{"gene":"SF3B2","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":1996,"finding":"Yeast CUS1 (ortholog of human SF3B2/SAP145) is an essential splicing factor required for U2 snRNP addition to the spliceosome. A dominant suppressor allele (CUS1-54) directly rescues the spliceosome assembly defect of a U2 stem loop IIa mutant in vitro, demonstrating that CUS1 acts at the step of U2 snRNP incorporation into the spliceosome. Genetic epistasis links CUS1 to PRP11 and PRP5, placing it in the same assembly step.","method":"Suppressor screen in S. cerevisiae, in vitro spliceosome assembly assay, genetic epistasis (allele specificity tests, multicopy suppression of prp11 and prp5 mutations)","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro spliceosome assembly rescue combined with genetic epistasis, replicated across multiple allele-specificity and multicopy suppression tests","pmids":["8566755"],"is_preprint":false},{"year":2015,"finding":"PRMT9 methylates SF3B2 (SAP145) at arginine 508, depositing monomethylarginine (MMA) and symmetrically dimethylated arginine (SDMA). This methylation event generates a binding site for the Tudor domain of the Survival of Motor Neuron (SMN) protein, thereby priming the U2 snRNP for interaction with SMN. PRMT9 was identified as a binding partner of both SAP145 and SAP49, linking it to U2 snRNP maturation.","method":"Co-immunoprecipitation (PRMT9 binding partners), in vitro methyltransferase assay, mass spectrometry identification of methylation site, site-directed mutagenesis, Tudor domain binding assay, RNA-seq (splicing changes upon PRMT9 attenuation)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro enzymatic assay with mutagenesis, MS identification of modification site, functional binding assay for SMN Tudor domain, replicated by independent study (PMID:25979344)","pmids":["25737013"],"is_preprint":false},{"year":2015,"finding":"PRMT9 methylates SF3B2 at Arg-508, but a peptide containing this residue alone is not recognized by PRMT9 in vitro, indicating that the full protein context is required. Moving the arginine residue within its sequence abolishes methylation. PRMT9 and PRMT5 have non-redundant substrate specificities; loss of PRMT5 causes near-complete loss of SDMA in mouse embryo fibroblasts, confirming PRMT5 as the primary SDMA-forming enzyme and PRMT9 as specifically responsible for SF3B2 Arg-508 methylation.","method":"In vitro methyltransferase assay with peptides and full-length protein, site-directed mutagenesis of SF3B2 and PRMT9, PRMT5 knockout in mouse embryo fibroblasts with SDMA immunoblotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, genetic KO model, single lab with multiple orthogonal methods","pmids":["25979344"],"is_preprint":false},{"year":2006,"finding":"HIV-1 Vpr induces G2 checkpoint activation and cell cycle arrest by binding to the CUS1 domain of SAP145 (SF3B2) through its C-terminal domain, disrupting the SAP145-SAP49 complex. Depletion of either SAP145 or SAP49 alone recapitulates checkpoint-mediated G2 arrest with gamma-H2AX and BRCA1 nuclear foci. Vpr expression colocalizes with SAP145 in nuclear speckles and excludes SAP49 from these speckles.","method":"Co-immunoprecipitation, co-localization (immunofluorescence in nuclear speckles), siRNA depletion of SAP145/SAP49 with cell cycle analysis and gamma-H2AX/BRCA1 foci readout, Vpr C-terminal domain mutant analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, colocalization, and functional knockdown with defined cell cycle phenotype, single lab","pmids":["16923959"],"is_preprint":false},{"year":2007,"finding":"HIV-1 Vpr inhibits cellular pre-mRNA splicing by directly interacting with SAP145 (SF3B2); the third alpha-helical domain and arginine-rich region of Vpr are required for both binding SAP145 and inhibiting splicing. Vpr binding to SAP145 interferes with SAP145-SAP49 complex formation, as demonstrated by in vitro competitive binding assays, thereby blocking spliceosome assembly.","method":"Co-immunoprecipitation (Vpr-SAP145 interaction), in vitro splicing assays (beta-globin and IgM pre-mRNA), in vitro competitive binding assay (Vpr displacing SAP49 from SAP145), Vpr domain mutant analysis","journal":"Microbes and infection","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro splicing assay and competitive binding assay, Co-IP with domain mutants, single lab","pmids":["17347016"],"is_preprint":false},{"year":2016,"finding":"The RRM1 domain of human SF3b49 (SAP49) interacts with a fragment of SF3B2 (SF3b145) spanning residues 598-631, with residues 607-616 of SF3B2 adopting a helical structure that binds RRM1 predominantly via its alpha1 helix in an antiparallel helix-helix interaction. This mode of interaction is unique among RRM-peptide complexes. All interacting residues are evolutionarily conserved across eukaryotes.","method":"NMR solution structure determination of SF3b49 RRM1, NMR chemical shift mapping of SF3B2 fragment interaction, NOESY-based docking model, site-directed mutagenesis confirmed by GST pull-down assay","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with chemical shift mapping and docking, validated by mutagenesis and GST pull-down, single lab with multiple orthogonal methods","pmids":["27862552"],"is_preprint":false},{"year":2019,"finding":"SF3B2 controls the splicing of androgen receptor (AR) pre-mRNA to generate the constitutively active AR-V7 splice variant in prostate cancer cells. PAR-CLIP analysis revealed direct SF3B2 binding to target pre-mRNAs including AR. SF3B2-mediated aggressive phenotypes in vivo were reversed by AR-V7 knockout, placing SF3B2 upstream of AR-V7 in driving castration resistance.","method":"CRISPR/Cas9 loss-of-function, PAR-CLIP (direct RNA binding), transcriptome analysis (RNA-seq), in vivo xenograft rescue by AR-V7 knockout, pharmacological inhibition with pladienolide B","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — PAR-CLIP direct binding, genetic epistasis by AR-V7 KO rescue, in vivo models, multiple orthogonal approaches","pmids":["31431456"],"is_preprint":false},{"year":2021,"finding":"RNF6, a RING finger E3 ubiquitin ligase, transcriptionally activates SF3B2 by binding directly to the SF3B2 promoter. SF3B2 knockout abrogates the tumor-promoting effect of RNF6 overexpression, and re-expression of SF3B2 rescues cell growth and migration/invasion in RNF6 knockout cells, establishing SF3B2 as the functional downstream effector of RNF6 in colorectal cancer.","method":"ChIP-sequencing (RNF6 binding to SF3B2 promoter), RNA-sequencing, CRISPR/Cas9 knockout, transgenic mouse model (RNF6 overexpression), CRC organoids, xenograft in vivo models, rescue experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq demonstrating direct promoter binding, genetic epistasis via KO and rescue, in vivo models, multiple orthogonal methods","pmids":["34611311"],"is_preprint":false},{"year":2022,"finding":"SF3B2 binds to gene regulatory elements (enriched around promoters) and to mRNA (enriched at transcription termination sites) in head and neck squamous cell carcinoma cells, exhibiting a dual function in regulating both transcription and RNA stability. Mechanistically, SF3B2 promotes binding of SMC1A and CTCF to SF3B2-occupied genomic regions and modulates CTCF transcriptional activity, and also regulates RNA polymerase II activity.","method":"ChIP-seq (SF3B2 chromatin binding), CLIP-seq/RNA binding analysis, knockdown with gene expression and RNA stability assays, functional rescue in mouse xenograft models, CTCF binding analysis","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and RNA binding profiling with functional knockdown, single lab, mechanistic follow-up is partial","pmids":["35715826"],"is_preprint":false},{"year":2022,"finding":"Neuronal knockdown of SF3B2 in EAE mice preserves retinal ganglion cell survival and axonal integrity. In vitro, SF3B2 knockdown in cortical neurons exposed to inflammatory stimuli suppresses expression of injury-response and necroptosis genes and prevents activation of SARM1, a key enzyme mediating programmed axon degeneration.","method":"siRNA knockdown in vitro (cortical neurons under inflammatory conditions), in vivo EAE mouse model with SF3B2 knockdown, cell viability assay, axon integrity assessment, gene expression analysis for necroptosis pathway and SARM1","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo knockdown with defined cellular phenotype and pathway placement (SARM1/necroptosis), single lab","pmids":["36574260"],"is_preprint":false},{"year":2025,"finding":"Loss of SF3B2 in zebrafish causes widespread mRNA splicing disruption, including aberrant splicing of mdm2 (a key regulator of Tp53-mediated apoptosis). Genetic inhibition of tp53 in sf3b2 mutants reduces early cell death but does not rescue proliferation or craniofacial cartilage development, indicating that SF3B2 loss causes both Tp53-dependent cell death and Tp53-independent defects in cranial neural crest cell proliferation.","method":"sf3b2-null zebrafish (genetic KO), human iPSC differentiation with CRISPR/Cas9 heterozygous truncating variant, RNA-seq (splicing analysis), tp53 genetic inhibition in zebrafish (epistasis), apoptosis and proliferation assays","journal":"Journal of dental research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — zebrafish KO with RNA-seq splicing analysis, genetic epistasis with tp53, human iPSC model, multiple orthogonal approaches in single study","pmids":["40275713"],"is_preprint":false},{"year":2025,"finding":"YTHDF1 promotes SF3B2 protein translation via m6A modification of the SF3B2 coding sequence (CDS) region. YTHDF1 knockdown reduces SF3B2 protein levels without altering SF3B2 mRNA expression, and SF3B2 overexpression rescues the suppressed proliferation and invasion caused by YTHDF1 knockdown in pancreatic cancer cells.","method":"Co-immunoprecipitation/RIP (YTHDF1-SF3B2 mRNA interaction), YTHDF1 knockdown and overexpression with western blot (protein) and RT-qPCR (mRNA), m6A modification analysis, rescue experiments with SF3B2 overexpression","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP demonstrating direct YTHDF1-SF3B2 mRNA interaction, protein vs mRNA level dissociation, genetic rescue, single lab","pmids":["40211730"],"is_preprint":false},{"year":2026,"finding":"SF3B2 is modified by lysine myristoylation at K10, and HDAC11 efficiently removes this modification in cells, establishing SF3B2 as a direct enzymatic substrate of HDAC11. A de-myristoylation mimetic mutant (SF3B2 K10R) exhibits altered pre-mRNA binding activity in a context-dependent manner; in HCC cells, loss of SF3B2 lysine myristoylation enhances SF3B2 association with androgen receptor (AR) splice variant loci and promotes alternative splicing towards the AR-v7 variant.","method":"Metabolic labeling, mass spectrometry (identification of K10 myristoylation), click chemistry, HDAC11 overexpression/knockdown with AR splicing readout, SF3B2 K10R mutagenesis, pre-mRNA binding assays, HDAC11 catalytic mutant controls","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — MS identification of modification + enzymatic substrate validation + mutagenesis + functional splicing readout, preprint not yet peer-reviewed","pmids":["42124652"],"is_preprint":true}],"current_model":"SF3B2 (SAP145) is an essential component of the U2 snRNP that directly mediates spliceosome assembly by facilitating U2 snRNP addition to pre-mRNA; its activity is regulated by multiple post-translational modifications including PRMT9-catalyzed symmetric dimethylation of Arg-508 (creating an SMN Tudor domain binding site), HDAC11-mediated removal of lysine myristoylation at K10 (modulating pre-mRNA binding and alternative splicing), and YTHDF1-driven m6A-dependent translational enhancement; SF3B2 directly binds pre-mRNA targets (including androgen receptor) via PAR-CLIP, interacts with SF3b49 (SAP49) through a unique helix-helix interface involving residues 607-616, and additionally exerts transcriptional regulatory functions by binding gene regulatory elements and modulating CTCF and RNA polymerase II activity."},"narrative":{"mechanistic_narrative":"SF3B2 (SAP145) is an essential pre-mRNA splicing factor of the U2 snRNP that mediates spliceosome assembly by facilitating U2 snRNP incorporation into the spliceosome, a role first established through its yeast ortholog CUS1 and placed genetically in the same assembly step as PRP11 and PRP5 [PMID:8566755]. Within the U2 snRNP it binds its partner SF3b49 (SAP49) through a distinctive antiparallel helix-helix interface, in which SF3B2 residues 607-616 adopt a helical conformation that docks onto the SF3b49 RRM1 alpha1 helix [PMID:27862552]. SF3B2 directly engages target pre-mRNAs, including androgen receptor (AR), and controls production of the constitutively active AR-V7 splice variant that drives castration-resistant prostate cancer growth in vivo [PMID:31431456]; its loss broadly disrupts splicing, exemplified by aberrant mdm2 splicing that triggers both Tp53-dependent cell death and Tp53-independent neural crest proliferation defects [PMID:40275713]. SF3B2 activity is tuned by post-translational modifications: PRMT9 methylates Arg-508 to generate symmetrically dimethylated arginine that creates an SMN Tudor-domain docking site, coupling the U2 snRNP to the SMN machinery [PMID:25737013, PMID:25979344]; HDAC11-catalyzed removal of K10 lysine myristoylation alters pre-mRNA binding and shifts splicing toward AR-V7 [PMID:42124652]. Beyond splicing, SF3B2 binds gene regulatory elements, promotes SMC1A and CTCF occupancy, and modulates RNA polymerase II activity, indicating a coupled transcriptional and RNA-stability function [PMID:35715826]. Its abundance is controlled at the transcriptional level by the E3 ligase RNF6, which binds the SF3B2 promoter [PMID:34611311], and at the translational level by YTHDF1-driven m6A-dependent enhancement [PMID:40211730].","teleology":[{"year":1996,"claim":"Established the core function of SF3B2 by showing its yeast ortholog CUS1 is essential for adding U2 snRNP to the spliceosome, defining the assembly step at which it acts.","evidence":"Suppressor screen, in vitro spliceosome assembly rescue, and genetic epistasis in S. cerevisiae","pmids":["8566755"],"confidence":"High","gaps":["Did not resolve the human SF3B2 contacts within U2 snRNP","Mechanism of U2 snRNP recruitment to substrate not structurally defined"]},{"year":2006,"claim":"Showed that disrupting the SF3B2-SF3b49 complex has functional consequences for cell cycle control, using HIV-1 Vpr as a tool that targets the CUS1 domain of SF3B2.","evidence":"Co-IP, nuclear speckle colocalization, and siRNA depletion with G2 arrest and gamma-H2AX/BRCA1 foci readout","pmids":["16923959"],"confidence":"Medium","gaps":["Whether the G2 arrest reflects splicing loss or a separable SF3B2 function unclear","Single lab; phenotype driven via viral protein"]},{"year":2007,"claim":"Demonstrated mechanistically that occupying SF3B2 blocks splicing by competitively displacing SF3b49, directly linking the SF3B2-SF3b49 interface to spliceosome assembly.","evidence":"In vitro splicing assays, competitive binding assay, and Vpr domain mutants","pmids":["17347016"],"confidence":"Medium","gaps":["Structural basis of the displacement not resolved here","Single lab"]},{"year":2015,"claim":"Identified a PTM-based coupling of SF3B2 to the SMN pathway: PRMT9 methylates Arg-508 to create an SMN Tudor-domain binding site, defining how the U2 snRNP is primed for SMN interaction.","evidence":"Co-IP, in vitro methyltransferase assay, MS site mapping, mutagenesis, Tudor binding assay, and RNA-seq; replicated with PRMT5-KO MEF specificity controls","pmids":["25737013","25979344"],"confidence":"High","gaps":["Functional consequence of SMN-SF3B2 coupling for snRNP biogenesis not fully defined","In vivo requirement of Arg-508 methylation not established"]},{"year":2016,"claim":"Provided the structural basis of the SF3B2-SF3b49 interaction, defining a unique antiparallel helix-helix mode mediated by SF3B2 residues 607-616.","evidence":"NMR solution structure, chemical shift mapping, NOESY docking, and mutagenesis-validated GST pull-down","pmids":["27862552"],"confidence":"High","gaps":["Interface mapped on a fragment, not full-length complex","Role within assembled U2 snRNP not visualized"]},{"year":2019,"claim":"Connected SF3B2's splicing activity to disease by showing it directly binds AR pre-mRNA and drives AR-V7 generation, placing it upstream of castration resistance.","evidence":"CRISPR loss-of-function, PAR-CLIP direct binding, RNA-seq, in vivo xenograft rescue by AR-V7 KO, and pladienolide B inhibition","pmids":["31431456"],"confidence":"High","gaps":["Full target repertoire beyond AR not catalogued","Determinants of AR-V7 splice-site selection unresolved"]},{"year":2021,"claim":"Defined upstream transcriptional control of SF3B2 abundance, identifying RNF6 as a direct promoter-binding activator whose oncogenic effect depends on SF3B2.","evidence":"ChIP-seq, RNA-seq, CRISPR KO with rescue, transgenic mouse, organoid, and xenograft models in colorectal cancer","pmids":["34611311"],"confidence":"High","gaps":["Which SF3B2-dependent splicing or transcriptional outputs mediate the RNF6 phenotype unclear"]},{"year":2022,"claim":"Expanded SF3B2's role beyond splicing, showing it binds gene regulatory elements and mRNA and modulates CTCF/SMC1A occupancy and RNA Pol II activity.","evidence":"ChIP-seq, CLIP-seq, knockdown with gene expression and RNA stability assays, and xenograft rescue in HNSCC","pmids":["35715826"],"confidence":"Medium","gaps":["Direct vs indirect role in CTCF recruitment not separated","Mechanistic link between transcriptional and splicing functions unresolved"]},{"year":2022,"claim":"Placed SF3B2 in a neuronal injury pathway, showing its knockdown suppresses necroptosis genes and SARM1 activation to preserve axonal integrity under inflammatory stress.","evidence":"siRNA knockdown in cortical neurons and in vivo EAE mouse model with viability, axon integrity, and pathway gene readouts","pmids":["36574260"],"confidence":"Medium","gaps":["Whether splicing of specific necroptosis/SARM1 transcripts mediates the effect unknown","Single lab"]},{"year":2025,"claim":"Dissected the consequences of SF3B2 loss in vivo, separating Tp53-dependent cell death from Tp53-independent neural crest proliferation defects in craniofacial development.","evidence":"sf3b2-null zebrafish, RNA-seq splicing analysis, tp53 epistasis, and human iPSC model with truncating variant","pmids":["40275713"],"confidence":"High","gaps":["Identity of the Tp53-independent effector transcripts unknown","No human Mendelian disease causation established in this corpus"]},{"year":2025,"claim":"Identified translational control of SF3B2, showing YTHDF1 enhances SF3B2 protein output via m6A on the CDS without changing mRNA levels.","evidence":"RIP, YTHDF1 knockdown/overexpression with protein vs mRNA dissociation, m6A analysis, and SF3B2 overexpression rescue in pancreatic cancer cells","pmids":["40211730"],"confidence":"Medium","gaps":["Precise m6A sites and reader-mediated mechanism not mapped","Single lab"]},{"year":2026,"claim":"Established SF3B2 as an HDAC11 de-myristoylation substrate at K10 and linked this PTM to context-dependent pre-mRNA binding and AR-V7 splicing.","evidence":"Metabolic labeling, MS, click chemistry, HDAC11 manipulation with catalytic controls, K10R mutagenesis, and AR splicing readout (preprint)","pmids":["42124652"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","How K10 myristoylation alters RNA binding mechanistically unresolved"]},{"year":null,"claim":"How SF3B2's splicing, transcriptional, and RNA-stability functions are coordinated, and how its many PTMs are integrated to direct substrate-specific alternative splicing, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of SF3B2 within the assembled spliceosome and at chromatin","Crosstalk among Arg-508 methylation, K10 myristoylation, and m6A-driven translation not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6,8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,6,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8]}],"complexes":["U2 snRNP"],"partners":["SF3B49","PRMT9","SMN","HDAC11","YTHDF1","RNF6","CTCF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13435","full_name":"Splicing factor 3B subunit 2","aliases":["Pre-mRNA-splicing factor SF3b 145 kDa subunit","SF3b145","Spliceosome-associated protein 145","SAP 145"],"length_aa":895,"mass_kda":100.2,"function":"Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs (PubMed:12234937, 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, SF3B2 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; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q13435/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SF3B2","classification":"Common Essential","n_dependent_lines":1203,"n_total_lines":1208,"dependency_fraction":0.9958609271523179},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000087365","cell_line_id":"CID001448","localizations":[{"compartment":"chromatin","grade":3}],"interactors":[{"gene":"COMMD4","stoichiometry":10.0},{"gene":"PRPF4B","stoichiometry":10.0},{"gene":"RANBP2","stoichiometry":10.0},{"gene":"RBM17","stoichiometry":10.0},{"gene":"SF3A1","stoichiometry":10.0},{"gene":"SF3A2","stoichiometry":10.0},{"gene":"SF3A3","stoichiometry":10.0},{"gene":"SF3B1","stoichiometry":10.0},{"gene":"SNRPB2","stoichiometry":10.0},{"gene":"SNRPA1","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001448","total_profiled":1310},"omim":[{"mim_id":"612413","title":"RNA-BINDING MOTIF PROTEIN 7; RBM7","url":"https://www.omim.org/entry/612413"},{"mim_id":"605593","title":"SPLICING FACTOR 3B, SUBUNIT 4; SF3B4","url":"https://www.omim.org/entry/605593"},{"mim_id":"605592","title":"SPLICING FACTOR 3B, SUBUNIT 3; SF3B3","url":"https://www.omim.org/entry/605592"},{"mim_id":"605591","title":"SPLICING FACTOR 3B, SUBUNIT 2; SF3B2","url":"https://www.omim.org/entry/605591"},{"mim_id":"164210","title":"CRANIOFACIAL MICROSOMIA 1; CFM1","url":"https://www.omim.org/entry/164210"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear speckles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SF3B2"},"hgnc":{"alias_symbol":["SAP145","SF3b1","Cus1","SF3b145"],"prev_symbol":[]},"alphafold":{"accession":"Q13435","domains":[{"cath_id":"-","chopping":"17-66","consensus_level":"medium","plddt":85.7686,"start":17,"end":66},{"cath_id":"-","chopping":"450-493","consensus_level":"medium","plddt":90.7914,"start":450,"end":493},{"cath_id":"-","chopping":"610-695","consensus_level":"medium","plddt":82.8185,"start":610,"end":695},{"cath_id":"1.20.5","chopping":"154-188","consensus_level":"medium","plddt":83.7549,"start":154,"end":188}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13435","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13435-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13435-F1-predicted_aligned_error_v6.png","plddt_mean":65.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SF3B2","jax_strain_url":"https://www.jax.org/strain/search?query=SF3B2"},"sequence":{"accession":"Q13435","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13435.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13435/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13435"}},"corpus_meta":[{"pmid":"25737013","id":"PMC_25737013","title":"PRMT9 is a type II methyltransferase that methylates the splicing factor SAP145.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25737013","citation_count":188,"is_preprint":false},{"pmid":"25979344","id":"PMC_25979344","title":"Unique Features of Human Protein Arginine Methyltransferase 9 (PRMT9) and Its Substrate RNA Splicing Factor SF3B2.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25979344","citation_count":85,"is_preprint":false},{"pmid":"33712605","id":"PMC_33712605","title":"PGC1/PPAR drive cardiomyocyte maturation at single cell level via YAP1 and SF3B2.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33712605","citation_count":80,"is_preprint":false},{"pmid":"8566755","id":"PMC_8566755","title":"CUS1, a suppressor of cold-sensitive U2 snRNA mutations, is a novel yeast splicing factor homologous to human SAP 145.","date":"1996","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/8566755","citation_count":66,"is_preprint":false},{"pmid":"31431456","id":"PMC_31431456","title":"SF3B2-Mediated RNA Splicing Drives Human Prostate Cancer Progression.","date":"2019","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/31431456","citation_count":61,"is_preprint":false},{"pmid":"17347016","id":"PMC_17347016","title":"Human immunodeficiency virus type 1 Vpr interacts with spliceosomal protein SAP145 to mediate cellular pre-mRNA splicing inhibition.","date":"2007","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/17347016","citation_count":40,"is_preprint":false},{"pmid":"16923959","id":"PMC_16923959","title":"Human immunodeficiency virus type 1 Vpr induces G2 checkpoint activation by interacting with the splicing factor SAP145.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16923959","citation_count":27,"is_preprint":false},{"pmid":"31460703","id":"PMC_31460703","title":"Anionic Se-Substitution toward High-Performance CuS1- x Sex Nanosheet Cathode for Rechargeable Magnesium Batteries.","date":"2019","source":"Small (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/31460703","citation_count":24,"is_preprint":false},{"pmid":"34611311","id":"PMC_34611311","title":"RING-finger protein 6 promotes colorectal tumorigenesis by transcriptionally activating SF3B2.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34611311","citation_count":13,"is_preprint":false},{"pmid":"27862552","id":"PMC_27862552","title":"Solution structure of the first RNA recognition motif domain of human spliceosomal protein SF3b49 and its mode of interaction with a SF3b145 fragment.","date":"2016","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/27862552","citation_count":6,"is_preprint":false},{"pmid":"35715826","id":"PMC_35715826","title":"Dual function of SF3B2 on chromatin and RNA to regulate transcription in head and neck squamous cell carcinoma.","date":"2022","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/35715826","citation_count":5,"is_preprint":false},{"pmid":"40211730","id":"PMC_40211730","title":"YTHDF1 promotes pancreatic cancer cell progression by enhancing SF3B2 translation though m6A modification.","date":"2025","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40211730","citation_count":4,"is_preprint":false},{"pmid":"36574260","id":"PMC_36574260","title":"Downregulation of SF3B2 protects CNS neurons in models of multiple sclerosis.","date":"2022","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36574260","citation_count":2,"is_preprint":false},{"pmid":"40275713","id":"PMC_40275713","title":"Splicing Defects and Cell Death Cause SF3B2-Linked Craniofacial Microsomia.","date":"2025","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/40275713","citation_count":1,"is_preprint":false},{"pmid":"40615115","id":"PMC_40615115","title":"Haploinsufficiency of SF3B2 revealed by a craniofacial microsomia with atypical presentation: a case report.","date":"2025","source":"Journal of stomatology, oral and maxillofacial surgery","url":"https://pubmed.ncbi.nlm.nih.gov/40615115","citation_count":0,"is_preprint":false},{"pmid":"42124652","id":"PMC_42124652","title":"HDAC11 Regulates RNA Splicing via De-Fatty Acylation of SF3B2.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42124652","citation_count":0,"is_preprint":false},{"pmid":"41427026","id":"PMC_41427026","title":"Likely Pathogenic/Pathogenic Variants in the Spliceosome Complex Genes SNRNP200, SF3B1, SF3B2, and SF3B4 Implicated in Nonsyndromic Orofacial Cleft.","date":"2025","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/41427026","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.02.601767","title":"Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations","date":"2024-07-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.02.601767","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.09.632122","title":"Spatiotemporal variation in cutin polymerization and remodeling mediated by GDSL-hydrolase enzymes during tomato fruit development","date":"2025-01-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.09.632122","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11353,"output_tokens":4134,"usd":0.048035,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11997,"output_tokens":3978,"usd":0.079717,"stage2_stop_reason":"end_turn"},"total_usd":0.127752,"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\": 1996,\n      \"finding\": \"Yeast CUS1 (ortholog of human SF3B2/SAP145) is an essential splicing factor required for U2 snRNP addition to the spliceosome. A dominant suppressor allele (CUS1-54) directly rescues the spliceosome assembly defect of a U2 stem loop IIa mutant in vitro, demonstrating that CUS1 acts at the step of U2 snRNP incorporation into the spliceosome. Genetic epistasis links CUS1 to PRP11 and PRP5, placing it in the same assembly step.\",\n      \"method\": \"Suppressor screen in S. cerevisiae, in vitro spliceosome assembly assay, genetic epistasis (allele specificity tests, multicopy suppression of prp11 and prp5 mutations)\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro spliceosome assembly rescue combined with genetic epistasis, replicated across multiple allele-specificity and multicopy suppression tests\",\n      \"pmids\": [\"8566755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRMT9 methylates SF3B2 (SAP145) at arginine 508, depositing monomethylarginine (MMA) and symmetrically dimethylated arginine (SDMA). This methylation event generates a binding site for the Tudor domain of the Survival of Motor Neuron (SMN) protein, thereby priming the U2 snRNP for interaction with SMN. PRMT9 was identified as a binding partner of both SAP145 and SAP49, linking it to U2 snRNP maturation.\",\n      \"method\": \"Co-immunoprecipitation (PRMT9 binding partners), in vitro methyltransferase assay, mass spectrometry identification of methylation site, site-directed mutagenesis, Tudor domain binding assay, RNA-seq (splicing changes upon PRMT9 attenuation)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro enzymatic assay with mutagenesis, MS identification of modification site, functional binding assay for SMN Tudor domain, replicated by independent study (PMID:25979344)\",\n      \"pmids\": [\"25737013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRMT9 methylates SF3B2 at Arg-508, but a peptide containing this residue alone is not recognized by PRMT9 in vitro, indicating that the full protein context is required. Moving the arginine residue within its sequence abolishes methylation. PRMT9 and PRMT5 have non-redundant substrate specificities; loss of PRMT5 causes near-complete loss of SDMA in mouse embryo fibroblasts, confirming PRMT5 as the primary SDMA-forming enzyme and PRMT9 as specifically responsible for SF3B2 Arg-508 methylation.\",\n      \"method\": \"In vitro methyltransferase assay with peptides and full-length protein, site-directed mutagenesis of SF3B2 and PRMT9, PRMT5 knockout in mouse embryo fibroblasts with SDMA immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, genetic KO model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25979344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HIV-1 Vpr induces G2 checkpoint activation and cell cycle arrest by binding to the CUS1 domain of SAP145 (SF3B2) through its C-terminal domain, disrupting the SAP145-SAP49 complex. Depletion of either SAP145 or SAP49 alone recapitulates checkpoint-mediated G2 arrest with gamma-H2AX and BRCA1 nuclear foci. Vpr expression colocalizes with SAP145 in nuclear speckles and excludes SAP49 from these speckles.\",\n      \"method\": \"Co-immunoprecipitation, co-localization (immunofluorescence in nuclear speckles), siRNA depletion of SAP145/SAP49 with cell cycle analysis and gamma-H2AX/BRCA1 foci readout, Vpr C-terminal domain mutant analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, colocalization, and functional knockdown with defined cell cycle phenotype, single lab\",\n      \"pmids\": [\"16923959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HIV-1 Vpr inhibits cellular pre-mRNA splicing by directly interacting with SAP145 (SF3B2); the third alpha-helical domain and arginine-rich region of Vpr are required for both binding SAP145 and inhibiting splicing. Vpr binding to SAP145 interferes with SAP145-SAP49 complex formation, as demonstrated by in vitro competitive binding assays, thereby blocking spliceosome assembly.\",\n      \"method\": \"Co-immunoprecipitation (Vpr-SAP145 interaction), in vitro splicing assays (beta-globin and IgM pre-mRNA), in vitro competitive binding assay (Vpr displacing SAP49 from SAP145), Vpr domain mutant analysis\",\n      \"journal\": \"Microbes and infection\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro splicing assay and competitive binding assay, Co-IP with domain mutants, single lab\",\n      \"pmids\": [\"17347016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The RRM1 domain of human SF3b49 (SAP49) interacts with a fragment of SF3B2 (SF3b145) spanning residues 598-631, with residues 607-616 of SF3B2 adopting a helical structure that binds RRM1 predominantly via its alpha1 helix in an antiparallel helix-helix interaction. This mode of interaction is unique among RRM-peptide complexes. All interacting residues are evolutionarily conserved across eukaryotes.\",\n      \"method\": \"NMR solution structure determination of SF3b49 RRM1, NMR chemical shift mapping of SF3B2 fragment interaction, NOESY-based docking model, site-directed mutagenesis confirmed by GST pull-down assay\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with chemical shift mapping and docking, validated by mutagenesis and GST pull-down, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27862552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SF3B2 controls the splicing of androgen receptor (AR) pre-mRNA to generate the constitutively active AR-V7 splice variant in prostate cancer cells. PAR-CLIP analysis revealed direct SF3B2 binding to target pre-mRNAs including AR. SF3B2-mediated aggressive phenotypes in vivo were reversed by AR-V7 knockout, placing SF3B2 upstream of AR-V7 in driving castration resistance.\",\n      \"method\": \"CRISPR/Cas9 loss-of-function, PAR-CLIP (direct RNA binding), transcriptome analysis (RNA-seq), in vivo xenograft rescue by AR-V7 knockout, pharmacological inhibition with pladienolide B\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — PAR-CLIP direct binding, genetic epistasis by AR-V7 KO rescue, in vivo models, multiple orthogonal approaches\",\n      \"pmids\": [\"31431456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF6, a RING finger E3 ubiquitin ligase, transcriptionally activates SF3B2 by binding directly to the SF3B2 promoter. SF3B2 knockout abrogates the tumor-promoting effect of RNF6 overexpression, and re-expression of SF3B2 rescues cell growth and migration/invasion in RNF6 knockout cells, establishing SF3B2 as the functional downstream effector of RNF6 in colorectal cancer.\",\n      \"method\": \"ChIP-sequencing (RNF6 binding to SF3B2 promoter), RNA-sequencing, CRISPR/Cas9 knockout, transgenic mouse model (RNF6 overexpression), CRC organoids, xenograft in vivo models, rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq demonstrating direct promoter binding, genetic epistasis via KO and rescue, in vivo models, multiple orthogonal methods\",\n      \"pmids\": [\"34611311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SF3B2 binds to gene regulatory elements (enriched around promoters) and to mRNA (enriched at transcription termination sites) in head and neck squamous cell carcinoma cells, exhibiting a dual function in regulating both transcription and RNA stability. Mechanistically, SF3B2 promotes binding of SMC1A and CTCF to SF3B2-occupied genomic regions and modulates CTCF transcriptional activity, and also regulates RNA polymerase II activity.\",\n      \"method\": \"ChIP-seq (SF3B2 chromatin binding), CLIP-seq/RNA binding analysis, knockdown with gene expression and RNA stability assays, functional rescue in mouse xenograft models, CTCF binding analysis\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and RNA binding profiling with functional knockdown, single lab, mechanistic follow-up is partial\",\n      \"pmids\": [\"35715826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Neuronal knockdown of SF3B2 in EAE mice preserves retinal ganglion cell survival and axonal integrity. In vitro, SF3B2 knockdown in cortical neurons exposed to inflammatory stimuli suppresses expression of injury-response and necroptosis genes and prevents activation of SARM1, a key enzyme mediating programmed axon degeneration.\",\n      \"method\": \"siRNA knockdown in vitro (cortical neurons under inflammatory conditions), in vivo EAE mouse model with SF3B2 knockdown, cell viability assay, axon integrity assessment, gene expression analysis for necroptosis pathway and SARM1\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo knockdown with defined cellular phenotype and pathway placement (SARM1/necroptosis), single lab\",\n      \"pmids\": [\"36574260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of SF3B2 in zebrafish causes widespread mRNA splicing disruption, including aberrant splicing of mdm2 (a key regulator of Tp53-mediated apoptosis). Genetic inhibition of tp53 in sf3b2 mutants reduces early cell death but does not rescue proliferation or craniofacial cartilage development, indicating that SF3B2 loss causes both Tp53-dependent cell death and Tp53-independent defects in cranial neural crest cell proliferation.\",\n      \"method\": \"sf3b2-null zebrafish (genetic KO), human iPSC differentiation with CRISPR/Cas9 heterozygous truncating variant, RNA-seq (splicing analysis), tp53 genetic inhibition in zebrafish (epistasis), apoptosis and proliferation assays\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish KO with RNA-seq splicing analysis, genetic epistasis with tp53, human iPSC model, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"40275713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF1 promotes SF3B2 protein translation via m6A modification of the SF3B2 coding sequence (CDS) region. YTHDF1 knockdown reduces SF3B2 protein levels without altering SF3B2 mRNA expression, and SF3B2 overexpression rescues the suppressed proliferation and invasion caused by YTHDF1 knockdown in pancreatic cancer cells.\",\n      \"method\": \"Co-immunoprecipitation/RIP (YTHDF1-SF3B2 mRNA interaction), YTHDF1 knockdown and overexpression with western blot (protein) and RT-qPCR (mRNA), m6A modification analysis, rescue experiments with SF3B2 overexpression\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP demonstrating direct YTHDF1-SF3B2 mRNA interaction, protein vs mRNA level dissociation, genetic rescue, single lab\",\n      \"pmids\": [\"40211730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SF3B2 is modified by lysine myristoylation at K10, and HDAC11 efficiently removes this modification in cells, establishing SF3B2 as a direct enzymatic substrate of HDAC11. A de-myristoylation mimetic mutant (SF3B2 K10R) exhibits altered pre-mRNA binding activity in a context-dependent manner; in HCC cells, loss of SF3B2 lysine myristoylation enhances SF3B2 association with androgen receptor (AR) splice variant loci and promotes alternative splicing towards the AR-v7 variant.\",\n      \"method\": \"Metabolic labeling, mass spectrometry (identification of K10 myristoylation), click chemistry, HDAC11 overexpression/knockdown with AR splicing readout, SF3B2 K10R mutagenesis, pre-mRNA binding assays, HDAC11 catalytic mutant controls\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MS identification of modification + enzymatic substrate validation + mutagenesis + functional splicing readout, preprint not yet peer-reviewed\",\n      \"pmids\": [\"42124652\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SF3B2 (SAP145) is an essential component of the U2 snRNP that directly mediates spliceosome assembly by facilitating U2 snRNP addition to pre-mRNA; its activity is regulated by multiple post-translational modifications including PRMT9-catalyzed symmetric dimethylation of Arg-508 (creating an SMN Tudor domain binding site), HDAC11-mediated removal of lysine myristoylation at K10 (modulating pre-mRNA binding and alternative splicing), and YTHDF1-driven m6A-dependent translational enhancement; SF3B2 directly binds pre-mRNA targets (including androgen receptor) via PAR-CLIP, interacts with SF3b49 (SAP49) through a unique helix-helix interface involving residues 607-616, and additionally exerts transcriptional regulatory functions by binding gene regulatory elements and modulating CTCF and RNA polymerase II activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SF3B2 (SAP145) is an essential pre-mRNA splicing factor of the U2 snRNP that mediates spliceosome assembly by facilitating U2 snRNP incorporation into the spliceosome, a role first established through its yeast ortholog CUS1 and placed genetically in the same assembly step as PRP11 and PRP5 [#0]. Within the U2 snRNP it binds its partner SF3b49 (SAP49) through a distinctive antiparallel helix-helix interface, in which SF3B2 residues 607-616 adopt a helical conformation that docks onto the SF3b49 RRM1 alpha1 helix [#5]. SF3B2 directly engages target pre-mRNAs, including androgen receptor (AR), and controls production of the constitutively active AR-V7 splice variant that drives castration-resistant prostate cancer growth in vivo [#6]; its loss broadly disrupts splicing, exemplified by aberrant mdm2 splicing that triggers both Tp53-dependent cell death and Tp53-independent neural crest proliferation defects [#10]. SF3B2 activity is tuned by post-translational modifications: PRMT9 methylates Arg-508 to generate symmetrically dimethylated arginine that creates an SMN Tudor-domain docking site, coupling the U2 snRNP to the SMN machinery [#1, #2]; HDAC11-catalyzed removal of K10 lysine myristoylation alters pre-mRNA binding and shifts splicing toward AR-V7 [#12]. Beyond splicing, SF3B2 binds gene regulatory elements, promotes SMC1A and CTCF occupancy, and modulates RNA polymerase II activity, indicating a coupled transcriptional and RNA-stability function [#8]. Its abundance is controlled at the transcriptional level by the E3 ligase RNF6, which binds the SF3B2 promoter [#7], and at the translational level by YTHDF1-driven m6A-dependent enhancement [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the core function of SF3B2 by showing its yeast ortholog CUS1 is essential for adding U2 snRNP to the spliceosome, defining the assembly step at which it acts.\",\n      \"evidence\": \"Suppressor screen, in vitro spliceosome assembly rescue, and genetic epistasis in S. cerevisiae\",\n      \"pmids\": [\"8566755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the human SF3B2 contacts within U2 snRNP\", \"Mechanism of U2 snRNP recruitment to substrate not structurally defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed that disrupting the SF3B2-SF3b49 complex has functional consequences for cell cycle control, using HIV-1 Vpr as a tool that targets the CUS1 domain of SF3B2.\",\n      \"evidence\": \"Co-IP, nuclear speckle colocalization, and siRNA depletion with G2 arrest and gamma-H2AX/BRCA1 foci readout\",\n      \"pmids\": [\"16923959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the G2 arrest reflects splicing loss or a separable SF3B2 function unclear\", \"Single lab; phenotype driven via viral protein\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated mechanistically that occupying SF3B2 blocks splicing by competitively displacing SF3b49, directly linking the SF3B2-SF3b49 interface to spliceosome assembly.\",\n      \"evidence\": \"In vitro splicing assays, competitive binding assay, and Vpr domain mutants\",\n      \"pmids\": [\"17347016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the displacement not resolved here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a PTM-based coupling of SF3B2 to the SMN pathway: PRMT9 methylates Arg-508 to create an SMN Tudor-domain binding site, defining how the U2 snRNP is primed for SMN interaction.\",\n      \"evidence\": \"Co-IP, in vitro methyltransferase assay, MS site mapping, mutagenesis, Tudor binding assay, and RNA-seq; replicated with PRMT5-KO MEF specificity controls\",\n      \"pmids\": [\"25737013\", \"25979344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of SMN-SF3B2 coupling for snRNP biogenesis not fully defined\", \"In vivo requirement of Arg-508 methylation not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural basis of the SF3B2-SF3b49 interaction, defining a unique antiparallel helix-helix mode mediated by SF3B2 residues 607-616.\",\n      \"evidence\": \"NMR solution structure, chemical shift mapping, NOESY docking, and mutagenesis-validated GST pull-down\",\n      \"pmids\": [\"27862552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interface mapped on a fragment, not full-length complex\", \"Role within assembled U2 snRNP not visualized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected SF3B2's splicing activity to disease by showing it directly binds AR pre-mRNA and drives AR-V7 generation, placing it upstream of castration resistance.\",\n      \"evidence\": \"CRISPR loss-of-function, PAR-CLIP direct binding, RNA-seq, in vivo xenograft rescue by AR-V7 KO, and pladienolide B inhibition\",\n      \"pmids\": [\"31431456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full target repertoire beyond AR not catalogued\", \"Determinants of AR-V7 splice-site selection unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined upstream transcriptional control of SF3B2 abundance, identifying RNF6 as a direct promoter-binding activator whose oncogenic effect depends on SF3B2.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, CRISPR KO with rescue, transgenic mouse, organoid, and xenograft models in colorectal cancer\",\n      \"pmids\": [\"34611311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which SF3B2-dependent splicing or transcriptional outputs mediate the RNF6 phenotype unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded SF3B2's role beyond splicing, showing it binds gene regulatory elements and mRNA and modulates CTCF/SMC1A occupancy and RNA Pol II activity.\",\n      \"evidence\": \"ChIP-seq, CLIP-seq, knockdown with gene expression and RNA stability assays, and xenograft rescue in HNSCC\",\n      \"pmids\": [\"35715826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect role in CTCF recruitment not separated\", \"Mechanistic link between transcriptional and splicing functions unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed SF3B2 in a neuronal injury pathway, showing its knockdown suppresses necroptosis genes and SARM1 activation to preserve axonal integrity under inflammatory stress.\",\n      \"evidence\": \"siRNA knockdown in cortical neurons and in vivo EAE mouse model with viability, axon integrity, and pathway gene readouts\",\n      \"pmids\": [\"36574260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether splicing of specific necroptosis/SARM1 transcripts mediates the effect unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Dissected the consequences of SF3B2 loss in vivo, separating Tp53-dependent cell death from Tp53-independent neural crest proliferation defects in craniofacial development.\",\n      \"evidence\": \"sf3b2-null zebrafish, RNA-seq splicing analysis, tp53 epistasis, and human iPSC model with truncating variant\",\n      \"pmids\": [\"40275713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the Tp53-independent effector transcripts unknown\", \"No human Mendelian disease causation established in this corpus\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified translational control of SF3B2, showing YTHDF1 enhances SF3B2 protein output via m6A on the CDS without changing mRNA levels.\",\n      \"evidence\": \"RIP, YTHDF1 knockdown/overexpression with protein vs mRNA dissociation, m6A analysis, and SF3B2 overexpression rescue in pancreatic cancer cells\",\n      \"pmids\": [\"40211730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise m6A sites and reader-mediated mechanism not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established SF3B2 as an HDAC11 de-myristoylation substrate at K10 and linked this PTM to context-dependent pre-mRNA binding and AR-V7 splicing.\",\n      \"evidence\": \"Metabolic labeling, MS, click chemistry, HDAC11 manipulation with catalytic controls, K10R mutagenesis, and AR splicing readout (preprint)\",\n      \"pmids\": [\"42124652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"How K10 myristoylation alters RNA binding mechanistically unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SF3B2's splicing, transcriptional, and RNA-stability functions are coordinated, and how its many PTMs are integrated to direct substrate-specific alternative splicing, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of SF3B2 within the assembled spliceosome and at chromatin\", \"Crosstalk among Arg-508 methylation, K10 myristoylation, and m6A-driven translation not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 6, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"U2 snRNP\"\n    ],\n    \"partners\": [\n      \"SF3b49\",\n      \"PRMT9\",\n      \"SMN\",\n      \"HDAC11\",\n      \"YTHDF1\",\n      \"RNF6\",\n      \"CTCF\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}