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Showing HTATSF1 — TAT-SF1 is a alias.

HTATSF1

17S U2 SnRNP complex component HTATSF1 · UniProt O43719

Length
755 aa
Mass
85.9 kDa
Annotated
2026-06-10
14 papers in source corpus 13 papers cited in narrative 15 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

HTATSF1 (Tat-SF1) is a multifunctional nuclear RNA-binding protein that links RNA polymerase II transcription elongation to pre-mRNA splicing (PMID:8849451, PMID:19952111). It was first identified as a cellular cofactor required for HIV-1 Tat-mediated stimulation of transcriptional elongation, containing two RNA recognition motifs and serving as a substrate of an associated cellular kinase (PMID:8849451), and was subsequently shown to act as a general elongation factor rather than a strictly Tat-specific coactivator (PMID:9765201). Mechanistically, it associates with the RAP30 subunit of TFIIF and with hSPT5 (PMID:10454543) and collaborates non-redundantly with DSIF (Spt4-Spt5) and the Paf1 complex to promote elongation, in a process dependent on P-TEFb-mediated phosphorylation of the Spt5 C-terminal region (PMID:19952111). In splicing, HTATSF1 functions through U2 snRNP: its yeast homolog CUS2 binds U2 snRNA and refolds it into an assembly-competent structure (PMID:9710584), and the human protein engages the SF3b1 subunit of U2 snRNP through a U2AF homology motif (UHM)–ULM interface defined by high-resolution crystal structures (PMID:30567737). Depletion causes intron retention in short, GC-rich introns with weak 3' splice sites and impairs neural progenitor proliferation, establishing a developmental requirement for its splicing activity (PMID:28935704). Genome-wide analyses show it broadly activates transcript levels and independently regulates a distinct alternative-splicing program (PMID:21282347). Beyond gene expression, CK2 phosphorylates HTATSF1 at Ser748 to recruit TOPBP1 via its BRCT1/2 domains, loading RAD51 to drive homologous recombination repair (PMID:38762174, PMID:42251821), and HTATSF1 positively regulates innate antiviral immunity by promoting HECTD3-dependent K63-ubiquitination of TRAF3 and TAK1 recruitment to TRAF6 (PMID:41466838). In viral RNA biology it modulates the ratio of unspliced to spliced HIV-1 transcripts (PMID:19479034) and stimulates influenza RNA synthesis by chaperoning nucleoprotein (PMID:17991777).

Mechanistic history

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

    Established HTATSF1 as a discrete cellular factor needed for HIV-1 Tat-stimulated transcription elongation, defining its first molecular role and RNA-binding architecture.

    Evidence cDNA cloning with in vitro reconstituted transcription, complementation, and kinase substrate assay

    PMID:8849451

    Open questions at the time
    • Did not distinguish Tat-specific from general elongation roles
    • Identity of the associated kinase unresolved
    • No direct RNA target defined
  2. 1998 Medium

    Reframed HTATSF1 as a general elongation factor rather than a Tat-only coactivator, broadening its mechanistic relevance to host transcription.

    Evidence protein-affinity chromatography and in vitro transcription elongation assay

    PMID:9765201

    Open questions at the time
    • Identity of the required AIEF factor undefined
    • No in vivo confirmation
  3. 1998 High

    Revealed a conserved splicing function through the yeast homolog CUS2, linking HTATSF1 to U2 snRNA folding and SF3a/SF3b association prior to spliceosome assembly.

    Evidence suppressor screen, co-IP, in vitro RNA binding, RRM mutagenesis; human SF3a66 co-IP

    PMID:9710584

    Open questions at the time
    • Human splicing role inferred largely from yeast
    • Direct human U2 binding interface not yet mapped
  4. 1999 High

    Identified direct physical partners in the transcription machinery (TFIIF RAP30 and hSPT5), providing a recruitment mechanism for elongation control.

    Evidence co-IP, immunodepletion/recombinant complementation, in vivo overexpression

    PMID:10454543

    Open questions at the time
    • Structural basis of RAP30/hSPT5 contacts undefined
    • Stoichiometry of the complex unknown
  5. 2007 Medium

    Extended HTATSF1 function to influenza RNA synthesis via chaperoning of free nucleoprotein, indicating a role in viral RNP assembly.

    Evidence yeast replicon system, genome-wide deletion screen, co-IP, RNA-NP complex assay

    PMID:17991777

    Open questions at the time
    • Mechanism of NP chaperoning not structurally defined
    • Single study
  6. 2009 Medium

    Resolved the HIV-1 role as post-transcriptional, showing depletion shifts the unspliced/spliced transcript ratio rather than blocking LTR transcription.

    Evidence shRNA knockdown in two cell lines, RT-PCR of transcript ratios, infectivity assay

    PMID:19479034

    Open questions at the time
    • Contradicts earlier in vitro elongation reconstitution
    • Direct splicing mechanism on HIV RNA not mapped
  7. 2009 High

    Defined HTATSF1's non-redundant cooperation with DSIF and Paf1C and dependence on P-TEFb, integrating it into the elongation control circuit at a model gene.

    Evidence activity-based fractionation, ChIP at FOS, in vitro elongation, P-TEFb inhibition

    PMID:19952111

    Open questions at the time
    • Generality beyond FOS not established here
    • Order of recruitment events partly inferred
  8. 2011 Medium

    Genome-wide analysis showed transcription-activating and alternative-splicing functions are largely separable, arguing HTATSF1 does not obligately couple the two processes cellularly.

    Evidence RNAi knockdown, exon-array, bioinformatics

    PMID:21282347

    Open questions at the time
    • Mechanistic basis for two separable functions unexplained
    • Single primary method
  9. 2017 High

    In vivo Drosophila genetics defined the splicing substrate class (short, GC-rich, weak 3' splice site introns) and a developmental requirement in neural progenitors.

    Evidence Drosophila loss-of-function, co-IP with U2 snRNP, RNA-seq splicing analysis

    PMID:28935704

    Open questions at the time
    • Whether human introns share the same features not directly tested
    • Direct vs indirect splicing effects not fully separated
  10. 2018 High

    Provided the structural basis for U2 snRNP engagement, defining the UHM–ULM interface with SF3b1 at atomic resolution and mutual regulation of protein levels.

    Evidence X-ray crystallography (1.1–2.1 Å), UHM mutagenesis, binding affinity, RNAi

    PMID:30567737

    Open questions at the time
    • Functional consequence of disrupting interface in cells not exhaustively tested
    • Role within the assembling spliceosome not visualized
  11. 2024 Medium

    Uncovered a DNA repair function: CK2 phosphorylation at Ser748 recruits TOPBP1 to load RAD51 and promote homologous recombination.

    Evidence phosphorylation assay, co-IP, HR repair assay, mutant cells, tumor data

    PMID:38762174

    Open questions at the time
    • How a splicing/transcription factor accesses damage sites unclear
    • Single lab
  12. 2026 High

    Defined the structural basis of TOPBP1 recognition, showing cooperative BRCT1/BRCT2 binding of phospho-HTATSF1 with V158 conferring ligand specificity.

    Evidence X-ray crystallography (1.9 Å), mutagenesis, binding assays, AlphaFold3 modeling

    PMID:42251821

    Open questions at the time
    • In-cell validation of V158-dependent specificity limited
    • Integration with full HR machinery not shown
  13. 2025 Medium

    Established HTATSF1 as a positive regulator of innate antiviral immunity via HECTD3-dependent K63-ubiquitination of TRAF3 and TAK1-TRAF6 signaling, with an in vivo survival phenotype.

    Evidence co-IP, ubiquitination assays, mouse and cell knockouts, cytokine and viral infection models

    PMID:41466838

    Open questions at the time
    • Relationship between immune role and nuclear RNA functions unclear
    • Direct vs scaffolding role in ubiquitination not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HTATSF1's distinct activities — elongation, U2-dependent splicing, HR repair, and antiviral signaling — are coordinated or partitioned within a single protein remains unresolved.
  • No unified model linking nuclear RNA roles to repair and immune functions
  • Domain-level partitioning of the four activities undefined
  • Regulatory cues switching between functions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-73894 DNA Repair 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-168256 Immune System 1
Partners
GTF2F2HECTD3PRPF11SF3B1SUPT5HTOPBP1TRAF3TRAF6
Complex memberships
P-TEFb-associated elongation complexU2 snRNP

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Tat-SF1 is a cellular cofactor required for HIV-1 Tat-mediated stimulation of transcriptional elongation; it is a substrate of an associated cellular kinase and contains two RNA recognition motifs. Tat may stimulate elongation by recruiting a complex containing Tat-SF1 and this kinase to the HIV-1 promoter through a Tat-TAR interaction. cDNA isolation, in vitro reconstituted transcription, cotransfection/complementation, kinase assay Science High 8849451
1998 Tat-SF1 is a general transcription elongation factor, not solely a Tat-specific coactivator; a Tat-affinity column bound Tat-SF1 efficiently and selectively, and Tat-SF1 activity requires an ATP-inactivatable general elongation factor (AIEF) for which Tat can substitute functionally. Protein-affinity chromatography, in vitro transcription elongation assay Genes & development Medium 9765201
1998 The yeast homolog of Tat-SF1, CUS2, associates with U2 snRNA in splicing extracts, interacts with PRP11 (a subunit of SF3a), and is required to refold misfolded U2 RNA into a structure permissive for SF3b/SF3a binding prior to spliceosome assembly; anti-Tat-SF1 antibodies co-immunoprecipitate the human SF3a subunit SF3a66/SAP62, indicating a parallel splicing function in human cells. Suppressor screen, co-immunoprecipitation, in vitro RNA binding assay, RRM mutagenesis, genetic analysis Molecular and cellular biology High 9710584
1999 Tat-SF1 physically associates with RAP30 (but not RAP74) subunit of TFIIF and with human SPT5 (hSPT5); both hSPT5 and Tat-SF1 are required for Tat transactivation as shown by immunodepletion and complementation with recombinant proteins; overexpression of both factors specifically stimulates Tat-dependent transcription in vivo. Co-immunoprecipitation, immunodepletion, recombinant protein complementation, overexpression Molecular and cellular biology High 10454543
2007 Tat-SF1 acts as a stimulatory host factor for influenza virus RNA synthesis by interacting with free nucleoprotein (NP) but not RNA-associated NP, thereby facilitating formation of RNA-NP complexes, suggesting a molecular chaperone role for NP. Yeast replicon system, genome-wide deletion screen, co-immunoprecipitation, RNA-NP complex formation assay Proceedings of the National Academy of Sciences of the United States of America Medium 17991777
2009 Tat-SF1 is not required for Tat-dependent or basal HIV-1 transcription from the LTR in vivo; instead, depletion of Tat-SF1 by shRNA increases the ratio of unspliced to spliced HIV-1 RNAs, revealing a post-transcriptional (splicing) role in regulating viral transcript classes. shRNA knockdown in HeLa and T-REx-293 cells, HIV-1 infectivity assay, RT-PCR for spliced/unspliced RNA ratios PloS one Medium 19479034
2009 Tat-SF1 collaborates non-redundantly with DSIF (Spt4-Spt5) and the Paf1 complex to facilitate transcription elongation by RNA Pol II; these factors are recruited to the FOS gene in a temporally coordinated manner; elongation activation depends on P-TEFb-mediated phosphorylation of the Spt5 C-terminal region. Biochemical activity-based fractionation, chromatin immunoprecipitation (ChIP), in vitro transcription elongation assay, P-TEFb inhibition Genes & development High 19952111
2011 Genome-wide RNAi and exon-array analysis shows Tat-SF1 generally activates transcript levels (98% of affected genes down-regulated upon depletion) and independently regulates alternative splicing of a distinct gene set; the two functions show minimal overlap, indicating Tat-SF1 does not functionally couple transcription and splicing at the cellular level. RNAi knockdown, exon-specific microarray, bioinformatics RNA Medium 21282347
2017 In Drosophila, Barricade (Barc)/Tat-SF1 associates with components of the U2 snRNP complex and its depletion causes intron retention in a subset of introns characterized as short, GC-rich, with weak 3′ splice sites; loss of Barc impairs neural progenitor proliferation and differentiation during brain development. Genetic loss-of-function (Drosophila mutants), co-immunoprecipitation, RNA-seq/splicing assay, bioinformatics, cell culture splicing assay Development High 28935704
2018 Tat-SF1 contains a U2AF homology motif (UHM) that directly and preferentially binds the SF3b1 subunit of U2 snRNP via ULM motifs (particularly through SF3b1 Trp338 and electrostatic interactions with a basic ULM tail); crystal structures at 1.1 Å (free UHM), 1.9 Å, and 2.1 Å (UHM-ULM complexes) define the canonical binding interface; SF3b1 regulates Tat-SF1 protein levels and the two factors influence overlapping transcript sets. X-ray crystallography (1.1 Å, 1.9 Å, 2.1 Å resolution), co-immunoprecipitation, UHM mutagenesis, binding affinity measurements, RNAi/expression analysis The Journal of biological chemistry High 30567737
2024 CK2 kinase phosphorylates HTATSF1 at Ser748, which facilitates HTATSF1 interaction with TOPBP1, leading to RAD51 recruitment to DNA damage sites and promotion of homologous recombination (HR) repair; loss-of-function mutations in this axis increase HR deficiency. Phosphorylation assay, co-immunoprecipitation, HR repair assay, mutant cell lines, tumor data analysis The Journal of biological chemistry Medium 38762174
2025 HTATSF1 positively regulates innate antiviral immune signaling: upon viral infection it promotes HECTD3-catalyzed K63-linked polyubiquitination of TRAF3 (enabling TBK1 recruitment and IRF3 activation) and independently promotes TAK1 recruitment to TRAF6 (activating the TAK1-IKK-NF-κB axis); HTATSF1-deficient mice show decreased cytokine production and increased mortality upon viral infection. Co-immunoprecipitation, ubiquitination assay, gene knockout (mouse and cell), cytokine measurement, viral infection model Cell insight Medium 41466838
2026 Crystal structure of TopBP1 BRCT0-2 in complex with a phospho-HTATSF1 C-terminal peptide (at 1.9 Å resolution) reveals that TopBP1 cooperatively binds phosphorylated HTATSF1 through its BRCT1 and BRCT2 domains; key residue V158 in BRCT1 mediates specific hydrophobic contacts with the HTATSF1 ECT peptide, discriminating HTATSF1 from other phosphorylated ligands. X-ray crystallography (1.9 Å), mutagenesis, binding assays, AlphaFold3 modeling with biochemical validation Biochemical and biophysical research communications High 42251821
2024 HTATSF1 is found in complex with SF3B1 and P-TEFb on chromatin, along with the splicing factor SNW1; SF3B1 inhibition does not cause nuclear export of HTATSF1 (unlike SNW1), indicating HTATSF1 remains chromatin-associated after SF3B1 perturbation and its role in coupling transcription and splicing is partially separable from SNW1. Co-immunoprecipitation, nuclear fractionation/localization, SF3B1 inhibitor treatment bioRxivpreprint Low
2025 Computational simulations indicate TAT-SF1 acts as a 'molecular latch' maintaining the U2 snRNA branch-stem loop (BSL) in a supercoiled, high-energy 'loaded-spring' conformation; displacement of TAT-SF1 releases stored conformational energy that drives strand invasion for branch-site recognition during spliceosome assembly. All-atom and coarse-grained molecular dynamics simulations (computational only) bioRxivpreprint Low

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Tat-SF1: cofactor for stimulation of transcriptional elongation by HIV-1 Tat. Science (New York, N.Y.) 144 8849451
2009 DSIF, the Paf1 complex, and Tat-SF1 have nonredundant, cooperative roles in RNA polymerase II elongation. Genes & development 95 19952111
2007 An influenza virus replicon system in yeast identified Tat-SF1 as a stimulatory host factor for viral RNA synthesis. Proceedings of the National Academy of Sciences of the United States of America 74 17991777
1998 CUS2, a yeast homolog of human Tat-SF1, rescues function of misfolded U2 through an unusual RNA recognition motif. Molecular and cellular biology 74 9710584
1998 The HIV-1 Tat cellular coactivator Tat-SF1 is a general transcription elongation factor. Genes & development 61 9765201
1999 Tat-SF1 protein associates with RAP30 and human SPT5 proteins. Molecular and cellular biology 49 10454543
2018 The pre-mRNA splicing and transcription factor Tat-SF1 is a functional partner of the spliceosome SF3b1 subunit via a U2AF homology motif interface. The Journal of biological chemistry 35 30567737
2009 Tat-SF1 is not required for Tat transactivation but does regulate the relative levels of unspliced and spliced HIV-1 RNAs. PloS one 17 19479034
2011 Identification of Tat-SF1 cellular targets by exon array analysis reveals dual roles in transcription and splicing. RNA (New York, N.Y.) 16 21282347
2017 The splicing co-factor Barricade/Tat-SF1 is required for cell cycle and lineage progression in Drosophila neural stem cells. Development (Cambridge, England) 12 28935704
2012 Impact of sustained RNAi-mediated suppression of cellular cofactor Tat-SF1 on HIV-1 replication in CD4+ T cells. Virology journal 7 23153325
2025 HTATSF1 regulates innate antiviral immune response by orchestrating TRAF3-IRF3 and TRAF6-NF-κB pathways. Cell insight 2 41466838
2026 Structural mechanism of TopBP1 recognizing phosphorylated HTATSF1 in homologous recombination repair. Biochemical and biophysical research communications 0 42251821
2024 CK2-HTATSF1-TOPBP1 signaling axis modulates tumor chemotherapy response. The Journal of biological chemistry 0 38762174

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