SF3B3

SF3B3 is a conserved core subunit of the U2 snRNP SF3b complex required for pre-mRNA splicing, with orthologs in fission and budding yeast genetically placing it within the spliceosome and showing that its loss causes selective splicing failure and cell-cycle arrest (PMID:11350031, PMID:9819400). In human cells, SF3B3 governs alternative splicing decisions across multiple disease-relevant transcripts, including exon inclusion in EZH2, exon skipping in mTOR, and splicing of FXR, MARF1, and EXOSC2 pre-mRNAs, thereby shaping downstream programs in tumor progression (PMID:27879367, PMID:38671459, PMID:40986891, PMID:41864998, PMID:41961893). SF3B3 stability and incorporation into U2 snRNP are controlled post-translationally: CK2 phosphorylates SF3B3 at T1200 to promote USP7-mediated deubiquitination and stabilization, and the phosphorylated, stabilized protein is preferentially assembled into the spliceosome to drive EXOSC2 splicing (PMID:41961893). Its splicing activity is directed in part through physical partnership with regulatory factors, including nuclear AGO3, which couples SF3B3 to global and isoform-specific splicing in CD4+ T helper cells, and hnRNPA1, which redirects MARF1 exon-8 splicing toward an oncogenic isoform (PMID:38096048, PMID:41864998). De novo heterozygous missense variants in SF3B3 reduce protein levels and impair SF3b complex interactions, producing widespread intron retention and cell-cycle abnormalities, establishing SF3B3 dysfunction as a cause of a human Mendelian disorder (PMID:41709284).

1. 1998 High

   Established that the SF3B3 ortholog is a splicing factor whose loss has specific, traceable downstream consequences rather than a global collapse, by showing a single mis-spliced transcript can explain a cellular phenotype.

   Evidence Temperature-sensitive mutant screen in S. cerevisiae with genetic suppression by SAR1 dosage and intron deletion

   PMID:9819400

   Open questions at the time

   • Does not define SF3B3's biochemical role within SF3b
   • Yeast SAR1-secretion link does not establish mammalian targets
2. 2001 High

   Positioned SF3B3 as a bona fide SF3b/U2 snRNP subunit by demonstrating genetic interaction with the SF3b155 ortholog and linking its loss to a G2/M cell-cycle block through failure to splice a limiting transcript.

   Evidence Temperature-sensitive prp12 mutant analysis, splicing kinetics, prp12/prp10 genetic interaction, and GFP localization in S. pombe

   PMID:11350031

   Open questions at the time

   • Molecular function of SF3B3 within the complex not resolved
   • Human-specific targets not addressed
3. 2016 Medium

   Demonstrated that human SF3B3 directs alternative exon inclusion in a specific oncogenic transcript (EZH2), connecting its splicing activity to tumor suppression in renal cancer.

   Evidence RT-PCR splicing assay, siRNA knockdown, ectopic expression, and xenograft model

   PMID:27879367

   Open questions at the time

   • No in vitro reconstitution of the splicing event
   • Mechanism by which SF3B3 selects exon 14 unknown
4. 2021 Medium

   Showed SF3B3 splicing activity can be modulated by an lncRNA partner, expanding the determinants of its target specificity.

   Evidence Co-immunoprecipitation of SF3B3 with LINC01348, splicing assays, and in vitro/in vivo manipulation in hepatocellular carcinoma

   PMID:34140643

   Open questions at the time

   • Single Co-IP for the lncRNA interaction
   • Direct vs. indirect binding not resolved
5. 2022 Medium

   Identified a non-splicing antiviral role in which SF3B3 binds ZIKV NS5 and restricts viral replication, broadening its interaction repertoire beyond the spliceosome.

   Evidence Affinity pull-down with LC-MS/MS, overexpression/knockdown, and viral replication and ISG assays

   PMID:36572150

   Open questions at the time

   • Whether the antiviral effect requires splicing activity is unclear
   • Single lab, no reciprocal validation
6. 2023 Medium

   Established that nuclear AGO3 directly partners with SF3B3 to support global mRNA splicing, linking an Argonaute protein to spliceosome function in immune cells.

   Evidence Ago1/3/4-deficient mouse genetics, nuclear fractionation, direct interaction assay, and splicing transcriptomics in CD4+ T helper cells

   PMID:38096048

   Open questions at the time

   • Stoichiometry and structural basis of AGO3:SF3B3 contact unknown
   • Whether AGO3 confers target specificity not defined
7. 2024 Medium

   Extended SF3B3's target catalog to mTOR exon skipping, tying its splicing control to a lipogenic signaling axis and cell survival in colorectal cancer.

   Evidence RNA-seq, RNA immunoprecipitation, knockdown, and xenograft/organoid models with lipidomics

   PMID:38671459

   Open questions at the time

   • Direct RNA contact sites on mTOR pre-mRNA not mapped
   • Single lab
8. 2025 Medium

   Placed SF3B3 in a MYC-driven oncogenic circuit as a direct transcriptional target that in turn regulates FXR splicing, defining an upstream transcriptional input to its expression.

   Evidence RAP-MS identification, MYC target validation, and in vivo Sf3b3 deletion in a mouse HCC model

   PMID:40986891

   Open questions at the time

   • FXR splicing mechanism by SF3B3 not reconstituted
   • Generality beyond HCC unknown
9. 2026 High

   Defined a complete post-translational control module for SF3B3 stability and spliceosome incorporation, identifying CK2 as the kinase and USP7 as the deubiquitinase acting through phospho-T1200.

   Evidence Phosphoproteomics, T1200 mutagenesis, SF3B3-USP7 Co-IP, ubiquitination and U2 snRNP assembly assays, and xenograft model in esophageal squamous cell carcinoma

   PMID:41961893

   Open questions at the time

   • Whether other splicing targets depend on T1200 phosphorylation not tested
   • Structural basis of phospho-dependent USP7 binding not determined
10. 2026 Medium

    Showed hnRNPA1 physically partners with SF3B3 to redirect MARF1 splicing toward an oncogenic isoform that drives DNA-repair-dependent radioresistance, adding another specificity-conferring partner.

    Evidence Reciprocal Co-IP, splicing analysis, clonogenic survival, and xenograft model in oral squamous cell carcinoma

    PMID:41864998

    Open questions at the time

    • Direct vs. complex-mediated MARF1 RNA recognition unresolved
    • Single lab
11. 2026 Medium

    Linked SF3B3 dysfunction to human Mendelian disease by showing de novo missense variants lower protein levels, weaken SF3b interactions, and cause widespread intron retention and cell-cycle defects.

    Evidence Patient-derived fibroblast functional studies, western blot, molecular dynamics simulations, and splicing/cell-cycle transcriptome analysis

    PMID:41709284

    Open questions at the time

    • Genotype-phenotype correlation across variants not established
    • Structural impairment inferred from simulation, not experimental structure

• How SF3B3 achieves target-specific splicing decisions across its diverse pre-mRNA substrates, and whether the CK2/USP7 phospho-stabilization axis governs all of these events or only a subset, remains unresolved.
• No high-resolution structure of SF3B3 within human SF3b in the corpus
• Rules governing partner-directed target selection (AGO3, hnRNPA1, lncRNA) not unified
• No in vitro reconstituted splicing assay for SF3B3-dependent events