliceosome component) to aid global mRNA splicing in CD4+ T helper cells; this AGO3:SF3B3 complex regulates splicing of Nisch isoforms, and its disruption dysregulates type 2 immunity.","method":"Gain- and loss-of-function genetic experiments (Ago1/3/4-deficient mice), nuclear fractionation, direct protein interaction assay, transcriptome/splicing analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction shown, in vivo genetic loss-of-function with defined immunological phenotype, single lab","pmids":["38096048"],"is_preprint":false},{"year":2024,"finding":"SF3B3 regulates alternative splicing of mTOR pre-mRNA (exon skipping); silencing SF3B3 increases mTOR exon-skipped splicing, suppressing lipogenesis via the mTOR-SREBF1-FASN signaling axis and promoting apoptosis and mitochondrial ROS in colorectal cancer cells.","method":"RNA-seq, RNA immunoprecipitation, siRNA/shRNA knockdown, xenograft and organoid models, lipidomics, western blot","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA immunoprecipitation plus multiple in vitro and in vivo functional models, single lab","pmids":["38671459"],"is_preprint":false},{"year":2025,"finding":"SF3B3 is a direct transcriptional target of MYC and regulates alternative splicing of FXR (farnesoid X receptor) pre-mRNA in hepatocellular carcinoma; SF3B3 was identified as an FXR splicing regulator by RNA antisense purification-coupled mass spectrometry (RAP-MS), and deletion of Sf3b3 impeded MYC-driven hepatocarcinogenesis in mice.","method":"RAP-MS (RNA antisense purification with mass spectrometry), in silico and in vitro MYC target validation, qPCR/western blot, in vivo mouse HCC model (hydrodynamic injection), combination drug studies","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RAP-MS identification of SF3B3 as FXR splicing regulator, in vivo genetic deletion, multiple orthogonal methods, single lab","pmids":["40986891"],"is_preprint":false},{"year":2026,"finding":"CK2 kinase phosphorylates SF3B3 at T1200, enhancing its interaction with the deubiquitinase USP7; USP7-mediated deubiquitination stabilizes SF3B3 protein. Phosphorylated/stabilized SF3B3 is specifically incorporated into the U2 snRNP complex and drives alternative splicing of EXOSC2 (exon 4 inclusion), promoting esophageal squamous cell carcinoma progression.","method":"KSEA of proteomic/phosphoproteomic data, site-directed mutagenesis (T1200), co-immunoprecipitation (SF3B3–USP7 interaction), ubiquitination assay, U2 snRNP complex assembly assay, RNA splicing analysis, xenograft model","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — identified PTM writer (CK2) and eraser (USP7) with mutagenesis of phosphosite, direct complex assembly assay, multiple orthogonal methods in single rigorous study","pmids":["41961893"],"is_preprint":false},{"year":2026,"finding":"De novo heterozygous missense variants in SF3B3 reduce SF3B3 protein levels (~15–30%) in patient-derived fibroblasts, impair interactions of mutant SF3B3 with other SF3b complex components (shown by molecular dynamics simulations), and cause widespread alternative splicing defects (increased intron retention) and cell-cycle abnormalities.","method":"Patient fibroblast functional studies, western blot (protein quantification), all-atom molecular dynamics simulations, transcriptome profiling, alternative splicing analysis, cell-cycle assay","journal":"Genome medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional studies in patient-derived cells with multiple readouts, simulations support structural interpretation; single study","pmids":["41709284"],"is_preprint":false},{"year":2026,"finding":"hnRNPA1 physically interacts with SF3B3 (co-immunoprecipitation); this interaction inhibits exon 8 skipping of MARF1 pre-mRNA, promoting the oncogenic MARF1-L isoform that degrades PPP1R10 and activates Chk1-dependent homologous recombination repair, driving radioresistance in oral squamous cell carcinoma.","method":"Co-immunoprecipitation, immunofluorescence, RNA splicing analysis, clonogenic survival assay, xenograft model, western blot","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP demonstrating hnRNPA1-SF3B3 interaction, defined splicing and DNA-repair pathway placement, multiple functional assays, single lab","pmids":["41864998"],"is_preprint":false},{"year":2025,"finding":"ELK1 transcription factor regulates SF3B3 transcriptional expression in gastric cancer; SF3B3 knockdown or overexpression modulates MAPK pathway activity, cell proliferation, and apoptosis, placing SF3B3 downstream of ELK1 and upstream of MAPK signaling.","method":"Transcriptome analysis, western blot, CCK-8, colony formation, apoptosis assay, xenograft model, transcription factor binding analysis","journal":"Neoplasma","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptional regulation and pathway placement inferred from knockdown phenotypes and transcriptome data, no direct binding or reconstitution of ELK1-SF3B3 promoter interaction, single lab","pmids":["40958521"],"is_preprint":false}],"current_model":"SF3B3 is a core subunit of the U2 snRNP SF3b complex that is essential for pre-mRNA splicing; it is stabilized by CK2-mediated phosphorylation at T1200 (enabling USP7 deubiquitination) and facilitates U2 snRNP assembly, while also forming a nuclear complex with AGO3 to regulate global and target-specific splicing events (including EZH2, mTOR, FXR, MARF1, and EXOSC2 pre-mRNAs), with loss-of-function causing splicing defects, cell-cycle arrest, and impaired tumor progression across multiple cancer contexts."},"narrative":{"mechanistic_narrative":"SF3B3 is a conserved core subunit of the U2 snRNP SF3b complex required for pre-mRNA splicing, with orthologs in fission and budding yeast genetically placing it within the spliceosome and showing that its loss causes selective splicing failure and cell-cycle arrest [PMID:11350031, PMID:9819400]. In human cells, SF3B3 governs alternative splicing decisions across multiple disease-relevant transcripts, including exon inclusion in EZH2, exon skipping in mTOR, and splicing of FXR, MARF1, and EXOSC2 pre-mRNAs, thereby shaping downstream programs in tumor progression [PMID:27879367, PMID:38671459, PMID:40986891, PMID:41864998, PMID:41961893]. SF3B3 stability and incorporation into U2 snRNP are controlled post-translationally: CK2 phosphorylates SF3B3 at T1200 to promote USP7-mediated deubiquitination and stabilization, and the phosphorylated, stabilized protein is preferentially assembled into the spliceosome to drive EXOSC2 splicing [PMID:41961893]. Its splicing activity is directed in part through physical partnership with regulatory factors, including nuclear AGO3, which couples SF3B3 to global and isoform-specific splicing in CD4+ T helper cells, and hnRNPA1, which redirects MARF1 exon-8 splicing toward an oncogenic isoform [PMID:38096048, PMID:41864998]. De novo heterozygous missense variants in SF3B3 reduce protein levels and impair SF3b complex interactions, producing widespread intron retention and cell-cycle abnormalities, establishing SF3B3 dysfunction as a cause of a human Mendelian disorder [PMID:41709284].","teleology":[{"year":1998,"claim":"Established that the SF3B3 ortholog is a splicing factor whose loss has specific, traceable downstream consequences rather than a global collapse, by showing a single mis-spliced transcript can explain a cellular phenotype.","evidence":"Temperature-sensitive mutant screen in S. cerevisiae with genetic suppression by SAR1 dosage and intron deletion","pmids":["9819400"],"confidence":"High","gaps":["Does not define SF3B3's biochemical role within SF3b","Yeast SAR1-secretion link does not establish mammalian targets"]},{"year":2001,"claim":"Positioned SF3B3 as a bona fide SF3b/U2 snRNP subunit by demonstrating genetic interaction with the SF3b155 ortholog and linking its loss to a G2/M cell-cycle block through failure to splice a limiting transcript.","evidence":"Temperature-sensitive prp12 mutant analysis, splicing kinetics, prp12/prp10 genetic interaction, and GFP localization in S. pombe","pmids":["11350031"],"confidence":"High","gaps":["Molecular function of SF3B3 within the complex not resolved","Human-specific targets not addressed"]},{"year":2016,"claim":"Demonstrated that human SF3B3 directs alternative exon inclusion in a specific oncogenic transcript (EZH2), connecting its splicing activity to tumor suppression in renal cancer.","evidence":"RT-PCR splicing assay, siRNA knockdown, ectopic expression, and xenograft model","pmids":["27879367"],"confidence":"Medium","gaps":["No in vitro reconstitution of the splicing event","Mechanism by which SF3B3 selects exon 14 unknown"]},{"year":2021,"claim":"Showed SF3B3 splicing activity can be modulated by an lncRNA partner, expanding the determinants of its target specificity.","evidence":"Co-immunoprecipitation of SF3B3 with LINC01348, splicing assays, and in vitro/in vivo manipulation in hepatocellular carcinoma","pmids":["34140643"],"confidence":"Medium","gaps":["Single Co-IP for the lncRNA interaction","Direct vs. indirect binding not resolved"]},{"year":2022,"claim":"Identified a non-splicing antiviral role in which SF3B3 binds ZIKV NS5 and restricts viral replication, broadening its interaction repertoire beyond the spliceosome.","evidence":"Affinity pull-down with LC-MS/MS, overexpression/knockdown, and viral replication and ISG assays","pmids":["36572150"],"confidence":"Medium","gaps":["Whether the antiviral effect requires splicing activity is unclear","Single lab, no reciprocal validation"]},{"year":2023,"claim":"Established that nuclear AGO3 directly partners with SF3B3 to support global mRNA splicing, linking an Argonaute protein to spliceosome function in immune cells.","evidence":"Ago1/3/4-deficient mouse genetics, nuclear fractionation, direct interaction assay, and splicing transcriptomics in CD4+ T helper cells","pmids":["38096048"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of AGO3:SF3B3 contact unknown","Whether AGO3 confers target specificity not defined"]},{"year":2024,"claim":"Extended SF3B3's target catalog to mTOR exon skipping, tying its splicing control to a lipogenic signaling axis and cell survival in colorectal cancer.","evidence":"RNA-seq, RNA immunoprecipitation, knockdown, and xenograft/organoid models with lipidomics","pmids":["38671459"],"confidence":"Medium","gaps":["Direct RNA contact sites on mTOR pre-mRNA not mapped","Single lab"]},{"year":2025,"claim":"Placed SF3B3 in a MYC-driven oncogenic circuit as a direct transcriptional target that in turn regulates FXR splicing, defining an upstream transcriptional input to its expression.","evidence":"RAP-MS identification, MYC target validation, and in vivo Sf3b3 deletion in a mouse HCC model","pmids":["40986891"],"confidence":"Medium","gaps":["FXR splicing mechanism by SF3B3 not reconstituted","Generality beyond HCC unknown"]},{"year":2026,"claim":"Defined a complete post-translational control module for SF3B3 stability and spliceosome incorporation, identifying CK2 as the kinase and USP7 as the deubiquitinase acting through phospho-T1200.","evidence":"Phosphoproteomics, T1200 mutagenesis, SF3B3-USP7 Co-IP, ubiquitination and U2 snRNP assembly assays, and xenograft model in esophageal squamous cell carcinoma","pmids":["41961893"],"confidence":"High","gaps":["Whether other splicing targets depend on T1200 phosphorylation not tested","Structural basis of phospho-dependent USP7 binding not determined"]},{"year":2026,"claim":"Showed hnRNPA1 physically partners with SF3B3 to redirect MARF1 splicing toward an oncogenic isoform that drives DNA-repair-dependent radioresistance, adding another specificity-conferring partner.","evidence":"Reciprocal Co-IP, splicing analysis, clonogenic survival, and xenograft model in oral squamous cell carcinoma","pmids":["41864998"],"confidence":"Medium","gaps":["Direct vs. complex-mediated MARF1 RNA recognition unresolved","Single lab"]},{"year":2026,"claim":"Linked SF3B3 dysfunction to human Mendelian disease by showing de novo missense variants lower protein levels, weaken SF3b interactions, and cause widespread intron retention and cell-cycle defects.","evidence":"Patient-derived fibroblast functional studies, western blot, molecular dynamics simulations, and splicing/cell-cycle transcriptome analysis","pmids":["41709284"],"confidence":"Medium","gaps":["Genotype-phenotype correlation across variants not established","Structural impairment inferred from simulation, not experimental structure"]},{"year":null,"claim":"How SF3B3 achieves target-specific splicing decisions across its diverse pre-mRNA substrates, and whether the CK2/USP7 phospho-stabilization axis governs all of these events or only a subset, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of SF3B3 within human SF3b in the corpus","Rules governing partner-directed target selection (AGO3, hnRNPA1, lncRNA) not unified","No in vitro reconstituted splicing assay for SF3B3-dependent events"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6,0]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,8,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,6,7]}],"complexes":["SF3b complex","U2 snRNP"],"partners":["USP7","CK2","AGO3","HNRNPA1","SF3B1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15393","full_name":"Splicing factor 3B subunit 3","aliases":["Pre-mRNA-splicing factor SF3b 130 kDa subunit","SF3b130","STAF130","Spliceosome-associated protein 130","SAP 130"],"length_aa":1217,"mass_kda":135.6,"function":"Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs (PubMed:10490618, PubMed:10882114, PubMed:12234937, PubMed:27720643, PubMed:28781166, PubMed:32494006, PubMed:34822310). The 17S U2 SnRNP complex (1) directly participates in early spliceosome assembly and (2) mediates recognition of the intron branch site during pre-mRNA splicing by promoting the selection of the pre-mRNA branch-site adenosine, the nucleophile for the first step of splicing (PubMed:12234937, PubMed:32494006, PubMed:34822310). Within the 17S U2 SnRNP complex, SF3B3 is part of the SF3B subcomplex, which is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence in pre-mRNA (PubMed:12234937, PubMed:27720643). Sequence independent binding of SF3A and SF3B subcomplexes upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA (PubMed:12234937). May also be involved in the assembly of the 'E' complex (PubMed:10882114). Also acts as a component of the minor spliceosome, which is involved in the splicing of U12-type introns in pre-mRNAs (PubMed:15146077, PubMed:33509932)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q15393/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SF3B3","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000189091","cell_line_id":"CID001449","localizations":[{"compartment":"chromatin","grade":3}],"interactors":[{"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":"SNRPD2","stoichiometry":10.0},{"gene":"SF3B4","stoichiometry":10.0},{"gene":"SF3B6","stoichiometry":10.0},{"gene":"SF3B5","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001449","total_profiled":1310},"omim":[{"mim_id":"609962","title":"C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER E; CLEC4E","url":"https://www.omim.org/entry/609962"},{"mim_id":"609697","title":"SIN3A-ASSOCIATED PROTEIN, 130-KD; SAP130","url":"https://www.omim.org/entry/609697"},{"mim_id":"606576","title":"TAF3 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 140-KD; TAF3","url":"https://www.omim.org/entry/606576"},{"mim_id":"605817","title":"RECEPTOR-INTERACTING SERINE/THREONINE KINASE 3; RIPK3","url":"https://www.omim.org/entry/605817"},{"mim_id":"605592","title":"SPLICING FACTOR 3B, SUBUNIT 3; SF3B3","url":"https://www.omim.org/entry/605592"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoli rim","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SF3B3"},"hgnc":{"alias_symbol":["SAP130","SF3b130","RSE1","KIAA0017"],"prev_symbol":[]},"alphafold":{"accession":"Q15393","domains":[{"cath_id":"2.130.10.10","chopping":"63-87_102-381","consensus_level":"medium","plddt":93.9313,"start":63,"end":381},{"cath_id":"1.10.150.910","chopping":"1132-1215","consensus_level":"high","plddt":93.1448,"start":1132,"end":1215}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15393","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15393-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15393-F1-predicted_aligned_error_v6.png","plddt_mean":92.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SF3B3","jax_strain_url":"https://www.jax.org/strain/search?query=SF3B3"},"sequence":{"accession":"Q15393","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15393.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15393/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15393"}},"corpus_meta":[{"pmid":"27879367","id":"PMC_27879367","title":"Alternative Splicing of EZH2 pre-mRNA by SF3B3 Contributes to the Tumorigenic Potential of Renal Cancer.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/27879367","citation_count":91,"is_preprint":false},{"pmid":"34094830","id":"PMC_34094830","title":"Multi-omics approaches identify SF3B3 and SIRT3 as candidate autophagic regulators and druggable targets in invasive breast carcinoma.","date":"2020","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/34094830","citation_count":45,"is_preprint":false},{"pmid":"34140643","id":"PMC_34140643","title":"LINC01348 suppresses hepatocellular carcinoma metastasis through inhibition of SF3B3-mediated EZH2 pre-mRNA splicing.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34140643","citation_count":30,"is_preprint":false},{"pmid":"11350031","id":"PMC_11350031","title":"Mutation in the prp12+ gene encoding a homolog of SAP130/SF3b130 causes differential inhibition of pre-mRNA splicing and arrest of cell-cycle progression in Schizosaccharomyces pombe.","date":"2001","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11350031","citation_count":24,"is_preprint":false},{"pmid":"9819400","id":"PMC_9819400","title":"A link between secretion and pre-mRNA processing defects in Saccharomyces cerevisiae and the identification of a novel splicing gene, RSE1.","date":"1998","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9819400","citation_count":23,"is_preprint":false},{"pmid":"38671459","id":"PMC_38671459","title":"SF3B3-regulated mTOR alternative splicing promotes colorectal cancer progression and metastasis.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/38671459","citation_count":21,"is_preprint":false},{"pmid":"35025700","id":"PMC_35025700","title":"Depleted HDAC3 attenuates hyperuricemia-induced renal interstitial fibrosis via miR-19b-3p/SF3B3 axis.","date":"2022","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/35025700","citation_count":16,"is_preprint":false},{"pmid":"36572150","id":"PMC_36572150","title":"Splicing factor SF3B3, a NS5-binding protein, restricts ZIKV infection by targeting GCH1.","date":"2022","source":"Virologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/36572150","citation_count":8,"is_preprint":false},{"pmid":"36948007","id":"PMC_36948007","title":"The interplay between lncRNA NR_030777 and SF3B3 in neuronal damage caused by paraquat.","date":"2023","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/36948007","citation_count":5,"is_preprint":false},{"pmid":"33800128","id":"PMC_33800128","title":"Ambiguity about Splicing Factor 3b Subunit 3 (SF3B3) and Sin3A Associated Protein 130 (SAP130).","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33800128","citation_count":5,"is_preprint":false},{"pmid":"38096048","id":"PMC_38096048","title":"Argonaute3-SF3B3 complex controls pre-mRNA splicing to restrain type 2 immunity.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38096048","citation_count":5,"is_preprint":false},{"pmid":"25651737","id":"PMC_25651737","title":"Detection of SF3B3 gene mutations in oral cancer by high resolution melting analysis.","date":"2014","source":"Clinical laboratory","url":"https://pubmed.ncbi.nlm.nih.gov/25651737","citation_count":4,"is_preprint":false},{"pmid":"40986891","id":"PMC_40986891","title":"FXR splicing by SF3B3 promotes MYC-driven hepatocarcinogenesis.","date":"2025","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/40986891","citation_count":1,"is_preprint":false},{"pmid":"40958521","id":"PMC_40958521","title":"ELK1 modulates SF3B3 transcriptional activity to stimulate proliferation and inhibit apoptosis in gastric cancer through the activation of the MAPK pathway.","date":"2025","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/40958521","citation_count":0,"is_preprint":false},{"pmid":"41709284","id":"PMC_41709284","title":"A novel spliceosomopathy caused by de novo SF3B3 variants.","date":"2026","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41709284","citation_count":0,"is_preprint":false},{"pmid":"41961893","id":"PMC_41961893","title":"Casein kinase 2-mediated phosphorylation of the splicing factor SF3B3 plays a key role in esophageal squamous cell carcinoma progression.","date":"2026","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/41961893","citation_count":0,"is_preprint":false},{"pmid":"41864998","id":"PMC_41864998","title":"hnRNPA1-SF3B3 interaction drives radioresistance in oral squamous cell carcinoma by modulating MARF1 alternative splicing isoforms.","date":"2026","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/41864998","citation_count":0,"is_preprint":false},{"pmid":"41947220","id":"PMC_41947220","title":"Elucidating the role of SF3B3 in coronary atherosclerosis: integrating bioinformatics and machine learning for advanced insights.","date":"2026","source":"Journal of cardiothoracic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/41947220","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11630,"output_tokens":3223,"usd":0.041618,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10699,"output_tokens":3630,"usd":0.072123,"stage2_stop_reason":"end_turn"},"total_usd":0.113741,"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\": 2001,\n      \"finding\": \"S. pombe Prp12p (ortholog of human SF3B3/SAP130) is a subunit of the SF3b complex of U2 snRNP and is required for pre-mRNA splicing; genetic interaction with Prp10p (SAP155/SF3b155 ortholog) was demonstrated. Loss-of-function causes selective splicing defects and cell-cycle arrest (elongated cells, G2/M block), with the cdc phenotype attributable to failure to splice a limiting transcript required for G2/M transition. GFP-tagged Prp12p localizes uniformly in the nuclear DNA region.\",\n      \"method\": \"Temperature-sensitive mutant analysis, northern blot splicing kinetics, genetic interaction (prp12/prp10), GFP tagging and fluorescence microscopy in S. pombe\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic epistasis, splicing assays, localization), replicated across multiple prp mutants in same study\",\n      \"pmids\": [\"11350031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"S. cerevisiae RSE1 (ortholog of human SF3B3) is required for pre-mRNA splicing; rse1-1 mutants accumulate unspliced SAR1 pre-mRNA, causing a secondary ER-to-Golgi secretion defect that is rescued by increasing SAR1 dosage or deleting the SAR1 intron, placing RSE1 upstream of SAR1 splicing in the secretory pathway.\",\n      \"method\": \"Temperature-sensitive mutant screen, genetic suppression (SAR1 overexpression or intron deletion), accumulation of ER forms of invertase and CPY as secretion readout\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis confirmed by two independent suppression strategies, clean genetic placement of RSE1 in splicing upstream of SAR1\",\n      \"pmids\": [\"9819400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SF3B3 stimulates inclusion of alternative exon 14 in EZH2 pre-mRNA in renal cancer cells, generating a dominant-negative EZH2Δ14 isoform that abrogates EZH2-mediated suppression of DAB2IP and HOXA9 and inhibits EZH2-driven tumorigenesis; SF3B3 knockdown reduces exon 14 inclusion and promotes tumor growth.\",\n      \"method\": \"RT-PCR splicing assay, siRNA knockdown, ectopic expression, xenograft tumor model, western blot\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (in vitro + in vivo xenograft), single lab, no in vitro reconstitution of splicing\",\n      \"pmids\": [\"27879367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SF3B3 physically complexes with lncRNA LINC01348 in hepatocellular carcinoma cells; this complex modulates EZH2 pre-mRNA alternative splicing and alters JNK/c-Jun activity and Snail expression to control metastasis.\",\n      \"method\": \"Co-immunoprecipitation of SF3B3 with LINC01348, RT-PCR splicing assay, knockdown/overexpression in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP demonstrating lncRNA-SF3B3 interaction, multiple downstream functional readouts, single lab\",\n      \"pmids\": [\"34140643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SF3B3 binds directly to ZIKV NS5 protein (identified by affinity pull-down and LC-MS/MS); SF3B3 overexpression restricts ZIKV replication by promoting ISG expression and reducing GCH1 protein levels, whereas SF3B3 knockdown has the opposite effect.\",\n      \"method\": \"Affinity pull-down, LC-MS/MS, overexpression and siRNA knockdown, viral replication assay, ISG expression analysis, western blot\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down with MS identification of interaction, multiple functional assays, single lab\",\n      \"pmids\": [\"36572150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear AGO3 directly interacts with SF3B3 (a U2 spliceosome component) to aid global mRNA splicing in CD4+ T helper cells; this AGO3:SF3B3 complex regulates splicing of Nisch isoforms, and its disruption dysregulates type 2 immunity.\",\n      \"method\": \"Gain- and loss-of-function genetic experiments (Ago1/3/4-deficient mice), nuclear fractionation, direct protein interaction assay, transcriptome/splicing analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction shown, in vivo genetic loss-of-function with defined immunological phenotype, single lab\",\n      \"pmids\": [\"38096048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SF3B3 regulates alternative splicing of mTOR pre-mRNA (exon skipping); silencing SF3B3 increases mTOR exon-skipped splicing, suppressing lipogenesis via the mTOR-SREBF1-FASN signaling axis and promoting apoptosis and mitochondrial ROS in colorectal cancer cells.\",\n      \"method\": \"RNA-seq, RNA immunoprecipitation, siRNA/shRNA knockdown, xenograft and organoid models, lipidomics, western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA immunoprecipitation plus multiple in vitro and in vivo functional models, single lab\",\n      \"pmids\": [\"38671459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SF3B3 is a direct transcriptional target of MYC and regulates alternative splicing of FXR (farnesoid X receptor) pre-mRNA in hepatocellular carcinoma; SF3B3 was identified as an FXR splicing regulator by RNA antisense purification-coupled mass spectrometry (RAP-MS), and deletion of Sf3b3 impeded MYC-driven hepatocarcinogenesis in mice.\",\n      \"method\": \"RAP-MS (RNA antisense purification with mass spectrometry), in silico and in vitro MYC target validation, qPCR/western blot, in vivo mouse HCC model (hydrodynamic injection), combination drug studies\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RAP-MS identification of SF3B3 as FXR splicing regulator, in vivo genetic deletion, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40986891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CK2 kinase phosphorylates SF3B3 at T1200, enhancing its interaction with the deubiquitinase USP7; USP7-mediated deubiquitination stabilizes SF3B3 protein. Phosphorylated/stabilized SF3B3 is specifically incorporated into the U2 snRNP complex and drives alternative splicing of EXOSC2 (exon 4 inclusion), promoting esophageal squamous cell carcinoma progression.\",\n      \"method\": \"KSEA of proteomic/phosphoproteomic data, site-directed mutagenesis (T1200), co-immunoprecipitation (SF3B3–USP7 interaction), ubiquitination assay, U2 snRNP complex assembly assay, RNA splicing analysis, xenograft model\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — identified PTM writer (CK2) and eraser (USP7) with mutagenesis of phosphosite, direct complex assembly assay, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"41961893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"De novo heterozygous missense variants in SF3B3 reduce SF3B3 protein levels (~15–30%) in patient-derived fibroblasts, impair interactions of mutant SF3B3 with other SF3b complex components (shown by molecular dynamics simulations), and cause widespread alternative splicing defects (increased intron retention) and cell-cycle abnormalities.\",\n      \"method\": \"Patient fibroblast functional studies, western blot (protein quantification), all-atom molecular dynamics simulations, transcriptome profiling, alternative splicing analysis, cell-cycle assay\",\n      \"journal\": \"Genome medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional studies in patient-derived cells with multiple readouts, simulations support structural interpretation; single study\",\n      \"pmids\": [\"41709284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"hnRNPA1 physically interacts with SF3B3 (co-immunoprecipitation); this interaction inhibits exon 8 skipping of MARF1 pre-mRNA, promoting the oncogenic MARF1-L isoform that degrades PPP1R10 and activates Chk1-dependent homologous recombination repair, driving radioresistance in oral squamous cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, RNA splicing analysis, clonogenic survival assay, xenograft model, western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP demonstrating hnRNPA1-SF3B3 interaction, defined splicing and DNA-repair pathway placement, multiple functional assays, single lab\",\n      \"pmids\": [\"41864998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELK1 transcription factor regulates SF3B3 transcriptional expression in gastric cancer; SF3B3 knockdown or overexpression modulates MAPK pathway activity, cell proliferation, and apoptosis, placing SF3B3 downstream of ELK1 and upstream of MAPK signaling.\",\n      \"method\": \"Transcriptome analysis, western blot, CCK-8, colony formation, apoptosis assay, xenograft model, transcription factor binding analysis\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptional regulation and pathway placement inferred from knockdown phenotypes and transcriptome data, no direct binding or reconstitution of ELK1-SF3B3 promoter interaction, single lab\",\n      \"pmids\": [\"40958521\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SF3B3 is a core subunit of the U2 snRNP SF3b complex that is essential for pre-mRNA splicing; it is stabilized by CK2-mediated phosphorylation at T1200 (enabling USP7 deubiquitination) and facilitates U2 snRNP assembly, while also forming a nuclear complex with AGO3 to regulate global and target-specific splicing events (including EZH2, mTOR, FXR, MARF1, and EXOSC2 pre-mRNAs), with loss-of-function causing splicing defects, cell-cycle arrest, and impaired tumor progression across multiple cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SF3B3 is a conserved core subunit of the U2 snRNP SF3b complex required for pre-mRNA splicing, with orthologs in fission and budding yeast genetically placing it within the spliceosome and showing that its loss causes selective splicing failure and cell-cycle arrest [#0, #1]. In human cells, SF3B3 governs alternative splicing decisions across multiple disease-relevant transcripts, including exon inclusion in EZH2, exon skipping in mTOR, and splicing of FXR, MARF1, and EXOSC2 pre-mRNAs, thereby shaping downstream programs in tumor progression [#2, #6, #7, #10, #8]. SF3B3 stability and incorporation into U2 snRNP are controlled post-translationally: CK2 phosphorylates SF3B3 at T1200 to promote USP7-mediated deubiquitination and stabilization, and the phosphorylated, stabilized protein is preferentially assembled into the spliceosome to drive EXOSC2 splicing [#8]. Its splicing activity is directed in part through physical partnership with regulatory factors, including nuclear AGO3, which couples SF3B3 to global and isoform-specific splicing in CD4+ T helper cells, and hnRNPA1, which redirects MARF1 exon-8 splicing toward an oncogenic isoform [#5, #10]. De novo heterozygous missense variants in SF3B3 reduce protein levels and impair SF3b complex interactions, producing widespread intron retention and cell-cycle abnormalities, establishing SF3B3 dysfunction as a cause of a human Mendelian disorder [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that the SF3B3 ortholog is a splicing factor whose loss has specific, traceable downstream consequences rather than a global collapse, by showing a single mis-spliced transcript can explain a cellular phenotype.\",\n      \"evidence\": \"Temperature-sensitive mutant screen in S. cerevisiae with genetic suppression by SAR1 dosage and intron deletion\",\n      \"pmids\": [\"9819400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define SF3B3's biochemical role within SF3b\", \"Yeast SAR1-secretion link does not establish mammalian targets\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Positioned SF3B3 as a bona fide SF3b/U2 snRNP subunit by demonstrating genetic interaction with the SF3b155 ortholog and linking its loss to a G2/M cell-cycle block through failure to splice a limiting transcript.\",\n      \"evidence\": \"Temperature-sensitive prp12 mutant analysis, splicing kinetics, prp12/prp10 genetic interaction, and GFP localization in S. pombe\",\n      \"pmids\": [\"11350031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular function of SF3B3 within the complex not resolved\", \"Human-specific targets not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that human SF3B3 directs alternative exon inclusion in a specific oncogenic transcript (EZH2), connecting its splicing activity to tumor suppression in renal cancer.\",\n      \"evidence\": \"RT-PCR splicing assay, siRNA knockdown, ectopic expression, and xenograft model\",\n      \"pmids\": [\"27879367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the splicing event\", \"Mechanism by which SF3B3 selects exon 14 unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed SF3B3 splicing activity can be modulated by an lncRNA partner, expanding the determinants of its target specificity.\",\n      \"evidence\": \"Co-immunoprecipitation of SF3B3 with LINC01348, splicing assays, and in vitro/in vivo manipulation in hepatocellular carcinoma\",\n      \"pmids\": [\"34140643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP for the lncRNA interaction\", \"Direct vs. indirect binding not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a non-splicing antiviral role in which SF3B3 binds ZIKV NS5 and restricts viral replication, broadening its interaction repertoire beyond the spliceosome.\",\n      \"evidence\": \"Affinity pull-down with LC-MS/MS, overexpression/knockdown, and viral replication and ISG assays\",\n      \"pmids\": [\"36572150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the antiviral effect requires splicing activity is unclear\", \"Single lab, no reciprocal validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that nuclear AGO3 directly partners with SF3B3 to support global mRNA splicing, linking an Argonaute protein to spliceosome function in immune cells.\",\n      \"evidence\": \"Ago1/3/4-deficient mouse genetics, nuclear fractionation, direct interaction assay, and splicing transcriptomics in CD4+ T helper cells\",\n      \"pmids\": [\"38096048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structural basis of AGO3:SF3B3 contact unknown\", \"Whether AGO3 confers target specificity not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended SF3B3's target catalog to mTOR exon skipping, tying its splicing control to a lipogenic signaling axis and cell survival in colorectal cancer.\",\n      \"evidence\": \"RNA-seq, RNA immunoprecipitation, knockdown, and xenograft/organoid models with lipidomics\",\n      \"pmids\": [\"38671459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA contact sites on mTOR pre-mRNA not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed SF3B3 in a MYC-driven oncogenic circuit as a direct transcriptional target that in turn regulates FXR splicing, defining an upstream transcriptional input to its expression.\",\n      \"evidence\": \"RAP-MS identification, MYC target validation, and in vivo Sf3b3 deletion in a mouse HCC model\",\n      \"pmids\": [\"40986891\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FXR splicing mechanism by SF3B3 not reconstituted\", \"Generality beyond HCC unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a complete post-translational control module for SF3B3 stability and spliceosome incorporation, identifying CK2 as the kinase and USP7 as the deubiquitinase acting through phospho-T1200.\",\n      \"evidence\": \"Phosphoproteomics, T1200 mutagenesis, SF3B3-USP7 Co-IP, ubiquitination and U2 snRNP assembly assays, and xenograft model in esophageal squamous cell carcinoma\",\n      \"pmids\": [\"41961893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other splicing targets depend on T1200 phosphorylation not tested\", \"Structural basis of phospho-dependent USP7 binding not determined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed hnRNPA1 physically partners with SF3B3 to redirect MARF1 splicing toward an oncogenic isoform that drives DNA-repair-dependent radioresistance, adding another specificity-conferring partner.\",\n      \"evidence\": \"Reciprocal Co-IP, splicing analysis, clonogenic survival, and xenograft model in oral squamous cell carcinoma\",\n      \"pmids\": [\"41864998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. complex-mediated MARF1 RNA recognition unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked SF3B3 dysfunction to human Mendelian disease by showing de novo missense variants lower protein levels, weaken SF3b interactions, and cause widespread intron retention and cell-cycle defects.\",\n      \"evidence\": \"Patient-derived fibroblast functional studies, western blot, molecular dynamics simulations, and splicing/cell-cycle transcriptome analysis\",\n      \"pmids\": [\"41709284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype-phenotype correlation across variants not established\", \"Structural impairment inferred from simulation, not experimental structure\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SF3B3 achieves target-specific splicing decisions across its diverse pre-mRNA substrates, and whether the CK2/USP7 phospho-stabilization axis governs all of these events or only a subset, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of SF3B3 within human SF3b in the corpus\", \"Rules governing partner-directed target selection (AGO3, hnRNPA1, lncRNA) not unified\", \"No in vitro reconstituted splicing assay for SF3B3-dependent events\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 0]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 6, 7]}\n    ],\n    \"complexes\": [\"SF3b complex\", \"U2 snRNP\"],\n    \"partners\": [\"USP7\", \"CK2\", \"AGO3\", \"hnRNPA1\", \"SF3B1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}