Affinage

U2AF1

Splicing factor U2AF 35 kDa subunit · UniProt Q01081

Length
240 aa
Mass
27.9 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

U2AF1 (U2AF35) is the small subunit of the U2AF splicing factor heterodimer that directly recognizes the conserved AG dinucleotide at the 3' splice site during early spliceosome assembly, a function established by site-specific UV crosslinking and in vitro genetic selection (PMID:10617206, PMID:10617208). It is required for both constitutive and enhancer-dependent splicing, recruiting and stabilizing U2AF2 (U2AF65) on weak polypyrimidine tracts and bridging SR-protein enhancer complexes to U2AF65 (PMID:8647433, PMID:10567551, PMID:11421359). Structurally, U2AF1 engages U2AF65 through a 'tongue-in-groove' interface formed by reciprocal tryptophan residues between its atypical RRM and the U2AF65 proline-rich segment; this pseudo-RRM is unstructured in isolation and folds upon U2AF65 binding, while AG recognition is achieved through its zinc-finger domains (PMID:11551507, PMID:12297299, PMID:32958768, PMID:32116123). The heterodimer governs 3' splice site selection through a conformational equilibrium of U2AF65 tandem RRMs between closed and open states, tuned by polypyrimidine-tract strength (PMID:32343311). Recurrent MDS/AML mutations in the zinc fingers (S34F, Q157R) establish aberrant RNA contacts at the -3 and +1 positions of the 3' splice site, shifting sequence specificity (e.g. preferential CAG over UAG recognition), compromising U2AF65-RNA interactions, and driving genome-wide intron retention, exon skipping, and altered hematopoiesis in vivo (PMID:25267526, PMID:25311244, PMID:32958768, PMID:35303483, PMID:25965570). These mutant-driven mis-splicing events converge on disease-relevant targets including IRAK4 (a longer myddosome-activating isoform), H2AFY (controlling EBF1 and B-cell output), EIF4A2 (NMD-triggered loss inducing the integrated stress response), and ATG7 (aberrant polyadenylation causing autophagy defects) (PMID:31011167, PMID:34469727, PMID:38417135, PMID:27184077). Mutant U2AF1 additionally attenuates nonsense-mediated decay and exerts a splicing-independent cytoplasmic function, binding mature mRNA to negatively regulate translation (PMID:34215620, PMID:30842218, PMID:32116123). Recurrent mutations operate in a dosage-dependent, haplo-essential manner: the wild-type allele is required for survival of mutant hematopoietic cells (PMID:27776121, PMID:34546980).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1996 High

    Established that U2AF35 is functionally required for splicing and acts as a molecular bridge, resolving whether the small subunit had an essential role beyond merely partnering U2AF65.

    Evidence Nuclear extract depletion/complementation with recombinant U2AF35 and protein-RNA interaction assays

    PMID:8647433

    Open questions at the time
    • Direct RNA sequence recognized by U2AF35 not yet defined
    • Structural basis of bridging unknown
  2. 1999 High

    Identified the direct RNA target of U2AF35, showing it sequence-specifically contacts the 3' splice site AG and that this contact is critical for U2AF binding at weak polypyrimidine tracts.

    Evidence Site-specific UV crosslinking, in vitro genetic selection, splicing competition assays

    PMID:10567551 PMID:10617206 PMID:10617208

    Open questions at the time
    • Atomic-level basis of AG recognition not resolved
    • In vivo stoichiometry not established
  3. 2001 High

    Defined the structural and mechanistic basis of heterodimerization and dual function, answering how U2AF35 and U2AF65 physically interact and how U2AF35 contributes beyond stabilizing U2AF65.

    Evidence X-ray crystallography of the core heterodimer, NMR of free/complexed RRM, depletion/complementation with truncation mutants

    PMID:11421359 PMID:11551507 PMID:11604503 PMID:12297299

    Open questions at the time
    • Structure of zinc fingers bound to RNA not yet solved
    • Downstream spliceosomal events triggered by U2AF35 unidentified
  4. 2008 Medium

    Connected 3' splice site recognition to tri-snRNP recruitment, addressing how the prespliceosome transitions toward later assembly.

    Evidence Co-immunoprecipitation, pulldowns, domain mapping of SPF30 bridging U2AF35 and hPrp3

    PMID:18211889

    Open questions at the time
    • Functional consequence of disrupting the bridge not tested in vivo
    • Single-lab interaction mapping
  5. 2011 Medium

    Linked U2AF1 to human disease by identifying recurrent S34 zinc-finger mutations in MDS and demonstrating altered splicing, framing spliceosome mutation as a leukemia mechanism.

    Evidence Whole-genome sequencing of MDS patients and in vitro reporter splicing assays

    PMID:22158538

    Open questions at the time
    • Genome-wide splicing targets not yet mapped
    • Causal contribution to hematopoiesis untested in vivo
  6. 2014 High

    Defined the molecular consequence of the mutations, showing they alter 3' splice site sequence preference at specific nucleotide positions and reprogram splicing in a zinc-finger-specific manner.

    Evidence RNA-seq splice junction analysis, in vitro affinity-binding assays, cell culture expression, immunofluorescence

    PMID:25267526 PMID:25311244

    Open questions at the time
    • Atomic basis of changed specificity not yet visualized
    • Causal disease phenotypes from these splicing changes unresolved
  7. 2015 High

    Demonstrated in vivo that mutant U2AF1 drives genome-wide splicing changes and perturbs hematopoiesis, moving from cell-culture inference to organismal phenotype.

    Evidence Doxycycline-inducible S34F transgenic mouse model with whole-transcriptome RNA-seq

    PMID:25965570

    Open questions at the time
    • Which specific mis-spliced targets drive phenotype not isolated
    • Full leukemic transformation not recapitulated
  8. 2016 High

    Showed mutant effects scale with mutant:wild-type ratio and are explained by altered binding affinity, and uncovered an alternative-polyadenylation mechanism on ATG7 causing autophagy defects.

    Evidence Endogenous-locus genetic modification, quantitative RNA-seq, in vitro binding, 3'RACE, western blot, patient validation, xenografts

    PMID:27184077 PMID:27776121

    Open questions at the time
    • Generality of polyadenylation-based mechanism across targets unclear
    • Dependence on wild-type allele mechanistically unexplained
  9. 2019 High

    Expanded U2AF1 function beyond splicing by demonstrating a cytoplasmic translation-regulatory role and identified disease-relevant mis-spliced effectors (IRAK4, IL-8, ROS1).

    Evidence Cytoplasmic CLIP-seq, polysome profiling, proteomics, in vivo metastasis assays, patient RNA-seq with IRAK4 inhibitor experiments, isoform interactome analysis

    PMID:30842218 PMID:31011167 PMID:31504847 PMID:31836708

    Open questions at the time
    • Mechanism of translational repression on mRNA not defined
    • Relative disease contribution of splicing vs translation roles unresolved
  10. 2020 High

    Provided atomic and dynamic mechanism for 3' splice site selection, revealing how mutations alter RNA contacts and how the heterodimer samples closed/open conformations tuned by tract strength.

    Evidence X-ray crystallography of WT and mutant U2AF1-RNA complexes, single-molecule FRET with structure-guided mutagenesis, zinc-finger domain dissection, RAD51 mis-splicing assays

    PMID:32116123 PMID:32343311 PMID:32958768 PMID:35434831

    Open questions at the time
    • Conformational dynamics in intact spliceosome not captured
    • Therapeutic exploitation of DNA-damage sensitivity not validated clinically
  11. 2021 High

    Integrated the mutant pathomechanism across genomic instability, dosage dependence, and specific lineage defects, establishing wild-type allele haplo-essentiality and downstream NMD, stress-granule, and B-cell phenotypes.

    Evidence Single-nucleotide CLIP, conditional WT-allele knockout in mutant background, CRISPR NMD screen with RNase H1 rescue, transgenic H2afy rescue with ChIP, polysome/NPM1 depletion assays

    PMID:33137094 PMID:34215620 PMID:34469727 PMID:34546980 PMID:35303483

    Open questions at the time
    • Mechanistic link between mutant splicing and stress-granule induction incomplete
    • How wild-type allele rescues survival mechanistically unknown
  12. 2023 Medium

    Revealed a chromatin/cotranscriptional role through direct R-loop and G4 binding and phase separation, connecting U2AF1 occupancy at promoters to RNA Pol II distribution and splicing.

    Evidence ChIP-seq overlap, in vitro binding and phase-separation assays, Pol II ChIP-seq

    PMID:37733759

    Open questions at the time
    • In vivo relevance of phase separation to splicing not established
    • Single-lab finding awaiting orthogonal confirmation
  13. 2024 Medium

    Connected mutant splicing to a therapeutically actionable stress phenotype, showing EIF4A2 mis-splicing reduces global translation and induces the integrated stress response promoting chemoresistance.

    Evidence Integrative RNA-seq/binding analysis in AML cell lines, single-cell RNA-seq, ISRIB pharmacological inhibition, patient multiomics

    PMID:38417135

    Open questions at the time
    • Causal contribution of EIF4A2 vs other ISR triggers not isolated
    • Clinical efficacy of ISR inhibition unvalidated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How U2AF1's distinct nuclear splicing, chromatin/R-loop, and cytoplasmic translational activities are coordinated, and why mutant cells remain dependent on the wild-type allele, remain unresolved.
  • No unified model integrating splicing, translation, and R-loop functions
  • Molecular basis of wild-type allele dependence unknown
  • Mechanism linking mutant splicing to stress-response activation incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 7 GO:0140098 catalytic activity, acting on RNA 3 GO:0045182 translation regulator activity 2 GO:0060090 molecular adaptor activity 2 GO:0003677 DNA binding 1
Localization
GO:0005829 cytosol 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-392499 Metabolism of proteins 2 R-HSA-74160 Gene expression (Transcription) 1
Partners
HPRP3SPF30U2AF1 (SELF)U2AF2
Complex memberships
U2AF heterodimer (U2AF1/U2AF2)

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 U2AF35 (U2AF1) directly contacts the 3' splice site AG dinucleotide early during spliceosome assembly, demonstrated by site-specific UV crosslinking. Mutational analysis and in vitro genetic selection showed U2AF35 has sequence-specific RNA-binding activity recognizing the 3'-splice-site consensus AG/G. For introns with weak polypyrimidine tracts, this U2AF35-3'-splice-site interaction is critical for U2AF binding and splicing. Site-specific UV crosslinking, mutational analysis, in vitro genetic selection, splicing assays Nature High 10617206
1999 U2AF35 contacts the AG dinucleotide at the 3' splice site only when located in proximity to the polypyrimidine tract (shown by UV crosslinking). This interaction stabilizes U2AF65 binding, such that Sex-lethal (SXL) can no longer displace U2AF65 from the polypyrimidine tract. SXL-mediated splicing inhibition of msl-2 requires a combination of SXL binding at the polypyrimidine tract and an unusually long distance between the poly(Y) tract and the AG, which weakens U2AF35-AG interaction. UV crosslinking, in vitro splicing competition assays Nature High 10617208
1996 U2AF35 is required for constitutive splicing and functions as a mediator of enhancer-dependent splicing. Nuclear extracts deficient in U2AF35 are inactive; both constitutive and enhancer-dependent splicing are restored by recombinant U2AF35. In vitro protein-RNA interaction studies showed U2AF35 directly mediates interactions between U2AF65 and proteins bound to splicing enhancers, acting as a bridge to recruit U2AF65 to weak 3' splice sites. Nuclear extract depletion/complementation, in vitro splicing assays, protein-RNA interaction studies Genes & development High 8647433
2001 X-ray crystal structure of the human core U2AF heterodimer (U2AF35 central domain + proline-rich region of U2AF65) at 2.2 Å resolution revealed a novel 'tongue-in-groove' protein-protein interaction via reciprocal tryptophan residues between an atypical RRM of U2AF35 and U2AF65 polyproline segment. Biochemical experiments showed the core heterodimer binds RNA and that the interacting tryptophan side chains are essential for U2AF dimerization. X-ray crystallography (2.2 Å), site-directed mutagenesis, RNA-binding biochemical assays Cell High 11551507
2001 U2AF35 has a dual function in AG-dependent pre-mRNA splicing: (1) its interaction with the consensus 3' splice site AG stabilizes U2AF65 binding to weak polypyrimidine tracts, and (2) U2AF35 triggers additional downstream events in spliceosome assembly beyond U2AF65 stabilization. RS domain-mediated interactions with SR proteins bound to exonic splicing enhancers are dispensable for U2AF35 activity; a truncation mutant lacking the RS domain but retaining the pseudo-RRM is active in complementation assays. Nuclear extract depletion/complementation, UV crosslinking, in vitro splicing assays, truncation mutant analysis Molecular and cellular biology High 11604503
1999 U2AF35 has a substrate-specific requirement: recombinant U2AF65 alone is sufficient for splicing of two constitutively spliced pre-mRNAs in U2AF-depleted extracts, but both U2AF65 and U2AF35 (and their interaction) are required for splicing of an immunoglobulin µ pre-mRNA with a weak polypyrimidine tract and purine-rich exonic splicing enhancer. U2AF35 splicing activation occurs without changes in U2AF65 crosslinking to the polypyrimidine tract. Chromatographic depletion of U2AF, in vitro splicing complementation, UV crosslinking Molecular and cellular biology High 10567551
2001 Splicing activators (SR proteins on enhancers) promote binding of both U2AF65 and U2AF35 to weak 3' splice sites under splicing conditions, and U2AF35 is required for maximum levels of activator-dependent splicing. Base substitutions converting weak 3' splice sites to consensus relieve the requirement for splicing activators by increasing U2AF binding directly. In vitro splicing assays, RNA-protein binding assays, mutational analysis of splice sites RNA High 11421359
2002 The U2AF35 RRM is unstructured in isolation but its tertiary structure is induced upon binding to U2AF65. This induced folding is mediated specifically by the N-terminal proline-rich region of U2AF65 and does not involve the U2AF65 RRMs. Nuclear magnetic resonance (NMR) spectroscopy of free and complexed U2AF35 RRM FEBS letters High 12297299
2005 Direct interaction between U2AF35 and U2AF65 was demonstrated in vivo in live cell nuclei by FRET microscopy. Additionally, a novel U2AF35 self-interaction was discovered both in vivo (by FRET) and confirmed in vitro by biochemical assays, suggesting the U2AF complex stoichiometry may differ from the expected heterodimer in vivo. FRET microscopy in live cells, biochemical in vitro binding assays RNA Medium 16043505
2008 Splicing factor SPF30 bridges an interaction between U2AF35 (prespliceosome) and hPrp3 (tri-snRNP component). The N-terminal domain of SPF30 interacts with U2AF35, and the C-terminus of SPF30 interacts with hPrp3 simultaneously, potentially linking 3' splice site recognition to tri-snRNP addition. Co-immunoprecipitation, pulldown assays, domain mapping The Journal of biological chemistry Medium 18211889
2011 Missense mutations affecting Ser34 (S34F) in the zinc fingers of U2AF1 are recurrently found in MDS patients. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro, implicating altered pre-mRNA splicing as a mechanism for MDS pathogenesis. Whole-genome sequencing, reporter splicing assays in vitro Nature genetics Medium 22158538
2014 U2AF1 mutations (S34F/Y and Q157R/P) alter the preferred 3' splice site motif in patients, in cell culture, and in vitro. S34F/Y mutations cause preferential recognition of CAG over UAG 3' splice site sequences. Mutations in the first and second zinc fingers give rise to different alterations in splice site preference and largely distinct downstream splicing programs. RNA-seq splice junction analysis, in vitro RNA-binding assays, cell culture expression system Genome research High 25267526
2014 U2AF1 S34F mutation alters sequence specificity of RNA binding, decreasing affinity for uridine (relative to cytidine) at the -3 position immediately upstream of the splice acceptor site, leading to aberrant alternative splicing. U2AF1(S34F) co-localizes normally with U2AF2 within nuclear speckles (localization not disrupted by mutation). RNA-seq splice junction analysis, affinity-binding assays, immunofluorescence co-localization Leukemia High 25311244
2015 Mutant U2AF1(S34F) expressed in hematopoietic progenitor cells in a doxycycline-inducible transgenic mouse model causes changes in pre-mRNA splicing genome-wide and alters hematopoiesis in vivo. Common mutant U2AF1-induced splicing alterations are enriched in RNA processing genes, ribosomal genes, and MDS/AML-associated genes. Doxycycline-inducible transgenic mouse model, whole transcriptome RNA-seq Cancer cell High 25965570
2016 U2AF1(S34F) mutation causes aberrant selection of a distal cleavage and polyadenylation (CP) site in ATG7 pre-mRNA (not altered splicing), producing a longer ATG7 mRNA that is translated inefficiently, leading to decreased ATG7 levels, autophagy defect, and cellular transformation. This mechanism was confirmed in MDS/AML patient samples harboring U2AF1(S34F). Deep sequencing of transformed cell lines, 3' RACE, quantitative RT-PCR, western blot, patient sample validation Molecular cell High 27184077
2016 S34F-associated changes in alternative splicing are proportional to the ratio of S34F:wild-type U2AF1 gene products, not to absolute levels of either factor. Preferential recognition of specific 3' splice sites in S34F-expressing cells is largely explained by differential in vitro RNA-binding affinities of mutant versus wild-type U2AF1. Wild-type U2AF1 is required for cell survival regardless of S34F allele status. Endogenous locus genetic modification, quantitative RNA-seq, in vitro RNA-binding assays, in vivo tumor xenograft PLoS genetics High 27776121
2019 U2AF1 has a noncanonical function in translation regulation: it directly binds mature mRNA in the cytoplasm and negatively regulates mRNA translation. This splicing-independent role is altered by the S34F mutation; polysome profiling shows mutation affects translation of hundreds of mRNAs. One consequence is increased synthesis of secreted chemokine IL-8, contributing to metastasis and cancer progression. CLIP-seq (cytoplasmic), polysome profiling, quantitative proteomics, in vivo metastasis assays Genes & development High 30842218
2019 U2AF1 mutations induce expression of a longer IRAK4 isoform (IRAK4-L, retaining exon 4) that assembles with the myddosome and results in maximal NF-κB activation. IRAK4-L expression is mediated by mutant U2AF1, and inhibition of IRAK4-L abrogates leukemic growth in AML cells with high IRAK4-L expression. Exon usage analysis of patient RNA-seq, cell line functional assays, IRAK4 inhibitor experiments Nature cell biology High 31011167
2019 U2AF1 S34F preferentially binds and modulates splicing of introns containing CAG trinucleotides at their 3' splice junctions compared to wild-type. CLIP analysis showed a shift in cross-linking at 3' splice sites, significantly associated with alternative splicing of skipped exons. S34F also induces increased splicing of the long SLC34A2-ROS1 isoform, associated with enhanced tumor cell invasion. CLIP-seq, RNA-seq, functional invasion assays in cells with ROS1 translocation Nature communications High 31836708
2020 Crystal structures of wild-type and pathogenic mutant U2AF1 complexed with target RNA at the 3' splice site revealed the molecular mechanism of 3' splice site selection. The structures showed how S34F and Q157R mutations cause aberrant 3' splice site recognition by altering RNA contacts within the zinc finger domains. X-ray crystallography of WT and mutant U2AF1-RNA complexes Nature communications High 32958768
2020 U2AF1 subunit stabilizes a closed conformation of the U2AF2 (U2AF65) tandem RRMs in the absence of RNA (high FRET). Upon binding a strong uridine-rich splice site, U2AF2 switches to an open conformation. For weak uridine-poor polypyrimidine tracts, the heterodimer binds as a mixture of closed and open conformations, and the S34F mutation modulates this equilibrium. Structure-guided mutagenesis confirmed the conformational assignments. Single-molecule FRET, structure-guided mutagenesis Nucleic acids research High 32343311
2021 U2AF1 S34F and Q157R mutants establish new RNA contacts at positions -3 and +1 nucleotides of the 3' splice site AG, respectively (revealed by single-nucleotide resolution CLIP). These new contacts compromise U2AF2-RNA interactions, resulting predominantly in intron retention and exon exclusion. Mutant U2AF1-expressing cell lines and patient-derived MDS/AML blasts display a heightened stress granule response. High-resolution CLIP at single-nucleotide resolution, RNA-seq, single-cell RNA-seq, stress granule imaging in patient cells Molecular cell High 35303483
2021 U2AF1 S34F mutation results in misregulation of translation initiation and ribosome biogenesis machinery, increasing mRNA translation at the single-cell level. Among translationally upregulated targets is Nucleophosmin 1 (NPM1); depletion of NPM1 impairs viability of U2AF1-S34F mutant cells and causes ribosomal RNA processing defects, revealing a synthetic interaction between U2AF1, NPM1, and ribosome biogenesis. Polysome profiling, single-cell translation assays, NPM1 depletion functional assays, rRNA processing analysis PLoS biology Medium 33137094
2021 Deletion of U2af1 in mouse hematopoietic cells causes pancytopenia, ablation of hematopoietic stem/progenitor cells, bone marrow failure, increased DNA damage in progenitors, and early lethality. U2af1 deficiency induces splicing alterations in genes important for HSPC function including altered splicing of Nfya and Pbx1 transcription factors. Conditional U2af1 knockout mice, RNA-seq, flow cytometry, transplantation assays Leukemia High 33414485
2021 Mutant U2AF1(S34F)-induced mis-splicing of H2afy (producing reduced H2afy1.1 isoform) is responsible for reduced B cells in U2AF1(S34F) mice. H2AFY1.1 is enriched at the EBF1 promoter, and its reduction decreases Ebf1 expression. Induced expression of H2AFY1.1 in U2AF1(S34F) cells rescues reduced EBF1 expression and B cell numbers in vivo. Transgenic mouse model, RNA-seq, ChIP, lentiviral rescue experiments, flow cytometry Cell reports High 34469727
2021 U2AF1 mutant hematopoietic cells require expression of the wild-type U2AF1 allele for survival in vivo (haplo-essential). Deletion of the WT U2af1 allele in U2AF1(S34F) heterozygous mutant hematopoietic cells is lethal, while U2af1 heterozygous knockout alone has no hematopoietic phenotype. Mice transplanted with U2AF1(S34F) leukemia cells had reduced tumor burden and improved survival after WT U2af1 deletion. Conditional WT allele knockout in U2AF1(S34F) mutant background, transplantation model, survival analysis The Journal of clinical investigation High 34546980
2021 Cells with SF3B1 or U2AF1 mutations have attenuated nonsense-mediated RNA decay (NMD) activity and are more sensitive to NMD inhibition. This sensitivity is accompanied by elevated DNA replication obstruction, DNA damage, and chromosomal instability, and can be rescued by overexpression of RNase H1 (R-loop removal), establishing a functional link between spliceosome mutations, NMD activity, and R-loop-induced genomic instability. CRISPR-Cas9 genome-wide knockout screen with NMD reporter, NMD activity assays, RNase H1 rescue, DNA damage assays Cancer research Medium 34215620
2005 The Shigella effector IpaH9.8 has specific binding affinity to U2AF35 (U2AF1) and interferes with U2AF35-dependent splicing of IgM pre-mRNA. Reducing U2AF35 levels in HeLa cells decreases expression of pro-inflammatory cytokine genes (IL-8, RANTES, GM-CSF, IL-1β), establishing U2AF35 as a regulator of inflammatory gene expression downstream of splicing. Binding assays, in vitro splicing assay, siRNA knockdown with RT-PCR Biochemical and biophysical research communications Medium 15950937
2021 m6A methylation deposited at the 3' splice site AG by METT-10 (METTL16 ortholog) physically prevents U2AF35 from recognizing the 3' splice site, inhibiting splicing. This m6A-mediated inhibition of U2AF35 binding to the 3' splice site is conserved in mammals. In vitro binding competition assays with m6A-modified RNA, C. elegans genetic model, mammalian splicing reporter assays Cell High 33930289
2020 U2AF1 S34F induces mis-splicing of RAD51 in lung cancer cells, causing downregulation of RAD51 protein via aberrant exon usage and enhanced DNA damage. Overexpression of RAD51 rescues the defective DNA damage response. U2AF1-S34F cells are sensitized to ATR inhibitors, and the combination with RAD51 inhibitors exacerbates DNA damage. Ectopic expression of WT and mutant U2AF1 in A549 cells, RNA-seq, western blot, ATR/RAD51 inhibitor functional assays Clinical and experimental pharmacology & physiology Medium 35434831
2023 U2AF1 binds directly to R-loops and DNA G4 structures at low-nM affinity in promoter regions. U2AF1 can undergo phase separation, which is stimulated by binding with R-loops (but not duplex DNA, RNA/DNA hybrid, DNA G4, or single-stranded RNA). U2AF1 binding to promoter R-loops in cells competes with its interaction with 3' splice sites and leads to augmented distribution of RNA Pol II to promoters over gene bodies, modulating cotranscriptional pre-mRNA splicing. ChIP-seq overlap analysis, in vitro binding assays, phase separation assays, Pol II ChIP-seq Journal of the American Chemical Society Medium 37733759
2017 Single molecule methods showed U2AF35 and U2AF65 bind in 1:1 stoichiometry with a 3' splice site in the presence of ATP. Pre-mRNA molecules with two alternative 3' splice sites can be concurrently bound by two molecules of U2AF or two U2 snRNPs, but concurrent occupancy inhibits splicing. Stoichiometric binding requires conditions consistent with coalescence of 5' and 3' sites in a complex I; complex A formation is associated with loss of both U2AF65 and U2AF35. Single-molecule fluorescence imaging, stoichiometry analysis Nucleic acids research Medium 27683217
2019 Expression of U2AF1 isoforms (U2AF1a and U2AF1b, encoded by tandem alternative exons) is controlled by mTOR signaling. The two isoforms have distinct splice site sequence preferences and different protein interactomes. U2AF1a-driven transcriptomes feature alternative splicing events in 5'-UTRs favorable for translation, linking mTOR-regulated U2AF1 isoform switching to translational control. Genome editing, customized transcriptome profiling (RNA-seq), CLIP-based interactome analysis, mTOR inhibitor experiments Nucleic acids research Medium 31504847
2020 Both zinc finger domains of U2AF35 are required for splicing regulation, while only ZnF2 controls protein stability and contributes to interaction with U2AF65. A naturally occurring splice variant of the paralog U2AF26 lacking ZnF2 localizes to the cytoplasm and, together with U2AF35, increases translation when tethered to the 5'UTR of mRNA via MS2 tethering assay, providing evidence for a cytoplasmic translation-regulatory role of the zinc finger domains. Zinc finger domain mutant analysis, splicing reporter assays, MS2 tethering translation assay, Ribo-seq RNA biology Medium 32116123
2024 U2AF1 S34F and Q157R mutations orchestrate aberrant inclusion of exon 11 (encoding a premature termination codon) in EIF4A2 pre-mRNA, leading to reduced eIF4A2 protein via NMD. This causes a net decrease in global mRNA translation and induction of the integrated stress response (ISR), which promotes chemoresistance in AML. ISRIB (ISR inhibitor) sensitizes U2AF1-mutant cells to chemotherapy. Integrative analysis of RNA-seq and binding data from AML cell lines, single-cell RNA-seq, ISRIB pharmacological inhibition, patient multiomics data Cancer research Medium 38417135
2010 U2AF35-related protein Urp contacts the 3' splice site of both U12-type (minor class) and U2-type (major class) introns. For U12-type introns, Urp is recruited ATP-dependently to promote spliceosomal complex formation. For U2-type introns, Urp is specifically required for the second step of splicing. This establishes that through recognition of a common splicing element (3' splice site), Urp facilitates distinct steps of U2- and U12-type intron splicing. UV crosslinking, splicing complementation assays, spliceosomal complex assembly analysis Genes & development Medium 21041408

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nature genetics 495 22158538
1999 Functional recognition of the 3' splice site AG by the splicing factor U2AF35. Nature 369 10617206
1996 The splicing factor U2AF35 mediates critical protein-protein interactions in constitutive and enhancer-dependent splicing. Genes & development 263 8647433
2014 U2AF1 mutations alter splice site recognition in hematological malignancies. Genome research 258 25267526
2015 Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo. Cancer cell 256 25965570
1999 Inhibition of msl-2 splicing by Sex-lethal reveals interaction between U2AF35 and the 3' splice site AG. Nature 247 10617208
2019 U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies. Nature cell biology 205 31011167
2001 A novel peptide recognition mode revealed by the X-ray structure of a core U2AF35/U2AF65 heterodimer. Cell 184 11551507
2021 Splice site m6A methylation prevents binding of U2AF35 to inhibit RNA splicing. Cell 160 33930289
2014 A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered splicing events. PloS one 151 24498085
2013 Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms. Blood 138 23775717
2016 U2AF35(S34F) Promotes Transformation by Directing Aberrant ATG7 Pre-mRNA 3' End Formation. Molecular cell 120 27184077
2001 The role of U2AF35 and U2AF65 in enhancer-dependent splicing. RNA (New York, N.Y.) 114 11421359
2014 U2AF1 mutations alter sequence specificity of pre-mRNA binding and splicing. Leukemia 113 25311244
2014 Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 113 25412851
2001 DNA methylation is linked to deacetylation of histone H3, but not H4, on the imprinted genes Snrpn and U2af1-rs1. Molecular and cellular biology 111 11463825
2017 Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome. Nature communications 102 28067246
2005 Shigella effector IpaH9.8 binds to a splicing factor U2AF(35) to modulate host immune responses. Biochemical and biophysical research communications 98 15950937
2009 A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome. Human molecular genetics 92 19783846
1997 A protein related to splicing factor U2AF35 that interacts with U2AF65 and SR proteins in splicing of pre-mRNA. Nature 92 9237760
2016 Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival. PLoS genetics 87 27776121
1997 Mouse U2af1-rs1 is a neomorphic imprinted gene. Molecular and cellular biology 85 9001233
2019 The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation. Genes & development 81 30842218
2010 The U2AF35-related protein Urp contacts the 3' splice site to promote U12-type intron splicing and the second step of U2-type intron splicing. Genes & development 81 21041408
1999 Evidence for substrate-specific requirement of the splicing factor U2AF(35) and for its function after polypyrimidine tract recognition by U2AF(65). Molecular and cellular biology 79 10567551
2012 U2AF1 mutations in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome. PloS one 73 23029227
2001 Dual function for U2AF(35) in AG-dependent pre-mRNA splicing. Molecular and cellular biology 70 11604503
2004 The mouse Murr1 gene is imprinted in the adult brain, presumably due to transcriptional interference by the antisense-oriented U2af1-rs1 gene. Molecular and cellular biology 66 14673161
2018 Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene U2af1. Proceedings of the National Academy of Sciences of the United States of America 64 30322915
2002 A misspliced form of the cholecystokinin-B/gastrin receptor in pancreatic carcinoma: role of reduced sellular U2AF35 and a suboptimal 3'-splicing site leading to retention of the fourth intron. Cancer research 64 11830556
2022 Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies. Molecular cell 63 35303483
1999 U2AF35 is encoded by an essential gene clustered in an operon with RRM/cyclophilin in Caenorhabditis elegans. RNA (New York, N.Y.) 63 10199565
1995 Stage-specific induction and regulation by genomic imprinting of the mouse U2afbp-rs gene during preimplantation development. Developmental biology 63 7729597
2013 Mutational analysis of splicing machinery genes SF3B1, U2AF1 and SRSF2 in myelodysplasia and other common tumors. International journal of cancer 61 23280334
2013 Clinical implications of U2AF1 mutation in patients with myelodysplastic syndrome and its stability during disease progression. American journal of hematology 61 23861105
2017 Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes. Genes, chromosomes & cancer 57 29057546
2020 Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with acute myeloid leukemia. Leukemia 55 32358566
1995 Allele-specific methylation and expression of an imprinted U2af1-rs1 (SP2) gene. Nucleic acids research 53 7870588
2021 Nonsense-Mediated RNA Decay Is a Unique Vulnerability of Cancer Cells Harboring SF3B1 or U2AF1 Mutations. Cancer research 46 34215620
2015 Genetic landscape of recurrent ASXL1, U2AF1, SF3B1, SRSF2, and EZH2 mutations in 304 Chinese patients with myelodysplastic syndromes. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 46 26508027
1997 Parental chromosome-specific chromatin conformation in the imprinted U2af1-rs1 gene in the mouse. The Journal of biological chemistry 46 9252416
2006 Molecular characterization and phylogeny of U2AF35 homologs in plants. Plant physiology 45 16407443
2005 FRET analyses of the U2AF complex localize the U2AF35/U2AF65 interaction in vivo and reveal a novel self-interaction of U2AF35. RNA (New York, N.Y.) 44 16043505
2004 Diversity of vertebrate splicing factor U2AF35: identification of alternatively spliced U2AF1 mRNAS. The Journal of biological chemistry 43 15096518
2018 Circ-U2AF1 promotes human glioma via derepressing neuro-oncological ventral antigen 2 by sponging hsa-miR-7-5p. Journal of cellular physiology 42 30341906
2018 Mutations in DNMT3A, U2AF1, and EZH2 identify intermediate-risk acute myeloid leukemia patients with poor outcome after CR1. Blood cancer journal 41 29321554
2020 Elucidation of the aberrant 3' splice site selection by cancer-associated mutations on the U2AF1. Nature communications 40 32958768
2019 Functional significance of U2AF1 S34F mutations in lung adenocarcinomas. Nature communications 39 31836708
2021 U2af1 is required for survival and function of hematopoietic stem/progenitor cells. Leukemia 35 33414485
2002 Characterization of U2AF(6), a splicing factor related to U2AF(35). Molecular and cellular biology 33 11739736
1998 A methylation imprint mark in the mouse imprinted gene Grf1/Cdc25Mm locus shares a common feature with the U2afbp-rs gene: an association with a short tandem repeat and a hypermethylated region. Genomics 33 9570946
2022 Failure to Detect Mutations in U2AF1 due to Changes in the GRCh38 Reference Sequence. The Journal of molecular diagnostics : JMD 30 35041928
1996 Absence of imprinting in U2AFBPL, a human homologue of the imprinted mouse gene U2afbp-rs. Biochemical and biophysical research communications 30 8630064
1996 Inactive allele-specific methylation and chromatin structure of the imprinted gene U2af1-rs1 on mouse chromosome 11. Genomics 29 8661130
1997 Aberrant methylation of an imprinted gene U2af1-rs1(SP2) caused by its own transgene. The Journal of biological chemistry 28 9083040
1995 Isolation and mapping of human homologues of an imprinted mouse gene U2af1-rs1. Genomics 28 8586425
2015 Mutations in the Spliceosomal Machinery Genes SRSF2, U2AF1, and ZRSR2 and Response to Decitabine in Myelodysplastic Syndrome. Anticancer research 27 25964599
2002 Inhibition of histone deacetylases alters allelic chromatin conformation at the imprinted U2af1-rs1 locus in mouse embryonic stem cells. The Journal of biological chemistry 27 11821379
2020 A splice site-sensing conformational switch in U2AF2 is modulated by U2AF1 and its recurrent myelodysplasia-associated mutation. Nucleic acids research 26 32343311
1998 Association of a redefined proximal mouse chromosome 11 imprinting region and U2afbp-rs/U2af1-rs1 expression. Cytogenetics and cell genetics 25 9678333
2017 Stoichiometries of U2AF35, U2AF65 and U2 snRNP reveal new early spliceosome assembly pathways. Nucleic acids research 24 27683217
2000 The oocyte-specific methylated region of the U2afbp-rs/U2af1-rs1 gene is dispensable for its imprinted methylation. Biochemical and biophysical research communications 23 10679248
1997 An oocyte-specific methylation imprint center in the mouse U2afbp-rs/U2af1-rs1 gene marks the establishment of allele-specific methylation during preimplantation development. Genomics 23 9299233
2022 The Biological and Clinical Consequences of RNA Splicing Factor U2AF1 Mutation in Myeloid Malignancies. Cancers 22 36139566
2020 Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation. PLoS biology 21 33137094
2021 U2af1 is a haplo-essential gene required for hematopoietic cancer cell survival in mice. The Journal of clinical investigation 20 34546980
2009 Functional characterization and protein-protein interactions of trypanosome splicing factors U2AF35, U2AF65 and SF1. Molecular and biochemical parasitology 20 19320097
2023 Patients with telomere biology disorders show context specific somatic mosaic states with high frequency of U2AF1 variants. American journal of hematology 19 37665761
2021 U2AF1 mutation promotes tumorigenicity through facilitating autophagy flux mediated by FOXO3a activation in myelodysplastic syndromes. Cell death & disease 19 34183647
2021 Mutant U2AF1-induced alternative splicing of H2afy (macroH2A1) regulates B-lymphopoiesis in mice. Cell reports 19 34469727
2002 Induced folding of the U2AF35 RRM upon binding to U2AF65. FEBS letters 19 12297299
2023 Promoter R-Loops Recruit U2AF1 to Modulate Its Phase Separation and RNA Splicing. Journal of the American Chemical Society 18 37733759
2023 Discovery of U2AF1 neoantigens in myeloid neoplasms. Journal for immunotherapy of cancer 17 38164756
2018 Frequency of MAP2K1, TP53, and U2AF1 Mutations in BRAF-mutated Langerhans Cell Histiocytosis: Further Characterizing the Genomic Landscape of LCH. The American journal of surgical pathology 17 29649018
2017 The high frequency of the U2AF1 S34Y mutation and its association with isolated trisomy 8 in myelodysplastic syndrome in Asians, but not in Caucasians. Leukemia research 16 28938223
2024 Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia. Cancer research 15 38417135
2019 mTOR-regulated U2af1 tandem exon splicing specifies transcriptome features for translational control. Nucleic acids research 15 31504847
2016 Alternative splicing of U2AF1 reveals a shared repression mechanism for duplicated exons. Nucleic acids research 15 27566151
2008 Splicing factor SPF30 bridges an interaction between the prespliceosome protein U2AF35 and tri-small nuclear ribonucleoprotein protein hPrp3. The Journal of biological chemistry 15 18211889
2001 Disruption of imprinted expression of U2afbp-rs/U2af1-rs1 gene in mouse parthenogenetic fetuses. The Journal of biological chemistry 15 11306578
2017 The cancer-associated U2AF35 470A>G (Q157R) mutation creates an in-frame alternative 5' splice site that impacts splicing regulation in Q157R patients. RNA (New York, N.Y.) 14 28893951
1995 Cloning and mapping of the U2af1-rs2 gene with a high transmission distortion in interspecific backcross progeny. Genomics 14 7558001
2023 Impact of U2AF1 mutations on circular RNA expression in myelodysplastic neoplasms. Leukemia 13 36922625
2021 Down regulation of U2AF1 promotes ARV7 splicing and prostate cancer progression. Biochemical and biophysical research communications 12 33477033
2019 Knockdown of spliceosome U2AF1 significantly inhibits the development of human erythroid cells. Journal of cellular and molecular medicine 12 31144421
2015 Dosage of the Abcg1-U2af1 region modifies locomotor and cognitive deficits observed in the Tc1 mouse model of Down syndrome. PloS one 12 25706610
2020 Lysine in Combination With Estradiol Promote Dissemination of Estrogen Receptor Positive Breast Cancer via Upregulation of U2AF1 and RPN2 Proteins. Frontiers in oncology 11 33330095
2018 Integrative Profiling of Alternative Splicing Induced by U2AF1 S34F Mutation in Lung Adenocarcinoma Reveals a Mechanistic Link to Mitotic Stress. Molecules and cells 11 29991672
1996 The gene for human U2 snRNP auxiliary factor small 35-kDa subunit (U2AF1) maps to the progressive myoclonus epilepsy (EPM1) critical region on chromosome 21q22.3. Genomics 11 8660980
2023 U2AF1 and EZH2 mutations are associated with nonimmune hemolytic anemia in myelodysplastic syndromes. Blood advances 10 36129843
2023 U2AF1 in various neoplastic diseases and relevant targeted therapies for malignant cancers with complex mutations (Review). Oncology reports 10 37975232
2021 Mutant U2AF1-induced differential alternative splicing causes an oxidative stress in bone marrow stromal cells. Experimental biology and medicine (Maywood, N.J.) 10 34034558
2014 Alteration of the SETBP1 gene and splicing pathway genes SF3B1, U2AF1, and SRSF2 in childhood acute myeloid leukemia. Annals of laboratory medicine 10 25553291
2024 Prostate cancer cell-derived exosomes ZNF667-AS1 reduces TGFBR1 mRNA stability to inhibit Treg expansion and DTX resistance by binding to U2AF1. Molecular medicine (Cambridge, Mass.) 9 39425009
1999 Structures, sequence characteristics, and synteny relationships of the transcription factor E4TF1, the splicing factor U2AF35 and the cystathionine beta synthetase genes from Fugu rubripes. Gene 9 9931491
2020 Deoxynivalenol globally affects the selection of 3' splice sites in human cells by suppressing the splicing factors, U2AF1 and SF1. RNA biology 8 31992135
2020 The core spliceosomal factor U2AF1 controls cell-fate determination via the modulation of transcriptional networks. RNA biology 8 32150510
2019 The significance of PA28γ and U2AF1 in oral mucosal carcinogenesis. Oral diseases 8 31605415
2022 U2AF1 mutation connects DNA damage to the alternative splicing of RAD51 in lung adenocarcinomas. Clinical and experimental pharmacology & physiology 7 35434831
2020 The zinc finger domains in U2AF26 and U2AF35 have diverse functionalities including a role in controlling translation. RNA biology 6 32116123

Missed literature

Know a paper Affinage missed for U2AF1? Flag it for the maintainers and the community.

No submissions yet.