{"gene":"SF3A2","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":1993,"finding":"PRP11 (yeast ortholog of SF3A2) is required for U2 snRNP binding to pre-mRNA during spliceosome assembly in vitro. Genetic and biochemical complementation analyses indicate PRP9 and PRP11 interact, and that PRP5, PRP9, PRP11, and PRP21 act concertedly to promote U2 snRNP addition to the pre-spliceosome.","method":"In vitro spliceosome assembly assay, genetic analysis, biochemical complementation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro functional assays combined with genetic analyses, replicated across multiple labs","pmids":["8405998"],"is_preprint":false},{"year":1993,"finding":"PRP11 (yeast ortholog of SF3A2) interacts directly with SPP91 (yeast ortholog of SF3a60), but PRP9 and PRP11 do not interact directly with each other. Instead, SPP91/PRP21 serves as a bridge, allowing PRP9 and PRP11 to simultaneously bind SPP91, forming a PRP9–SPP91–PRP11 three-molecule complex essential for splicing.","method":"Protein-protein interaction assays, genetic synthetic lethality, biochemical fractionation","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction assays and genetic epistasis, replicated in multiple subsequent studies","pmids":["8211114"],"is_preprint":false},{"year":1994,"finding":"PRP11 (yeast ortholog of SF3A2) interacts directly with MUD2P (yeast U2AF65 homolog) as shown by two-hybrid assay, identifying a specific inter-snRNP protein-protein contact during spliceosome assembly that bridges commitment complexes and U2 snRNP addition.","method":"Yeast two-hybrid system, genetic synthetic lethality analysis","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — two-hybrid interaction confirmed genetically, single lab but multiple approaches","pmids":["7926772"],"is_preprint":false},{"year":1996,"finding":"Purified Prp9, Prp11, and Prp21 proteins reconstitute a functional Prp9·Prp11·Prp21 complex in vitro that is active in splicing assays. This complex influences U2 snRNP structure, altering the accessibility of the branch point pairing region of U2 snRNA to oligonucleotide-directed RNaseH cleavage, suggesting the complex activates U2 snRNP for prespliceosome assembly.","method":"Protein reconstitution from E. coli-expressed components, in vitro splicing assay, RNaseH accessibility assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct reconstitution of complex with functional validation in vitro, multiple orthogonal methods","pmids":["8969185"],"is_preprint":false},{"year":1996,"finding":"Deletion analyses of PRP21 defined domains required for interaction with PRP9 and PRP11 (the yeast SF3A2 ortholog). Most heat-sensitive prp21 mutations disrupted interaction with Prp9 but not Prp11, indicating these interactions are separable. The domains required for viability and PRP9/PRP11 binding are conserved through evolution.","method":"Mutational analysis, heat-sensitive mutant isolation, deletion analysis, protein-protein interaction assays","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis with functional readout, single lab","pmids":["8718683"],"is_preprint":false},{"year":1991,"finding":"PRP11 (yeast ortholog of SF3A2) encodes an essential pre-mRNA splicing function. Linker-insertion mutagenesis identified essential and non-essential regions; overproduction of the prp11-1 protein can reverse its temperature-sensitive phenotype, compatible with the defect affecting binding to the spliceosome.","method":"Linker-insertion mutagenesis, temperature-sensitive mutant analysis, overexpression complementation","journal":"Molecular & general genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis with functional readout, single lab","pmids":["2034220"],"is_preprint":false},{"year":2001,"finding":"Human SF3a66 (SF3A2) interacts with SF3a120 via its N-terminal domain but does not interact with SF3a60. The C2H2-type zinc finger domain of SF3a66 mediates integration into the 17S U2 snRNP, likely through interactions with Sm proteins. All domains required for SF3a heterotrimer formation and U2 snRNP assembly are also necessary for prespliceosome formation.","method":"Recombinant protein expression in insect cells, in vitro U2 snRNP assembly assay, domain deletion analysis, prespliceosome formation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with recombinant proteins, domain mutagenesis, multiple functional assays in single study","pmids":["11533230"],"is_preprint":false},{"year":2004,"finding":"SF3a66 (SF3A2) binds directly to beta-tubulin and to microtubules with high affinity, functioning as a novel microtubule-associated protein (MAP). Electron microscopy showed SF3a66 bundles microtubules via cross-bridging by high-molecular-mass oligomerized SF3a66 complexes. Ectopic expression in N1E-115 neuroblastoma cells induces neurite extension.","method":"Protein-binding screen, pull-down assay, electron microscopy, ectopic expression/morphology assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with EM validation and functional cellular readout, single lab","pmids":["15142036"],"is_preprint":false},{"year":2004,"finding":"Nuclear FGF-2 interacts specifically with SF3a66 (SF3A2). The interaction was identified by yeast two-hybrid screen and confirmed by pull-down assay. FGF-2 interacts with the C-terminus of SF3a66 via a domain common to both 18-kDa and 23-kDa FGF-2 isoforms.","method":"Yeast two-hybrid screen, pull-down assay","journal":"Biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid plus single pull-down, single lab, no functional mechanism established","pmids":["15653435"],"is_preprint":false},{"year":2018,"finding":"SF3A2 (Sf3A2) has a direct role in mitotic chromosome segregation independent of splicing. Antibody injection into Drosophila embryos disrupts mitotic division within 1 minute, too fast for splicing defects to account. SF3A2 and Prp31 bind spindle microtubules and the Ndc80 complex; depletion results in failure of Ndc80 to associate tightly with kinetochores. In HeLa cells, the Ndc80/HEC1–SF3A2 interaction is restricted to M phase.","method":"Antibody microinjection into Drosophila embryos, RNAi depletion in Drosophila and HeLa cells, co-immunoprecipitation, live imaging, immunofluorescence","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (antibody injection, RNAi, Co-IP, live imaging) in two model systems with clear mechanistic phenotype","pmids":["30475206"],"is_preprint":false},{"year":2023,"finding":"SF3A2 is acetylated at lysine 10 (K10) by the acetyltransferase p300. Ginsenoside Rb2 directly binds p300 and inhibits its activity, reducing SF3A2 K10 acetylation. This acetylation state regulates alternative splicing of mitochondrial function-related genes including Fscn1, and its reduction is associated with enhanced mitochondrial respiration in cardiomyocytes.","method":"4D-label-free acetylomics, co-immunoprecipitation, site-specific mutagenesis, shRNA interference, RNA-seq, cellular thermal shift assay, surface plasmon resonance, mitochondrial respiration measurement","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including acetylomics, mutagenesis, and functional assays, single lab","pmids":["38101749"],"is_preprint":false},{"year":2024,"finding":"SF3A2 is subject to ubiquitination-dependent degradation promoted by E3 ubiquitin ligase UBR5. SF3A2 in turn regulates UBR5, forming a feedback loop. SF3A2 specifically regulates alternative splicing of MKRN1, promoting expression of the oncogenic MKRN1-T1 isoform, and participates in regulation of both extrinsic and intrinsic apoptosis pathways leading to cisplatin resistance.","method":"Co-immunoprecipitation, knockdown/overexpression functional assays, alternative splicing analysis","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for protein interaction, functional knockdown with specific splicing and apoptosis readouts, single lab","pmids":["38569025"],"is_preprint":false},{"year":2014,"finding":"A semi-dominant mutation in SF3a66 (C. elegans ortholog) causes anterior-posterior axis reversal in one-cell embryos in a PAR-2-dependent manner, likely due to reduced PKC-3 levels from a general splicing defect allowing oocyte meiotic spindle microtubules to interfere with AP axis formation.","method":"Genetic mutant analysis, epistasis with PAR-2 and PKC-3, live imaging","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic mutant with phenotypic readout but mechanism proposed rather than directly demonstrated, single study","pmids":["25188372"],"is_preprint":false}],"current_model":"SF3A2 (also known as SF3a66, SAP62, PRPF11/PRP11) is a core subunit of the SF3a heterotrimer (with SF3a60 and SF3a120) that associates with U2 snRNP to promote prespliceosome assembly at the intron branch site; its N-terminal domain binds SF3a120, its C2H2 zinc finger mediates integration into the 17S U2 snRNP via Sm proteins, and the yeast ortholog PRP11 forms a PRP9–SPP91–PRP11 complex required for U2 snRNP activation; beyond its canonical splicing role, SF3A2 directly binds spindle microtubules and the Ndc80 kinetochore complex to regulate chromosome segregation in mitosis, acts as a microtubule-bundling MAP, is regulated by p300-mediated acetylation at K10 and by UBR5-mediated ubiquitination, and controls specific alternative splicing events (including MKRN1) relevant to cancer progression and cisplatin resistance."},"narrative":{"mechanistic_narrative":"SF3A2 is a core subunit of the SF3a complex that activates the U2 snRNP for stable association with the pre-mRNA branch site during prespliceosome assembly [PMID:8405998, PMID:8969185]. Its yeast ortholog PRP11 is essential for splicing and operates within a three-protein complex in which PRP21/SPP91 bridges PRP9 and PRP11, which do not contact each other directly; reconstitution of the purified Prp9·Prp11·Prp21 complex alters the accessibility of the U2 snRNA branch-point pairing region, defining how the complex activates U2 snRNP [PMID:8211114, PMID:8969185]. In the human protein, the N-terminal domain binds SF3a120 while the C2H2 zinc-finger domain mediates integration into the 17S U2 snRNP through Sm proteins, and these same domains are required for prespliceosome formation [PMID:11533230]. Beyond splicing, SF3A2 has a direct mitotic function: it binds spindle microtubules and the Ndc80/HEC1 kinetochore complex in an M phase-restricted manner, and its loss prevents stable Ndc80–kinetochore association, causing chromosome segregation failure on a timescale too rapid to reflect a splicing defect [PMID:15142036, PMID:30475206]. SF3A2 activity is controlled post-translationally by p300-mediated K10 acetylation, which tunes alternative splicing of mitochondrial-function genes, and by UBR5-mediated ubiquitination within a feedback loop, where SF3A2-directed splicing of MKRN1 toward an oncogenic isoform contributes to apoptosis regulation and cisplatin resistance [PMID:38101749, PMID:38569025].","teleology":[{"year":1993,"claim":"Established that the SF3A2 ortholog PRP11 is functionally required for U2 snRNP addition to the pre-spliceosome and acts concertedly with PRP5/PRP9/PRP21, defining its place in spliceosome assembly.","evidence":"In vitro spliceosome assembly assay with genetic and biochemical complementation in yeast","pmids":["8405998"],"confidence":"High","gaps":["Did not resolve the physical architecture connecting the PRP proteins","Mechanism of U2 snRNP activation not yet defined"]},{"year":1993,"claim":"Resolved the connectivity of the splicing factor complex, showing PRP11 binds SPP91 directly while PRP9 and PRP11 are bridged by SPP91/PRP21 into a three-molecule complex.","evidence":"Protein-protein interaction assays and genetic synthetic lethality in yeast","pmids":["8211114"],"confidence":"High","gaps":["Did not show the complex is sufficient for U2 activation in isolation","Functional consequence of complex assembly on U2 snRNA structure unknown"]},{"year":1994,"claim":"Identified a direct PRP11–MUD2P (U2AF65 homolog) contact, providing a molecular bridge between commitment complexes and U2 snRNP addition.","evidence":"Yeast two-hybrid and genetic synthetic lethality analysis","pmids":["7926772"],"confidence":"Medium","gaps":["Two-hybrid interaction not validated by reconstitution","Functional role of the contact during assembly not directly tested"]},{"year":1996,"claim":"Demonstrated mechanistically that the reconstituted Prp9·Prp11·Prp21 complex activates U2 snRNP by altering accessibility of the branch-point pairing region, linking complex assembly to a structural change enabling prespliceosome formation.","evidence":"Reconstitution from E. coli-expressed proteins, in vitro splicing, and RNaseH accessibility assay","pmids":["8969185"],"confidence":"High","gaps":["Structural basis of the U2 conformational change not resolved","Did not map human-specific contacts"]},{"year":2001,"claim":"Mapped the human SF3A2 domains, showing its N-terminus binds SF3a120 and its C2H2 zinc finger drives integration into the 17S U2 snRNP via Sm proteins, with the same domains required for prespliceosome formation.","evidence":"Recombinant expression in insect cells with domain deletion and in vitro U2 snRNP/prespliceosome assembly assays","pmids":["11533230"],"confidence":"High","gaps":["Atomic structure of the zinc finger–Sm interaction not determined","Did not address non-splicing functions"]},{"year":2004,"claim":"Revealed an unexpected cytoskeletal activity, showing SF3A2 binds beta-tubulin and microtubules directly and bundles them as an oligomeric MAP.","evidence":"Pull-down, electron microscopy, and ectopic expression morphology assay in neuroblastoma cells","pmids":["15142036"],"confidence":"Medium","gaps":["Physiological context of microtubule bundling not established","Relationship to splicing function unclear at this stage"]},{"year":2018,"claim":"Established a splicing-independent mitotic role, showing SF3A2 binds spindle microtubules and the Ndc80 complex in an M-phase-restricted manner and is required for stable Ndc80–kinetochore association and chromosome segregation.","evidence":"Antibody microinjection and RNAi in Drosophila embryos and HeLa cells, Co-IP, live imaging, immunofluorescence","pmids":["30475206"],"confidence":"High","gaps":["Structural basis of the SF3A2–Ndc80 interaction unresolved","How the same protein partitions between splicing and kinetochore roles unknown"]},{"year":2023,"claim":"Identified p300-mediated K10 acetylation as a regulatory mark on SF3A2 that controls alternative splicing of mitochondrial-function genes and modulates mitochondrial respiration.","evidence":"Acetylomics, site-specific mutagenesis, RNA-seq, and mitochondrial respiration assays with Ginsenoside Rb2 as a p300 inhibitor","pmids":["38101749"],"confidence":"Medium","gaps":["Mechanism by which K10 acetylation alters splice-site selection not defined","Single-lab finding without independent confirmation"]},{"year":2024,"claim":"Placed SF3A2 in a UBR5 ubiquitination feedback loop and linked its splicing of MKRN1 toward an oncogenic isoform to apoptosis regulation and cisplatin resistance.","evidence":"Co-IP, knockdown/overexpression, and alternative splicing/apoptosis assays","pmids":["38569025"],"confidence":"Medium","gaps":["Direct ubiquitination sites on SF3A2 not mapped","Single-lab study of the feedback loop"]},{"year":null,"claim":"How SF3A2 is partitioned and regulated between its spliceosomal, kinetochore, and cytoskeletal functions, and whether its post-translational modifications coordinate these roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating the splicing and mitotic functions","Cross-talk between acetylation/ubiquitination and the non-splicing roles untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7,9]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9]}],"complexes":["SF3a heterotrimer","17S U2 snRNP","PRP9-SPP91/PRP21-PRP11 complex"],"partners":["SF3A1","SF3A3","NDC80","PRPF31","UBR5","EP300","FGF2","MUD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15428","full_name":"Splicing factor 3A subunit 2","aliases":["SF3a66","Spliceosome-associated protein 62","SAP 62"],"length_aa":464,"mass_kda":49.3,"function":"Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs (PubMed:10882114, PubMed:11533230, 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:10882114, PubMed:11533230, PubMed:32494006, PubMed:34822310). Within the 17S U2 SnRNP complex, SF3A2 is part of the SF3A subcomplex that contributes to the assembly of the 17S U2 snRNP, and the subsequent assembly of the pre-spliceosome 'E' complex and the pre-catalytic spliceosome 'A' complex (PubMed:10882114, PubMed:11533230). Involved in pre-mRNA splicing as a component of pre-catalytic spliceosome 'B' complexes, including the Bact complex (PubMed:29360106, PubMed:29361316, PubMed:30315277). Interacts directly with the duplex formed by U2 snRNA and the intron (PubMed:29360106)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q15428/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SF3A2","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000104897","cell_line_id":"CID001445","localizations":[{"compartment":"chromatin","grade":3},{"compartment":"nuclear_punctae","grade":3}],"interactors":[{"gene":"SF3A1","stoichiometry":10.0},{"gene":"SF3B1","stoichiometry":10.0},{"gene":"HTATSF1","stoichiometry":10.0},{"gene":"SNRPB2","stoichiometry":10.0},{"gene":"SNRPA1","stoichiometry":10.0},{"gene":"SF3B5","stoichiometry":10.0},{"gene":"SF3B6","stoichiometry":10.0},{"gene":"SF3B2","stoichiometry":10.0},{"gene":"SF3A3","stoichiometry":10.0},{"gene":"SF3B4","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001445","total_profiled":1310},"omim":[{"mim_id":"617834","title":"PLECKSTRIN HOMOLOGY DOMAIN-CONTAINING PROTEIN, FAMILY J, MEMBER 1; PLEKHJ1","url":"https://www.omim.org/entry/617834"},{"mim_id":"605595","title":"SPLICING FACTOR 3A, SUBUNIT 1; SF3A1","url":"https://www.omim.org/entry/605595"},{"mim_id":"600796","title":"SPLICING FACTOR 3A, SUBUNIT 2; SF3A2","url":"https://www.omim.org/entry/600796"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SF3A2"},"hgnc":{"alias_symbol":["SF3a66","SAP62","PRPF11","Prp11"],"prev_symbol":[]},"alphafold":{"accession":"Q15428","domains":[{"cath_id":"-","chopping":"20-91","consensus_level":"high","plddt":88.1076,"start":20,"end":91},{"cath_id":"2.60.40.2690","chopping":"115-211","consensus_level":"high","plddt":91.4254,"start":115,"end":211}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15428","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15428-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15428-F1-predicted_aligned_error_v6.png","plddt_mean":64.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SF3A2","jax_strain_url":"https://www.jax.org/strain/search?query=SF3A2"},"sequence":{"accession":"Q15428","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15428.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15428/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15428"}},"corpus_meta":[{"pmid":"7926772","id":"PMC_7926772","title":"The yeast MUD2 protein: an interaction with PRP11 defines a bridge between commitment complexes and U2 snRNP addition.","date":"1994","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/7926772","citation_count":177,"is_preprint":false},{"pmid":"8405998","id":"PMC_8405998","title":"Four yeast spliceosomal proteins (PRP5, PRP9, PRP11, and PRP21) interact to promote U2 snRNP binding to pre-mRNA.","date":"1993","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/8405998","citation_count":125,"is_preprint":false},{"pmid":"8211114","id":"PMC_8211114","title":"Interaction between PRP11 and SPP91 yeast splicing factors and characterization of a PRP9-PRP11-SPP91 complex.","date":"1993","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8211114","citation_count":67,"is_preprint":false},{"pmid":"8001577","id":"PMC_8001577","title":"Pathogen-defence gene prp1-1 from potato encodes an auxin-responsive glutathione S-transferase.","date":"1994","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8001577","citation_count":55,"is_preprint":false},{"pmid":"11533230","id":"PMC_11533230","title":"Domains in human splicing factors SF3a60 and SF3a66 required for binding to SF3a120, assembly of the 17S U2 snRNP, and prespliceosome formation.","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11533230","citation_count":49,"is_preprint":false},{"pmid":"38569025","id":"PMC_38569025","title":"SF3A2 promotes progression and cisplatin resistance in triple-negative breast cancer via alternative splicing of MKRN1.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/38569025","citation_count":45,"is_preprint":false},{"pmid":"24916648","id":"PMC_24916648","title":"A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in 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one","url":"https://pubmed.ncbi.nlm.nih.gov/25188372","citation_count":1,"is_preprint":false},{"pmid":"41399366","id":"PMC_41399366","title":"SF3A2: a promising therapeutic target and predictive biomarker for immunotherapy in colorectal cancer.","date":"2026","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41399366","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11325,"output_tokens":3304,"usd":0.041767,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10769,"output_tokens":3149,"usd":0.066285,"stage2_stop_reason":"end_turn"},"total_usd":0.108052,"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\": 1993,\n      \"finding\": \"PRP11 (yeast ortholog of SF3A2) is required for U2 snRNP binding to pre-mRNA during spliceosome assembly in vitro. Genetic and biochemical complementation analyses indicate PRP9 and PRP11 interact, and that PRP5, PRP9, PRP11, and PRP21 act concertedly to promote U2 snRNP addition to the pre-spliceosome.\",\n      \"method\": \"In vitro spliceosome assembly assay, genetic analysis, biochemical complementation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro functional assays combined with genetic analyses, replicated across multiple labs\",\n      \"pmids\": [\"8405998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"PRP11 (yeast ortholog of SF3A2) interacts directly with SPP91 (yeast ortholog of SF3a60), but PRP9 and PRP11 do not interact directly with each other. Instead, SPP91/PRP21 serves as a bridge, allowing PRP9 and PRP11 to simultaneously bind SPP91, forming a PRP9–SPP91–PRP11 three-molecule complex essential for splicing.\",\n      \"method\": \"Protein-protein interaction assays, genetic synthetic lethality, biochemical fractionation\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction assays and genetic epistasis, replicated in multiple subsequent studies\",\n      \"pmids\": [\"8211114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"PRP11 (yeast ortholog of SF3A2) interacts directly with MUD2P (yeast U2AF65 homolog) as shown by two-hybrid assay, identifying a specific inter-snRNP protein-protein contact during spliceosome assembly that bridges commitment complexes and U2 snRNP addition.\",\n      \"method\": \"Yeast two-hybrid system, genetic synthetic lethality analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — two-hybrid interaction confirmed genetically, single lab but multiple approaches\",\n      \"pmids\": [\"7926772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Purified Prp9, Prp11, and Prp21 proteins reconstitute a functional Prp9·Prp11·Prp21 complex in vitro that is active in splicing assays. This complex influences U2 snRNP structure, altering the accessibility of the branch point pairing region of U2 snRNA to oligonucleotide-directed RNaseH cleavage, suggesting the complex activates U2 snRNP for prespliceosome assembly.\",\n      \"method\": \"Protein reconstitution from E. coli-expressed components, in vitro splicing assay, RNaseH accessibility assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct reconstitution of complex with functional validation in vitro, multiple orthogonal methods\",\n      \"pmids\": [\"8969185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Deletion analyses of PRP21 defined domains required for interaction with PRP9 and PRP11 (the yeast SF3A2 ortholog). Most heat-sensitive prp21 mutations disrupted interaction with Prp9 but not Prp11, indicating these interactions are separable. The domains required for viability and PRP9/PRP11 binding are conserved through evolution.\",\n      \"method\": \"Mutational analysis, heat-sensitive mutant isolation, deletion analysis, protein-protein interaction assays\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"8718683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"PRP11 (yeast ortholog of SF3A2) encodes an essential pre-mRNA splicing function. Linker-insertion mutagenesis identified essential and non-essential regions; overproduction of the prp11-1 protein can reverse its temperature-sensitive phenotype, compatible with the defect affecting binding to the spliceosome.\",\n      \"method\": \"Linker-insertion mutagenesis, temperature-sensitive mutant analysis, overexpression complementation\",\n      \"journal\": \"Molecular & general genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"2034220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human SF3a66 (SF3A2) interacts with SF3a120 via its N-terminal domain but does not interact with SF3a60. The C2H2-type zinc finger domain of SF3a66 mediates integration into the 17S U2 snRNP, likely through interactions with Sm proteins. All domains required for SF3a heterotrimer formation and U2 snRNP assembly are also necessary for prespliceosome formation.\",\n      \"method\": \"Recombinant protein expression in insect cells, in vitro U2 snRNP assembly assay, domain deletion analysis, prespliceosome formation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with recombinant proteins, domain mutagenesis, multiple functional assays in single study\",\n      \"pmids\": [\"11533230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SF3a66 (SF3A2) binds directly to beta-tubulin and to microtubules with high affinity, functioning as a novel microtubule-associated protein (MAP). Electron microscopy showed SF3a66 bundles microtubules via cross-bridging by high-molecular-mass oligomerized SF3a66 complexes. Ectopic expression in N1E-115 neuroblastoma cells induces neurite extension.\",\n      \"method\": \"Protein-binding screen, pull-down assay, electron microscopy, ectopic expression/morphology assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with EM validation and functional cellular readout, single lab\",\n      \"pmids\": [\"15142036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Nuclear FGF-2 interacts specifically with SF3a66 (SF3A2). The interaction was identified by yeast two-hybrid screen and confirmed by pull-down assay. FGF-2 interacts with the C-terminus of SF3a66 via a domain common to both 18-kDa and 23-kDa FGF-2 isoforms.\",\n      \"method\": \"Yeast two-hybrid screen, pull-down assay\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid plus single pull-down, single lab, no functional mechanism established\",\n      \"pmids\": [\"15653435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SF3A2 (Sf3A2) has a direct role in mitotic chromosome segregation independent of splicing. Antibody injection into Drosophila embryos disrupts mitotic division within 1 minute, too fast for splicing defects to account. SF3A2 and Prp31 bind spindle microtubules and the Ndc80 complex; depletion results in failure of Ndc80 to associate tightly with kinetochores. In HeLa cells, the Ndc80/HEC1–SF3A2 interaction is restricted to M phase.\",\n      \"method\": \"Antibody microinjection into Drosophila embryos, RNAi depletion in Drosophila and HeLa cells, co-immunoprecipitation, live imaging, immunofluorescence\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (antibody injection, RNAi, Co-IP, live imaging) in two model systems with clear mechanistic phenotype\",\n      \"pmids\": [\"30475206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SF3A2 is acetylated at lysine 10 (K10) by the acetyltransferase p300. Ginsenoside Rb2 directly binds p300 and inhibits its activity, reducing SF3A2 K10 acetylation. This acetylation state regulates alternative splicing of mitochondrial function-related genes including Fscn1, and its reduction is associated with enhanced mitochondrial respiration in cardiomyocytes.\",\n      \"method\": \"4D-label-free acetylomics, co-immunoprecipitation, site-specific mutagenesis, shRNA interference, RNA-seq, cellular thermal shift assay, surface plasmon resonance, mitochondrial respiration measurement\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including acetylomics, mutagenesis, and functional assays, single lab\",\n      \"pmids\": [\"38101749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SF3A2 is subject to ubiquitination-dependent degradation promoted by E3 ubiquitin ligase UBR5. SF3A2 in turn regulates UBR5, forming a feedback loop. SF3A2 specifically regulates alternative splicing of MKRN1, promoting expression of the oncogenic MKRN1-T1 isoform, and participates in regulation of both extrinsic and intrinsic apoptosis pathways leading to cisplatin resistance.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression functional assays, alternative splicing analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for protein interaction, functional knockdown with specific splicing and apoptosis readouts, single lab\",\n      \"pmids\": [\"38569025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A semi-dominant mutation in SF3a66 (C. elegans ortholog) causes anterior-posterior axis reversal in one-cell embryos in a PAR-2-dependent manner, likely due to reduced PKC-3 levels from a general splicing defect allowing oocyte meiotic spindle microtubules to interfere with AP axis formation.\",\n      \"method\": \"Genetic mutant analysis, epistasis with PAR-2 and PKC-3, live imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic mutant with phenotypic readout but mechanism proposed rather than directly demonstrated, single study\",\n      \"pmids\": [\"25188372\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SF3A2 (also known as SF3a66, SAP62, PRPF11/PRP11) is a core subunit of the SF3a heterotrimer (with SF3a60 and SF3a120) that associates with U2 snRNP to promote prespliceosome assembly at the intron branch site; its N-terminal domain binds SF3a120, its C2H2 zinc finger mediates integration into the 17S U2 snRNP via Sm proteins, and the yeast ortholog PRP11 forms a PRP9–SPP91–PRP11 complex required for U2 snRNP activation; beyond its canonical splicing role, SF3A2 directly binds spindle microtubules and the Ndc80 kinetochore complex to regulate chromosome segregation in mitosis, acts as a microtubule-bundling MAP, is regulated by p300-mediated acetylation at K10 and by UBR5-mediated ubiquitination, and controls specific alternative splicing events (including MKRN1) relevant to cancer progression and cisplatin resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SF3A2 is a core subunit of the SF3a complex that activates the U2 snRNP for stable association with the pre-mRNA branch site during prespliceosome assembly [#0, #3]. Its yeast ortholog PRP11 is essential for splicing and operates within a three-protein complex in which PRP21/SPP91 bridges PRP9 and PRP11, which do not contact each other directly; reconstitution of the purified Prp9·Prp11·Prp21 complex alters the accessibility of the U2 snRNA branch-point pairing region, defining how the complex activates U2 snRNP [#1, #3]. In the human protein, the N-terminal domain binds SF3a120 while the C2H2 zinc-finger domain mediates integration into the 17S U2 snRNP through Sm proteins, and these same domains are required for prespliceosome formation [#6]. Beyond splicing, SF3A2 has a direct mitotic function: it binds spindle microtubules and the Ndc80/HEC1 kinetochore complex in an M phase-restricted manner, and its loss prevents stable Ndc80–kinetochore association, causing chromosome segregation failure on a timescale too rapid to reflect a splicing defect [#7, #9]. SF3A2 activity is controlled post-translationally by p300-mediated K10 acetylation, which tunes alternative splicing of mitochondrial-function genes, and by UBR5-mediated ubiquitination within a feedback loop, where SF3A2-directed splicing of MKRN1 toward an oncogenic isoform contributes to apoptosis regulation and cisplatin resistance [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that the SF3A2 ortholog PRP11 is functionally required for U2 snRNP addition to the pre-spliceosome and acts concertedly with PRP5/PRP9/PRP21, defining its place in spliceosome assembly.\",\n      \"evidence\": \"In vitro spliceosome assembly assay with genetic and biochemical complementation in yeast\",\n      \"pmids\": [\"8405998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the physical architecture connecting the PRP proteins\", \"Mechanism of U2 snRNP activation not yet defined\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Resolved the connectivity of the splicing factor complex, showing PRP11 binds SPP91 directly while PRP9 and PRP11 are bridged by SPP91/PRP21 into a three-molecule complex.\",\n      \"evidence\": \"Protein-protein interaction assays and genetic synthetic lethality in yeast\",\n      \"pmids\": [\"8211114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show the complex is sufficient for U2 activation in isolation\", \"Functional consequence of complex assembly on U2 snRNA structure unknown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Identified a direct PRP11–MUD2P (U2AF65 homolog) contact, providing a molecular bridge between commitment complexes and U2 snRNP addition.\",\n      \"evidence\": \"Yeast two-hybrid and genetic synthetic lethality analysis\",\n      \"pmids\": [\"7926772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Two-hybrid interaction not validated by reconstitution\", \"Functional role of the contact during assembly not directly tested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrated mechanistically that the reconstituted Prp9·Prp11·Prp21 complex activates U2 snRNP by altering accessibility of the branch-point pairing region, linking complex assembly to a structural change enabling prespliceosome formation.\",\n      \"evidence\": \"Reconstitution from E. coli-expressed proteins, in vitro splicing, and RNaseH accessibility assay\",\n      \"pmids\": [\"8969185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the U2 conformational change not resolved\", \"Did not map human-specific contacts\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapped the human SF3A2 domains, showing its N-terminus binds SF3a120 and its C2H2 zinc finger drives integration into the 17S U2 snRNP via Sm proteins, with the same domains required for prespliceosome formation.\",\n      \"evidence\": \"Recombinant expression in insect cells with domain deletion and in vitro U2 snRNP/prespliceosome assembly assays\",\n      \"pmids\": [\"11533230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the zinc finger–Sm interaction not determined\", \"Did not address non-splicing functions\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed an unexpected cytoskeletal activity, showing SF3A2 binds beta-tubulin and microtubules directly and bundles them as an oligomeric MAP.\",\n      \"evidence\": \"Pull-down, electron microscopy, and ectopic expression morphology assay in neuroblastoma cells\",\n      \"pmids\": [\"15142036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context of microtubule bundling not established\", \"Relationship to splicing function unclear at this stage\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a splicing-independent mitotic role, showing SF3A2 binds spindle microtubules and the Ndc80 complex in an M-phase-restricted manner and is required for stable Ndc80–kinetochore association and chromosome segregation.\",\n      \"evidence\": \"Antibody microinjection and RNAi in Drosophila embryos and HeLa cells, Co-IP, live imaging, immunofluorescence\",\n      \"pmids\": [\"30475206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the SF3A2–Ndc80 interaction unresolved\", \"How the same protein partitions between splicing and kinetochore roles unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified p300-mediated K10 acetylation as a regulatory mark on SF3A2 that controls alternative splicing of mitochondrial-function genes and modulates mitochondrial respiration.\",\n      \"evidence\": \"Acetylomics, site-specific mutagenesis, RNA-seq, and mitochondrial respiration assays with Ginsenoside Rb2 as a p300 inhibitor\",\n      \"pmids\": [\"38101749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which K10 acetylation alters splice-site selection not defined\", \"Single-lab finding without independent confirmation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed SF3A2 in a UBR5 ubiquitination feedback loop and linked its splicing of MKRN1 toward an oncogenic isoform to apoptosis regulation and cisplatin resistance.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, and alternative splicing/apoptosis assays\",\n      \"pmids\": [\"38569025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination sites on SF3A2 not mapped\", \"Single-lab study of the feedback loop\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SF3A2 is partitioned and regulated between its spliceosomal, kinetochore, and cytoskeletal functions, and whether its post-translational modifications coordinate these roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating the splicing and mitotic functions\", \"Cross-talk between acetylation/ubiquitination and the non-splicing roles untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\"SF3a heterotrimer\", \"17S U2 snRNP\", \"PRP9-SPP91/PRP21-PRP11 complex\"],\n    \"partners\": [\"SF3A1\", \"SF3A3\", \"NDC80\", \"PRPF31\", \"UBR5\", \"EP300\", \"FGF2\", \"MUD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}