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SF3A2

Splicing factor 3A subunit 2 · UniProt Q15428

Length
464 aa
Mass
49.3 kDa
Annotated
2026-06-10
20 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1993 High

    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

    PMID:8405998

    Open questions at the time
    • Did not resolve the physical architecture connecting the PRP proteins
    • Mechanism of U2 snRNP activation not yet defined
  2. 1993 High

    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

    PMID:8211114

    Open questions at the time
    • Did not show the complex is sufficient for U2 activation in isolation
    • Functional consequence of complex assembly on U2 snRNA structure unknown
  3. 1994 Medium

    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

    PMID:7926772

    Open questions at the time
    • Two-hybrid interaction not validated by reconstitution
    • Functional role of the contact during assembly not directly tested
  4. 1996 High

    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

    PMID:8969185

    Open questions at the time
    • Structural basis of the U2 conformational change not resolved
    • Did not map human-specific contacts
  5. 2001 High

    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

    PMID:11533230

    Open questions at the time
    • Atomic structure of the zinc finger–Sm interaction not determined
    • Did not address non-splicing functions
  6. 2004 Medium

    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

    PMID:15142036

    Open questions at the time
    • Physiological context of microtubule bundling not established
    • Relationship to splicing function unclear at this stage
  7. 2018 High

    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

    PMID:30475206

    Open questions at the time
    • Structural basis of the SF3A2–Ndc80 interaction unresolved
    • How the same protein partitions between splicing and kinetochore roles unknown
  8. 2023 Medium

    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

    PMID:38101749

    Open questions at the time
    • Mechanism by which K10 acetylation alters splice-site selection not defined
    • Single-lab finding without independent confirmation
  9. 2024 Medium

    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

    PMID:38569025

    Open questions at the time
    • Direct ubiquitination sites on SF3A2 not mapped
    • Single-lab study of the feedback loop

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SF3A2 is partitioned and regulated between its spliceosomal, kinetochore, and cytoskeletal functions, and whether its post-translational modifications coordinate these roles, remains unresolved.
  • No structural model integrating the splicing and mitotic functions
  • Cross-talk between acetylation/ubiquitination and the non-splicing roles untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0008092 cytoskeletal protein binding 2 GO:0005198 structural molecule activity 1
Localization
GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-1640170 Cell Cycle 1
Partners
EP300FGF2MUD2NDC80PRPF31SF3A1SF3A3UBR5
Complex memberships
17S U2 snRNPPRP9-SPP91/PRP21-PRP11 complexSF3a heterotrimer

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 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. In vitro spliceosome assembly assay, genetic analysis, biochemical complementation Genes & development High 8405998
1993 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. Protein-protein interaction assays, genetic synthetic lethality, biochemical fractionation Science High 8211114
1994 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. Yeast two-hybrid system, genetic synthetic lethality analysis Genes & development Medium 7926772
1996 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. Protein reconstitution from E. coli-expressed components, in vitro splicing assay, RNaseH accessibility assay The Journal of biological chemistry High 8969185
1996 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. Mutational analysis, heat-sensitive mutant isolation, deletion analysis, protein-protein interaction assays RNA Medium 8718683
1991 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. Linker-insertion mutagenesis, temperature-sensitive mutant analysis, overexpression complementation Molecular & general genetics Medium 2034220
2001 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. Recombinant protein expression in insect cells, in vitro U2 snRNP assembly assay, domain deletion analysis, prespliceosome formation assay Molecular and cellular biology High 11533230
2004 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. Protein-binding screen, pull-down assay, electron microscopy, ectopic expression/morphology assay The Biochemical journal Medium 15142036
2004 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. Yeast two-hybrid screen, pull-down assay Biological chemistry Low 15653435
2018 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. Antibody microinjection into Drosophila embryos, RNAi depletion in Drosophila and HeLa cells, co-immunoprecipitation, live imaging, immunofluorescence eLife High 30475206
2023 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. 4D-label-free acetylomics, co-immunoprecipitation, site-specific mutagenesis, shRNA interference, RNA-seq, cellular thermal shift assay, surface plasmon resonance, mitochondrial respiration measurement Journal of advanced research Medium 38101749
2024 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. Co-immunoprecipitation, knockdown/overexpression functional assays, alternative splicing analysis Science advances Medium 38569025
2014 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. Genetic mutant analysis, epistasis with PAR-2 and PKC-3, live imaging PloS one Low 25188372

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 The yeast MUD2 protein: an interaction with PRP11 defines a bridge between commitment complexes and U2 snRNP addition. Genes & development 177 7926772
1993 Four yeast spliceosomal proteins (PRP5, PRP9, PRP11, and PRP21) interact to promote U2 snRNP binding to pre-mRNA. Genes & development 125 8405998
1993 Interaction between PRP11 and SPP91 yeast splicing factors and characterization of a PRP9-PRP11-SPP91 complex. Science (New York, N.Y.) 67 8211114
1994 Pathogen-defence gene prp1-1 from potato encodes an auxin-responsive glutathione S-transferase. European journal of biochemistry 55 8001577
2001 Domains in human splicing factors SF3a60 and SF3a66 required for binding to SF3a120, assembly of the 17S U2 snRNP, and prespliceosome formation. Molecular and cellular biology 49 11533230
2024 SF3A2 promotes progression and cisplatin resistance in triple-negative breast cancer via alternative splicing of MKRN1. Science advances 45 38569025
2014 A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese. European journal of human genetics : EJHG 45 24916648
1995 The genes for a spliceosome protein (SAP62) and the anti-Müllerian hormone (AMH) are contiguous. Human molecular genetics 42 8541848
1996 In vitro studies of the Prp9.Prp11.Prp21 complex indicate a pathway for U2 small nuclear ribonucleoprotein activation. The Journal of biological chemistry 36 8969185
2018 Splicing factors Sf3A2 and Prp31 have direct roles in mitotic chromosome segregation. eLife 35 30475206
2023 Ginsenoside Rb2 inhibits p300-mediated SF3A2 acetylation at lysine 10 to promote Fscn1 alternative splicing against myocardial ischemic/reperfusion injury. Journal of advanced research 25 38101749
2004 Nuclear fibroblast growth factor-2 interacts specifically with splicing factor SF3a66. Biological chemistry 19 15653435
2004 The pre-mRNA-splicing factor SF3a66 functions as a microtubule-binding and -bundling protein. The Biochemical journal 17 15142036
1996 Essential domains of the PRP21 splicing factor are implicated in the binding to PRP9 and PRP11 proteins and are conserved through evolution. RNA (New York, N.Y.) 13 8718683
1991 Genetic studies of the PRP11 gene of Saccharomyces cerevisiae. Molecular & general genetics : MGG 9 2034220
2001 An expressed GNRP-like gene shares a bi-directional promoter with SF3A2 (SAP62) immediately upstream of AMH. Gene 8 11602354
2023 Phylogenetic Analysis of Spliceosome SF3a2 in Different Plant Species. International journal of molecular sciences 3 36982311
2026 Preliminary exploration of the putative function of SF3A2 in clear cell renal cell carcinoma. Molecular medicine reports 1 41508957
2014 A semi-dominant mutation in the general splicing factor SF3a66 causes anterior-posterior axis reversal in one-cell stage C. elegans embryos. PloS one 1 25188372
2026 SF3A2: a promising therapeutic target and predictive biomarker for immunotherapy in colorectal cancer. International journal of medical sciences 0 41399366

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