{"gene":"SNW1","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":1998,"finding":"SNW1/SKIP (NCoA-62) was identified as a direct binding partner of the vitamin D receptor (VDR) ligand binding domain via yeast two-hybrid and in vitro GST pull-down assays, and its coexpression augmented 1,25-dihydroxyvitamin D3-activated transcription, establishing it as a transcriptional coactivator for VDR and other nuclear receptors.","method":"Yeast two-hybrid, GST pull-down, transient transcription assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assays plus functional transactivation assay; replicated in subsequent studies","pmids":["9632709"],"is_preprint":false},{"year":1998,"finding":"SNW1/SKIP was identified as an interaction partner of the Ski oncoprotein via yeast two-hybrid and shown to be a nuclear protein homologous to Drosophila Bx42; the Ski-SKIP interaction maps to a conserved region of Ski required for transforming activity.","method":"Yeast two-hybrid, nuclear localization confirmed by immunofluorescence","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — yeast two-hybrid plus subcellular localization; single lab","pmids":["9569025"],"is_preprint":false},{"year":2000,"finding":"SNW1/SKIP was identified as a CBF1-binding protein that also interacts with NotchIC and the SMRT corepressor; the SMRT and NotchIC interactions with SKIP are mutually exclusive. A mutation in the fourth ankyrin repeat of Notch abolished interaction with SKIP but not CBF1, and antisense SKIP prevented NotchIC from blocking muscle differentiation, establishing SKIP as required for Notch signal transduction.","method":"Yeast two-hybrid, GST pull-down, competition binding, antisense loss-of-function, reporter assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including binding competition and in vivo functional readout; replicated in subsequent papers","pmids":["10713164"],"is_preprint":false},{"year":2000,"finding":"SNW1/SKIP interacts with the EBNA2 viral transactivator (via conserved region 5, distinct from the CBF1 interaction region) and with components of the CBF1 corepressor complex (SMRT, CIR, Sin3A, HDAC2); EBNA2 co-localizes with SKIP by immunofluorescence, and both CBF1 and SKIP contacts are required for efficient EBNA2-mediated promoter activation.","method":"Yeast two-hybrid, GST affinity assay, mammalian two-hybrid, immunofluorescence co-localization, reporter assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — multiple binding assays plus functional reporter with defined mutations; replicated across two labs","pmids":["10644367"],"is_preprint":false},{"year":2001,"finding":"The SNW domain of SKIP is the interaction region for Ski and is also the domain responsible for SKIP's transcriptional activation activity; addition of Ski further augments SNW-domain-dependent transcriptional activation.","method":"Deletion mapping, reporter transcription assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping with functional consequence; single lab","pmids":["11522815"],"is_preprint":false},{"year":2001,"finding":"SNW1/SKIP forms a ternary complex with the liganded VDR-RXR heterodimer and SRC coactivator proteins, contacts a distinct domain from SRC on VDR, and synergizes with SRCs to enhance VDR-mediated transcription; both coactivator classes are required.","method":"Ternary complex binding assay, LXXLL peptide competition, transactivation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1/2 — reconstituted ternary complexes with competition experiments and functional validation","pmids":["11514567"],"is_preprint":false},{"year":2001,"finding":"The fission yeast SKIP ortholog (spSNW1) interacts with the small subunit of the splicing factor U2AF (spU2AF23), linking SNW1 to the spliceosome; spSNW1 is an essential gene in S. pombe.","method":"Yeast two-hybrid, co-precipitation from nuclear extracts, gene deletion","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — co-precipitation validated two-hybrid interaction; ortholog with conserved function","pmids":["11414703"],"is_preprint":false},{"year":2002,"finding":"SNW1/SKIP interacts directly with the retinoblastoma protein (pRb) through amino acids 171–353 of the conserved SNW domain, and SKIP together with Ski can overcome pRb-induced transcriptional repression and G1 arrest.","method":"GST pull-down, reporter assay, cell-cycle phenotype rescue","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding mapped plus functional phenotype; single lab","pmids":["12466551"],"is_preprint":false},{"year":2002,"finding":"The yeast SNW1 ortholog Prp45 SNW domain (N-terminal half, aa 1–190) is sufficient for viability; Prp45 activates reporter transcription in yeast dependent on conserved helical repeats and charged C-terminal domain; Prp45-GFP localizes to nuclear speckles.","method":"Complementation/deletion analysis, reporter transcription assay, GFP localization","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — genetic complementation plus subcellular localization; yeast ortholog","pmids":["12359070"],"is_preprint":false},{"year":2004,"finding":"MAGE-A1 interacts with SKIP via yeast two-hybrid (confirmed biochemically), and through this interaction inhibits SKIP-dependent Notch1 transactivation; MAGE-A1 also recruits HDAC1 to act as a transcriptional repressor.","method":"Yeast two-hybrid, deletion analysis, reporter assay, HDAC recruitment assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple binding and functional assays; single lab","pmids":["15316101"],"is_preprint":false},{"year":2001,"finding":"The HPV-16 E7 oncoprotein binds SKIP via its C-terminal region and the proline-rich sequences of the SNW domain, inhibiting SKIP transcriptional activation activity in vivo; transformation-defective E7 mutants fail both to bind SKIP and to inhibit its activity.","method":"Yeast two-hybrid, co-immunoprecipitation, reporter assay, E7 mutant analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — binding mapped to domain level plus functional inhibition demonstrated with mutants; single lab","pmids":["11753645"],"is_preprint":false},{"year":2003,"finding":"SNW1/SKIP interacts with specific residues in helix H10 of VDR (distinct from the AF-2/heterodimerization domain) in an AF-2-independent manner; these same H10 residues are also contacted by TFIIB and RXR, and mutation reduces SKIP interaction and ligand-dependent transactivation.","method":"GST pull-down, mutagenesis, transactivation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — mutagenesis with functional consequence; single lab","pmids":["12529369"],"is_preprint":false},{"year":2004,"finding":"SNW1/SKIP is a nuclear matrix-associated spliceosomal component and transcriptional coregulator whose SNW domain mediates interactions with splicing factors Prp8 and the U5 200 kDa helicase; ChIP shows ligand-dependent recruitment of NCoA-62/SKIP to VDR-responsive promoters at a distal step after VDR and SRC entry.","method":"Chromatin immunoprecipitation, nuclear fractionation, co-IP with splicing factors","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and biochemical fractionation; single lab review summarizing multiple experiments","pmids":["15225769"],"is_preprint":false},{"year":2004,"finding":"Human SKIP functionally complements deletion of the yeast PRP45 splicing gene, rescuing the lethal phenotype, demonstrating that SNW1/SKIP can act as a bona fide pre-mRNA splicing factor.","method":"Genetic complementation in S. cerevisiae","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct complementation of splicing-essential yeast gene; single experiment","pmids":["15194481"],"is_preprint":false},{"year":2005,"finding":"SNW1/SKIP associates with P-TEFb (CycT1:CDK9) and Tat:P-TEFb complexes in nuclear extracts and with recombinant Tat:P-TEFb:TAR RNA in vitro; SKIP is required for Tat transactivation in vivo and stimulates HIV-1 transcription elongation but not initiation in vitro; SKIP also associates with U5snRNP proteins and facilitates recognition of an alternative Tat-specific splice site. All activities map to the SNW domain.","method":"Co-IP from nuclear extracts, in vitro transcription elongation assay, RNAi, ChIP, alternative splice-site assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro reconstitution plus multiple orthogonal cellular assays; strong mechanistic characterization in single paper","pmids":["15905409"],"is_preprint":false},{"year":2006,"finding":"PPIL1 (a cyclophilin spliceosomal component) directly binds a disordered N-terminal region of SKIP (residues 59–129) with a dissociation constant of 1.25×10⁻⁷ M; binding site on PPIL1 is distinct from the PPIase active site, leaving it available for isomerase activity; the complex is part of the 35S U5 snRNP and activated spliceosome.","method":"NMR structure determination, GST pull-down, surface plasmon resonance, chemical shift perturbation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structure plus SPR quantitative binding; replicated by subsequent structural study","pmids":["16595688"],"is_preprint":false},{"year":2009,"finding":"A large intrinsically disordered region in SKIP (residues 59–129) undergoes a disorder-to-order transition upon binding PPIL1; the minimal PPIL1-binding fragment (PBF, residues 59–79) forms a defined hook-like structure with PPIL1 via electrostatic and hydrophobic interactions; this structural rearrangement may facilitate spliceosome activation.","method":"NMR structure of PBF·PPIL1 complex, disordered-region characterization by NMR","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with functional implication for spliceosome rearrangement","pmids":["20007319"],"is_preprint":false},{"year":2009,"finding":"The yeast SNW1 ortholog Prp45 genetically interacts with NTC spliceosomal components (SYF1, CLF1, NTC20, CEF1) and second-step splicing factors (SLU7, PRP17, PRP18, PRP22); Prp45 affects the stoichiometry of Prp22 in Cwc2-associated spliceosomal complexes, and is required for efficient splicing of non-consensus substrates at the second step.","method":"Synthetic lethality screen, spliceosome purification/co-IP, in vivo splicing assays with mutant substrates","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis plus biochemical spliceosomal complex analysis; multiple orthogonal methods","pmids":["19016306"],"is_preprint":false},{"year":2009,"finding":"SNW1/SKIP associates with c-Myc and Menin (a subunit of the MLL1 H3K4me3 complex) and acts downstream of Tat:P-TEFb to recruit c-Myc and TRRAP to the HIV-1 promoter; SKIP is also recruited by the RNF20 H2B ubiquitin ligase to the basal HIV-1 promoter in a step bypassed by Tat. HIV-1 Tat transactivation requires c-Myc and Menin but not MLL1 or H3K4me3.","method":"Co-IP, RNAi-ChIP, reporter assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus RNAi-ChIP with defined pathway ordering; single lab with multiple orthogonal methods","pmids":["19818711"],"is_preprint":false},{"year":2009,"finding":"SNW1/SKIP interacts with retinoic acid receptor (RAR) in a RA-dependent manner through a region overlapping the SIRT1 binding site; SKIP augments RAR transactivation by cooperating with SRC-1, while SIRT1 suppresses SKIP/SRC-1-enhanced RAR activity via its deacetylase activity; overexpression of SKIP impairs SIRT1 recruitment to the RARβ2 promoter.","method":"Binding assays, reporter assay, ChIP, RNAi, overexpression","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus functional assays with defined binding competition; single lab","pmids":["19934264"],"is_preprint":false},{"year":2010,"finding":"Xenopus SKIP/SNW1 forms a ternary complex with LEF1 and HDAC1 and mediates transcriptional repression of Wnt target genes; SKIP is required for Wnt signaling-induced target gene transactivation; C-terminally truncated SKIP can stabilize β-catenin and enhance Wnt signaling; knockdown or overexpression of Skip in Xenopus reduces neural crest induction consistent with altered Wnt signaling.","method":"Co-IP, reporter assay, morpholino knockdown, overexpression in Xenopus embryos","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical complex demonstrated plus in vivo functional readout; single lab","pmids":["20103590"],"is_preprint":false},{"year":2010,"finding":"The crystal structure of PPIL1 bound to cyclosporine A was determined at 1.15 Å; a 36-residue SKIP fragment (centered on an 8-residue epitope) suffices to bind PPIL1 in pull-down experiments; molecular docking reveals a proline residue of SKIP buried in a hydrophobic pocket of PPIL1, surrounded by hydrogen bonds.","method":"X-ray crystallography (SAD phasing), peptide array, pull-down, molecular docking","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus biochemical validation of binding epitope","pmids":["20368803"],"is_preprint":false},{"year":2011,"finding":"SNW1 is required for neural crest specification in Xenopus and zebrafish; dorsally expressed SNW1 regulates a specific domain of BMP activity (phospho-Smad1) at the neural plate border at post-gastrula stages, acting upstream of BMP receptors; targeted BMP overexpression at the neural plate border restores neural crest formation in SNW1 morphants.","method":"Antisense morpholino knockdown in Xenopus and zebrafish, immunostaining for pSmad1, BMP reporter transgenic line, tissue explants, epistasis by BMP overexpression rescue","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 — two-organism genetic knockdown plus epistasis rescue with multiple orthogonal readouts","pmids":["21358802"],"is_preprint":false},{"year":2014,"finding":"SNW1 and PRPF8 are essential for sister chromatid cohesion in human cells; transcriptome-wide analysis shows SNW1 depletion causes intron retention in a subset of pre-mRNAs including sororin (CDCA5) and APC2; reduced sororin levels destabilize cohesin on DNA, while reduced APC2 delays mitosis causing cohesion fatigue. Simultaneous expression of intron-less sororin and APC2 cDNAs restores cohesion in SNW1-depleted cells.","method":"RNAi depletion, RNA-seq transcriptome-wide splicing analysis, cohesin chromatin fractionation, cDNA rescue experiment, live-cell imaging","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1/2 — transcriptome-wide splicing screen plus genetic rescue with intron-less cDNAs; rigorous causal chain established","pmids":["25257309"],"is_preprint":false},{"year":2014,"finding":"SNW1 directly associates with spliceosome components EFTUD2 (Snu114) and SNRNP200 (Brr2) as shown by proteomics and biochemical assays; the SKIP region of SNW1 interacts with the N-terminus of EFTUD2 and two independent C-terminal regions of SNRNP200; depletion of SNW1 or EFTUD2 induces apoptosis in breast cancer cells.","method":"Proteomics, co-IP, domain mapping, RNAi, apoptosis assay","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding mapped to domains plus cellular phenotype; single lab","pmids":["25450007"],"is_preprint":false},{"year":2015,"finding":"UV cross-linking of purified yeast Bact spliceosomes shows that Prp45 (SNW1 ortholog) contacts nucleotides surrounding the branch-site upon step 1 catalysis; this interaction is enhanced relative to earlier spliceosomal complexes, indicating dynamic Prp45-pre-mRNA contacts during catalytic activation.","method":"UV cross-linking of purified spliceosomal complexes, site-specifically labeled pre-mRNA","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1 — reconstituted purified spliceosomal complexes with site-specific labeling; direct contact demonstrated","pmids":["26393790"],"is_preprint":false},{"year":2019,"finding":"SNW1 detaches from its splicing complex (formed with SNRNP200 and SNRNP220) upon NF-κB activation, binds to the NF-κB heterodimer in the nucleus, and recruits p-TEFb to facilitate transcriptional elongation of NF-κB target genes (IL-8, TNF); SNW1 does not regulate cytoplasmic NF-κB pathway components.","method":"Genome-wide RNAi screen, co-IP, ChIP, RNAi knockdown with target gene expression readout","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — genome-wide functional screen plus co-IP and ChIP defining pathway position; multiple orthogonal methods","pmids":["30397075"],"is_preprint":false},{"year":2019,"finding":"SNW1 acts as a novel RBPJ-interacting partner and regulates expression of Notch target genes in neuroblastoma; silencing RBPJ prevents SNW1-mediated Notch gene expression, placing SNW1 in the RBPJ-dependent Notch transcriptional complex.","method":"Co-IP, RNAi, reporter assay, gene expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus epistasis RNAi; single lab, single publication","pmids":["30642633"],"is_preprint":false},{"year":2002,"finding":"Drosophila Bx42 (SNW1 ortholog) is essential for development of many tissues; RNAi-mediated knockdown of Bx42 produces phenotypes resembling Notch mutants, and target genes of Notch signaling (cut, E(spl)m8) are suppressed; the wing phenotype from Suppressor of Hairless overexpression is strongly enhanced by simultaneous Bx42 RNAi, placing Bx42/SNW1 in the Notch pathway downstream of Notch signaling.","method":"Inducible RNAi in Drosophila, genetic epistasis with Notch pathway components, in situ target gene expression","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo RNAi with genetic epistasis in Drosophila ortholog; supports conserved Notch pathway role","pmids":["12204255"],"is_preprint":false}],"current_model":"SNW1/SKIP is a conserved nuclear protein that functions dually as an essential spliceosome component (residing in the U5 snRNP/activated spliceosome and contacting pre-mRNA branch-site nucleotides via its SNW domain) and as a transcriptional coregulator that bridges multiple signaling pathways—including Notch/RBPJ, VDR, RAR, Wnt/β-catenin, NF-κB, and Ski/pRb—by competing with corepressor complexes (SMRT/HDAC) for contacts on DNA-binding proteins and by recruiting elongation factors (P-TEFb/CDK9) and chromatin regulators (c-Myc, Menin, TRRAP) to promoters; its spliceosomal role is mechanistically critical for mitosis because SNW1-dependent splicing of sororin and APC2 pre-mRNAs is required for sister chromatid cohesion, and its N-terminal disordered region mediates a disorder-to-order transition upon binding the cyclophilin PPIL1 to facilitate spliceosome activation."},"narrative":{"teleology":[{"year":1998,"claim":"The initial identification of SNW1/SKIP as a nuclear coactivator for the vitamin D receptor and as a Ski oncoprotein-interacting partner established its dual identity as a transcriptional coregulator connected to nuclear receptor signaling and oncogenic pathways.","evidence":"Yeast two-hybrid, GST pull-down, and transient transcription assays in mammalian cells; independent nuclear localization by immunofluorescence","pmids":["9632709","9569025"],"confidence":"High","gaps":["Mechanism by which SKIP activates transcription (direct chromatin contact vs. bridging factor) was unknown","Whether SKIP had signaling-pathway-specific or general coactivator function was unresolved"]},{"year":2000,"claim":"Demonstration that SNW1 binds both NotchIC and the corepressor SMRT in a mutually exclusive manner on CBF1 revealed a competitive switching mechanism by which SNW1 converts CBF1 from a repressor to an activator during Notch signaling, and extended its coregulator role to Notch and EBNA2 viral transactivation.","evidence":"GST pull-down competition, antisense loss-of-function blocking Notch-dependent muscle differentiation inhibition, reporter assays; EBNA2 binding mapped to a distinct SKIP region","pmids":["10713164","10644367"],"confidence":"High","gaps":["Whether SKIP displaces SMRT or is displaced by SMRT in vivo was not kinetically resolved","Whether SKIP's splicing and transcriptional coregulator roles are functionally separable remained unknown"]},{"year":2001,"claim":"Domain mapping established the SNW domain as the hub for transcriptional activation, VDR ternary complex formation with SRC coactivators, interactions with pRb, Ski, and HPV E7 oncoprotein, while the fission yeast ortholog linked SNW1 to the spliceosome via U2AF interaction and showed essentiality.","evidence":"Deletion/mutagenesis, ternary complex reconstitution, LXXLL peptide competition, yeast two-hybrid with U2AF23, gene deletion lethality in S. pombe","pmids":["11522815","11514567","11414703","12466551","11753645"],"confidence":"High","gaps":["How SNW1 could simultaneously participate in splicing and transcription was mechanistically unclear","No structural information on the SNW domain itself was available"]},{"year":2004,"claim":"Cross-species complementation (human SNW1 rescuing yeast PRP45 deletion) proved SNW1 is a bona fide splicing factor, while ChIP showed ligand-dependent recruitment to VDR-responsive promoters at a late step after VDR/SRC entry, and its association with U5 snRNP components Prp8 and the 200-kDa helicase was demonstrated.","evidence":"Genetic complementation in S. cerevisiae, ChIP at endogenous promoters, co-IP with U5 components, nuclear matrix fractionation","pmids":["15194481","15225769"],"confidence":"Medium","gaps":["Whether SNW1's splicing and transcriptional roles are exerted on the same gene simultaneously was unknown","No direct RNA contact by SNW1 had been demonstrated"]},{"year":2005,"claim":"The discovery that SNW1 recruits P-TEFb (CycT1:CDK9) to promote transcriptional elongation—demonstrated in the context of HIV-1 Tat transactivation—provided the first mechanistic explanation for how SNW1 activates transcription: by coupling elongation factor recruitment to DNA-bound activators and to alternative splice-site selection.","evidence":"Co-IP from nuclear extracts, in vitro transcription elongation assay showing stimulation of elongation but not initiation, RNAi, ChIP, alternative splice-site assay","pmids":["15905409"],"confidence":"High","gaps":["Whether P-TEFb recruitment by SNW1 occurs in non-HIV transcriptional contexts was not yet shown","How SNW1 coordinates elongation factor delivery with its spliceosomal activity was unresolved"]},{"year":2006,"claim":"NMR structural determination of the PPIL1–SKIP complex revealed that a disordered N-terminal region of SKIP (residues 59–129) undergoes a disorder-to-order transition upon binding PPIL1, forming a hook-like structure; this interaction occurs at a site distinct from the PPIase active site, leaving PPIL1 catalytically competent within the activated spliceosome.","evidence":"NMR structure, SPR (Kd = 1.25 × 10⁻⁷ M), chemical shift perturbation, GST pull-down; confirmed by subsequent crystallography and peptide array","pmids":["16595688","20007319","20368803"],"confidence":"High","gaps":["Functional consequence of PPIL1 isomerase activity while bound to SKIP was not identified","Whether the disorder-to-order transition is required for spliceosome catalytic activation was not tested"]},{"year":2009,"claim":"Genetic interaction mapping of yeast Prp45 with NTC components and second-step splicing factors established SNW1 as critical for the second catalytic step, especially for non-consensus splice sites, while in mammalian cells SNW1 was shown to recruit c-Myc, Menin, and TRRAP downstream of P-TEFb to chromatin.","evidence":"Synthetic lethality screen with NTC/step-2 factors, spliceosome purification, co-IP/RNAi-ChIP for c-Myc/Menin/TRRAP at HIV-1 promoter","pmids":["19016306","19818711"],"confidence":"High","gaps":["Whether c-Myc/TRRAP recruitment is specific to viral promoters or general to SNW1-dependent genes was unknown","The structural basis for Prp45/SNW1 contacts at the catalytic center was not resolved"]},{"year":2010,"claim":"Identification of SNW1 as a component of a LEF1–HDAC1 ternary complex that mediates both transcriptional repression and Wnt-induced activation of target genes extended SNW1's coregulator function to the Wnt/β-catenin pathway, with C-terminal truncation stabilizing β-catenin.","evidence":"Co-IP, reporter assay, morpholino knockdown and overexpression in Xenopus embryos affecting neural crest induction","pmids":["20103590"],"confidence":"Medium","gaps":["Whether SNW1 directly contacts β-catenin was not demonstrated","The relationship between SNW1's splicing role and its Wnt signaling role in neural crest was not dissected"]},{"year":2011,"claim":"In vivo epistasis experiments in Xenopus and zebrafish demonstrated that SNW1 regulates a specific domain of BMP signaling (phospho-Smad1) at the neural plate border required for neural crest specification, with BMP overexpression rescuing the SNW1 morphant phenotype.","evidence":"Morpholino knockdown in two organisms, pSmad1 immunostaining, BMP reporter transgenic, tissue explant assays, epistasis rescue","pmids":["21358802"],"confidence":"High","gaps":["Whether SNW1 regulates BMP signaling through its splicing or transcriptional coregulator function was not resolved","No direct interaction between SNW1 and BMP pathway components was shown"]},{"year":2014,"claim":"Transcriptome-wide splicing analysis after SNW1 depletion revealed that its spliceosomal role is specifically required for sister chromatid cohesion through splicing of sororin and APC2 pre-mRNAs; simultaneous expression of intron-less cDNAs rescued cohesion, establishing a causal chain from splicing to mitotic fidelity.","evidence":"RNAi, RNA-seq, cohesin chromatin fractionation, intron-less cDNA rescue, live-cell imaging; domain-mapped interactions with EFTUD2 and SNRNP200","pmids":["25257309","25450007"],"confidence":"High","gaps":["What feature of sororin/APC2 introns makes them particularly SNW1-dependent was not determined","Whether other mitotic phenotypes arise from SNW1-dependent splicing of additional transcripts was unexplored"]},{"year":2015,"claim":"UV cross-linking of purified Bact spliceosomes demonstrated that yeast Prp45 directly contacts nucleotides surrounding the branch site during catalytic activation, providing the first evidence that SNW1 physically engages the pre-mRNA substrate at the catalytic center.","evidence":"UV cross-linking with site-specifically labeled pre-mRNA in purified Bact complexes","pmids":["26393790"],"confidence":"High","gaps":["Whether SNW1/Prp45 branch-site contact is catalytic or structural was not distinguished","No high-resolution structure of SNW1 within the intact spliceosome was available at this time"]},{"year":2019,"claim":"A genome-wide RNAi screen identified SNW1 as an NF-κB transcriptional coactivator that detaches from its spliceosomal complex upon NF-κB activation to bind the NF-κB heterodimer and recruit P-TEFb for elongation of inflammatory target genes, providing a signal-dependent mechanism for toggling between splicing and transcription functions.","evidence":"Genome-wide RNAi screen, co-IP showing dissociation from SNRNP200/SNRNP220, ChIP at IL-8/TNF promoters","pmids":["30397075"],"confidence":"High","gaps":["The signal that triggers SNW1 release from the spliceosomal complex upon NF-κB activation was not identified","Whether this switching mechanism operates for other signaling pathways (Notch, VDR) was not tested"]},{"year":null,"claim":"A central unresolved question is how SNW1 partitions between its spliceosomal and transcriptional coregulator functions at the molecular level—whether these activities are temporally or spatially separated, and whether co-transcriptional splicing provides a unified context for both roles.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of human SNW1 in the spliceosomal context has been published in the timeline","Whether distinct SNW1 pools exist for splicing versus transcription has not been quantified","The full set of SNW1-dependent splice-sensitive transcripts beyond sororin/APC2 is not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[14,15,16,25]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,5,14,18,26]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,7,20,26]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,14,18,26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,8,12,26]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[8,12,15]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,13,14,15,16,17,23,25]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,5,14,18,26]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,20,22,27]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[26]}],"complexes":["U5 snRNP","Activated spliceosome (Bact)","P-TEFb (CycT1:CDK9)"],"partners":["PPIL1","PRPF8","SNRNP200","EFTUD2","CDK9","RBPJ","VDR","SMRT"],"other_free_text":[]},"mechanistic_narrative":"SNW1 (also called SKIP/NCoA-62) is a conserved nuclear protein that functions both as an essential spliceosome component and as a transcriptional coregulator linking multiple signaling pathways to RNA polymerase II elongation. Within the spliceosome, SNW1 resides in the U5 snRNP and activated (Bact) complex, directly contacts pre-mRNA branch-site nucleotides via its SNW domain, interacts with core splicing factors PRPF8, SNRNP200/Brr2, and EFTUD2/Snu114, and undergoes a disorder-to-order transition upon binding the cyclophilin PPIL1 through an N-terminal disordered region [PMID:26393790, PMID:16595688, PMID:25450007, PMID:25257309]. Its spliceosomal activity is mechanistically required for sister chromatid cohesion, as SNW1 depletion causes intron retention in sororin and APC2 pre-mRNAs, and simultaneous expression of intron-less cDNAs rescues the cohesion defect [PMID:25257309]. As a transcriptional coregulator, SNW1 bridges DNA-bound factors—including VDR, RAR, Notch/RBPJ, LEF1/β-catenin, and NF-κB—to P-TEFb (CycT1:CDK9), c-Myc, Menin, and TRRAP, while competing with corepressor complexes (SMRT/HDAC) for binding on the same transcription factors [PMID:9632709, PMID:10713164, PMID:15905409, PMID:19818711, PMID:30397075, PMID:20103590]."},"prefetch_data":{"uniprot":{"accession":"Q13573","full_name":"SNW domain-containing protein 1","aliases":["Nuclear protein SkiP","Nuclear receptor coactivator NCoA-62","Ski-interacting protein"],"length_aa":536,"mass_kda":61.5,"function":"Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28076346, PubMed:28502770). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). Required for the specific splicing of CDKN1A pre-mRNA; the function probably involves the recruitment of U2AF2 to the mRNA. May recruit PPIL1 to the spliceosome. May be involved in cyclin-D1/CCND1 mRNA stability through the SNARP complex which associates with both the 3'end of the CCND1 gene and its mRNA. Involved in transcriptional regulation. Modulates TGF-beta-mediated transcription via association with SMAD proteins, MYOD1-mediated transcription via association with PABPN1, RB1-mediated transcriptional repression, and retinoid-X receptor (RXR)- and vitamin D receptor (VDR)-dependent gene transcription in a cell line-specific manner probably involving coactivators NCOA1 and GRIP1. Is involved in NOTCH1-mediated transcriptional activation. Binds to multimerized forms of Notch intracellular domain (NICD) and is proposed to recruit transcriptional coactivators such as MAML1 to form an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ to form a transcriptional activation complex by releasing SNW1 and redundant NOTCH1 NICD (Microbial infection) Is recruited by HIV-1 Tat to Tat:P-TEFb:TAR RNA complexes and is involved in Tat transcription by recruitment of MYC, MEN1 and TRRAP to the HIV promoter (Microbial infection) Proposed to be involved in transcriptional activation by EBV EBNA2 of CBF-1/RBPJ-repressed promoters","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13573/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SNW1","classification":"Common 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SKIIP","url":"https://www.omim.org/entry/603055"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNW1"},"hgnc":{"alias_symbol":["NCoA-62","SKIP","Prp45","PRPF45","Bx42","SKIP1","FUN20"],"prev_symbol":["SKIIP"]},"alphafold":{"accession":"Q13573","domains":[{"cath_id":"-","chopping":"35-119","consensus_level":"medium","plddt":89.4834,"start":35,"end":119},{"cath_id":"1.20.5","chopping":"284-332","consensus_level":"medium","plddt":92.1141,"start":284,"end":332}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13573","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13573-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13573-F1-predicted_aligned_error_v6.png","plddt_mean":78.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNW1","jax_strain_url":"https://www.jax.org/strain/search?query=SNW1"},"sequence":{"accession":"Q13573","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13573.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13573/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13573"}},"corpus_meta":[{"pmid":"9030939","id":"PMC_9030939","title":"Frequency 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diseases","url":"https://pubmed.ncbi.nlm.nih.gov/32417793","citation_count":20,"is_preprint":false},{"pmid":"28329143","id":"PMC_28329143","title":"Epidermal growth factor receptor mutations are linked to skip N2 lymph node metastasis in resected non-small-cell lung cancer adenocarcinomas.","date":"2017","source":"European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/28329143","citation_count":20,"is_preprint":false},{"pmid":"26376412","id":"PMC_26376412","title":"Regulation of insulin signaling in skeletal muscle by PIP3 phosphatase, SKIP, and endoplasmic reticulum molecular chaperone glucose-regulated protein 78.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26376412","citation_count":19,"is_preprint":false},{"pmid":"29771942","id":"PMC_29771942","title":"Antisense PMO cocktails effectively skip dystrophin exons 45-55 in myotubes transdifferentiated from DMD patient fibroblasts.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29771942","citation_count":19,"is_preprint":false},{"pmid":"35134199","id":"PMC_35134199","title":"SKIP Regulates ABA Signaling through Alternative Splicing in Arabidopsis.","date":"2022","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35134199","citation_count":19,"is_preprint":false},{"pmid":"38772367","id":"PMC_38772367","title":"To modulate or to skip: De-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy.","date":"2024","source":"Cell systems","url":"https://pubmed.ncbi.nlm.nih.gov/38772367","citation_count":18,"is_preprint":false},{"pmid":"15194481","id":"PMC_15194481","title":"The human Ski-interacting protein functionally substitutes for the yeast PRP45 gene.","date":"2004","source":"Biochemical and biophysical research 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Cancer.","date":"2021","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/34659126","citation_count":17,"is_preprint":false},{"pmid":"31902592","id":"PMC_31902592","title":"Survival benefit of skip metastases in surgically resected N2 non-small cell lung cancer: A multicenter observational study of a large cohort of the Chinese patients.","date":"2019","source":"European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31902592","citation_count":17,"is_preprint":false},{"pmid":"33340715","id":"PMC_33340715","title":"Mesenteric Neural Crest Cells Are the Embryological Basis of Skip Segment Hirschsprung's Disease.","date":"2020","source":"Cellular and molecular gastroenterology and 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regulate fibronectin-dependent cell migration in glioblastoma.","date":"2019","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/30695232","citation_count":15,"is_preprint":false},{"pmid":"24562596","id":"PMC_24562596","title":"Venous thromboembolism in colorectal surgery: skip SCIP or comply?","date":"2014","source":"Techniques in coloproctology","url":"https://pubmed.ncbi.nlm.nih.gov/24562596","citation_count":15,"is_preprint":false},{"pmid":"15936017","id":"PMC_15936017","title":"Echinococcus multilocularis: cloning and characterization of a member of the SNW/SKIP family of transcriptional coregulators.","date":"2005","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/15936017","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47812,"output_tokens":6606,"usd":0.121263},"stage2":{"model":"claude-opus-4-6","input_tokens":10311,"output_tokens":4063,"usd":0.229695},"total_usd":0.350958,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"SNW1/SKIP (NCoA-62) was identified as a direct binding partner of the vitamin D receptor (VDR) ligand binding domain via yeast two-hybrid and in vitro GST pull-down assays, and its coexpression augmented 1,25-dihydroxyvitamin D3-activated transcription, establishing it as a transcriptional coactivator for VDR and other nuclear receptors.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, transient transcription assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays plus functional transactivation assay; replicated in subsequent studies\",\n      \"pmids\": [\"9632709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SNW1/SKIP was identified as an interaction partner of the Ski oncoprotein via yeast two-hybrid and shown to be a nuclear protein homologous to Drosophila Bx42; the Ski-SKIP interaction maps to a conserved region of Ski required for transforming activity.\",\n      \"method\": \"Yeast two-hybrid, nuclear localization confirmed by immunofluorescence\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid plus subcellular localization; single lab\",\n      \"pmids\": [\"9569025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SNW1/SKIP was identified as a CBF1-binding protein that also interacts with NotchIC and the SMRT corepressor; the SMRT and NotchIC interactions with SKIP are mutually exclusive. A mutation in the fourth ankyrin repeat of Notch abolished interaction with SKIP but not CBF1, and antisense SKIP prevented NotchIC from blocking muscle differentiation, establishing SKIP as required for Notch signal transduction.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, competition binding, antisense loss-of-function, reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including binding competition and in vivo functional readout; replicated in subsequent papers\",\n      \"pmids\": [\"10713164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SNW1/SKIP interacts with the EBNA2 viral transactivator (via conserved region 5, distinct from the CBF1 interaction region) and with components of the CBF1 corepressor complex (SMRT, CIR, Sin3A, HDAC2); EBNA2 co-localizes with SKIP by immunofluorescence, and both CBF1 and SKIP contacts are required for efficient EBNA2-mediated promoter activation.\",\n      \"method\": \"Yeast two-hybrid, GST affinity assay, mammalian two-hybrid, immunofluorescence co-localization, reporter assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding assays plus functional reporter with defined mutations; replicated across two labs\",\n      \"pmids\": [\"10644367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The SNW domain of SKIP is the interaction region for Ski and is also the domain responsible for SKIP's transcriptional activation activity; addition of Ski further augments SNW-domain-dependent transcriptional activation.\",\n      \"method\": \"Deletion mapping, reporter transcription assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with functional consequence; single lab\",\n      \"pmids\": [\"11522815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SNW1/SKIP forms a ternary complex with the liganded VDR-RXR heterodimer and SRC coactivator proteins, contacts a distinct domain from SRC on VDR, and synergizes with SRCs to enhance VDR-mediated transcription; both coactivator classes are required.\",\n      \"method\": \"Ternary complex binding assay, LXXLL peptide competition, transactivation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — reconstituted ternary complexes with competition experiments and functional validation\",\n      \"pmids\": [\"11514567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The fission yeast SKIP ortholog (spSNW1) interacts with the small subunit of the splicing factor U2AF (spU2AF23), linking SNW1 to the spliceosome; spSNW1 is an essential gene in S. pombe.\",\n      \"method\": \"Yeast two-hybrid, co-precipitation from nuclear extracts, gene deletion\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-precipitation validated two-hybrid interaction; ortholog with conserved function\",\n      \"pmids\": [\"11414703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SNW1/SKIP interacts directly with the retinoblastoma protein (pRb) through amino acids 171–353 of the conserved SNW domain, and SKIP together with Ski can overcome pRb-induced transcriptional repression and G1 arrest.\",\n      \"method\": \"GST pull-down, reporter assay, cell-cycle phenotype rescue\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding mapped plus functional phenotype; single lab\",\n      \"pmids\": [\"12466551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The yeast SNW1 ortholog Prp45 SNW domain (N-terminal half, aa 1–190) is sufficient for viability; Prp45 activates reporter transcription in yeast dependent on conserved helical repeats and charged C-terminal domain; Prp45-GFP localizes to nuclear speckles.\",\n      \"method\": \"Complementation/deletion analysis, reporter transcription assay, GFP localization\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic complementation plus subcellular localization; yeast ortholog\",\n      \"pmids\": [\"12359070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MAGE-A1 interacts with SKIP via yeast two-hybrid (confirmed biochemically), and through this interaction inhibits SKIP-dependent Notch1 transactivation; MAGE-A1 also recruits HDAC1 to act as a transcriptional repressor.\",\n      \"method\": \"Yeast two-hybrid, deletion analysis, reporter assay, HDAC recruitment assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding and functional assays; single lab\",\n      \"pmids\": [\"15316101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The HPV-16 E7 oncoprotein binds SKIP via its C-terminal region and the proline-rich sequences of the SNW domain, inhibiting SKIP transcriptional activation activity in vivo; transformation-defective E7 mutants fail both to bind SKIP and to inhibit its activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, reporter assay, E7 mutant analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding mapped to domain level plus functional inhibition demonstrated with mutants; single lab\",\n      \"pmids\": [\"11753645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SNW1/SKIP interacts with specific residues in helix H10 of VDR (distinct from the AF-2/heterodimerization domain) in an AF-2-independent manner; these same H10 residues are also contacted by TFIIB and RXR, and mutation reduces SKIP interaction and ligand-dependent transactivation.\",\n      \"method\": \"GST pull-down, mutagenesis, transactivation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with functional consequence; single lab\",\n      \"pmids\": [\"12529369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SNW1/SKIP is a nuclear matrix-associated spliceosomal component and transcriptional coregulator whose SNW domain mediates interactions with splicing factors Prp8 and the U5 200 kDa helicase; ChIP shows ligand-dependent recruitment of NCoA-62/SKIP to VDR-responsive promoters at a distal step after VDR and SRC entry.\",\n      \"method\": \"Chromatin immunoprecipitation, nuclear fractionation, co-IP with splicing factors\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and biochemical fractionation; single lab review summarizing multiple experiments\",\n      \"pmids\": [\"15225769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human SKIP functionally complements deletion of the yeast PRP45 splicing gene, rescuing the lethal phenotype, demonstrating that SNW1/SKIP can act as a bona fide pre-mRNA splicing factor.\",\n      \"method\": \"Genetic complementation in S. cerevisiae\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct complementation of splicing-essential yeast gene; single experiment\",\n      \"pmids\": [\"15194481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SNW1/SKIP associates with P-TEFb (CycT1:CDK9) and Tat:P-TEFb complexes in nuclear extracts and with recombinant Tat:P-TEFb:TAR RNA in vitro; SKIP is required for Tat transactivation in vivo and stimulates HIV-1 transcription elongation but not initiation in vitro; SKIP also associates with U5snRNP proteins and facilitates recognition of an alternative Tat-specific splice site. All activities map to the SNW domain.\",\n      \"method\": \"Co-IP from nuclear extracts, in vitro transcription elongation assay, RNAi, ChIP, alternative splice-site assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro reconstitution plus multiple orthogonal cellular assays; strong mechanistic characterization in single paper\",\n      \"pmids\": [\"15905409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PPIL1 (a cyclophilin spliceosomal component) directly binds a disordered N-terminal region of SKIP (residues 59–129) with a dissociation constant of 1.25×10⁻⁷ M; binding site on PPIL1 is distinct from the PPIase active site, leaving it available for isomerase activity; the complex is part of the 35S U5 snRNP and activated spliceosome.\",\n      \"method\": \"NMR structure determination, GST pull-down, surface plasmon resonance, chemical shift perturbation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure plus SPR quantitative binding; replicated by subsequent structural study\",\n      \"pmids\": [\"16595688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A large intrinsically disordered region in SKIP (residues 59–129) undergoes a disorder-to-order transition upon binding PPIL1; the minimal PPIL1-binding fragment (PBF, residues 59–79) forms a defined hook-like structure with PPIL1 via electrostatic and hydrophobic interactions; this structural rearrangement may facilitate spliceosome activation.\",\n      \"method\": \"NMR structure of PBF·PPIL1 complex, disordered-region characterization by NMR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with functional implication for spliceosome rearrangement\",\n      \"pmids\": [\"20007319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The yeast SNW1 ortholog Prp45 genetically interacts with NTC spliceosomal components (SYF1, CLF1, NTC20, CEF1) and second-step splicing factors (SLU7, PRP17, PRP18, PRP22); Prp45 affects the stoichiometry of Prp22 in Cwc2-associated spliceosomal complexes, and is required for efficient splicing of non-consensus substrates at the second step.\",\n      \"method\": \"Synthetic lethality screen, spliceosome purification/co-IP, in vivo splicing assays with mutant substrates\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis plus biochemical spliceosomal complex analysis; multiple orthogonal methods\",\n      \"pmids\": [\"19016306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SNW1/SKIP associates with c-Myc and Menin (a subunit of the MLL1 H3K4me3 complex) and acts downstream of Tat:P-TEFb to recruit c-Myc and TRRAP to the HIV-1 promoter; SKIP is also recruited by the RNF20 H2B ubiquitin ligase to the basal HIV-1 promoter in a step bypassed by Tat. HIV-1 Tat transactivation requires c-Myc and Menin but not MLL1 or H3K4me3.\",\n      \"method\": \"Co-IP, RNAi-ChIP, reporter assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus RNAi-ChIP with defined pathway ordering; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19818711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SNW1/SKIP interacts with retinoic acid receptor (RAR) in a RA-dependent manner through a region overlapping the SIRT1 binding site; SKIP augments RAR transactivation by cooperating with SRC-1, while SIRT1 suppresses SKIP/SRC-1-enhanced RAR activity via its deacetylase activity; overexpression of SKIP impairs SIRT1 recruitment to the RARβ2 promoter.\",\n      \"method\": \"Binding assays, reporter assay, ChIP, RNAi, overexpression\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus functional assays with defined binding competition; single lab\",\n      \"pmids\": [\"19934264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Xenopus SKIP/SNW1 forms a ternary complex with LEF1 and HDAC1 and mediates transcriptional repression of Wnt target genes; SKIP is required for Wnt signaling-induced target gene transactivation; C-terminally truncated SKIP can stabilize β-catenin and enhance Wnt signaling; knockdown or overexpression of Skip in Xenopus reduces neural crest induction consistent with altered Wnt signaling.\",\n      \"method\": \"Co-IP, reporter assay, morpholino knockdown, overexpression in Xenopus embryos\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical complex demonstrated plus in vivo functional readout; single lab\",\n      \"pmids\": [\"20103590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The crystal structure of PPIL1 bound to cyclosporine A was determined at 1.15 Å; a 36-residue SKIP fragment (centered on an 8-residue epitope) suffices to bind PPIL1 in pull-down experiments; molecular docking reveals a proline residue of SKIP buried in a hydrophobic pocket of PPIL1, surrounded by hydrogen bonds.\",\n      \"method\": \"X-ray crystallography (SAD phasing), peptide array, pull-down, molecular docking\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus biochemical validation of binding epitope\",\n      \"pmids\": [\"20368803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SNW1 is required for neural crest specification in Xenopus and zebrafish; dorsally expressed SNW1 regulates a specific domain of BMP activity (phospho-Smad1) at the neural plate border at post-gastrula stages, acting upstream of BMP receptors; targeted BMP overexpression at the neural plate border restores neural crest formation in SNW1 morphants.\",\n      \"method\": \"Antisense morpholino knockdown in Xenopus and zebrafish, immunostaining for pSmad1, BMP reporter transgenic line, tissue explants, epistasis by BMP overexpression rescue\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two-organism genetic knockdown plus epistasis rescue with multiple orthogonal readouts\",\n      \"pmids\": [\"21358802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SNW1 and PRPF8 are essential for sister chromatid cohesion in human cells; transcriptome-wide analysis shows SNW1 depletion causes intron retention in a subset of pre-mRNAs including sororin (CDCA5) and APC2; reduced sororin levels destabilize cohesin on DNA, while reduced APC2 delays mitosis causing cohesion fatigue. Simultaneous expression of intron-less sororin and APC2 cDNAs restores cohesion in SNW1-depleted cells.\",\n      \"method\": \"RNAi depletion, RNA-seq transcriptome-wide splicing analysis, cohesin chromatin fractionation, cDNA rescue experiment, live-cell imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — transcriptome-wide splicing screen plus genetic rescue with intron-less cDNAs; rigorous causal chain established\",\n      \"pmids\": [\"25257309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SNW1 directly associates with spliceosome components EFTUD2 (Snu114) and SNRNP200 (Brr2) as shown by proteomics and biochemical assays; the SKIP region of SNW1 interacts with the N-terminus of EFTUD2 and two independent C-terminal regions of SNRNP200; depletion of SNW1 or EFTUD2 induces apoptosis in breast cancer cells.\",\n      \"method\": \"Proteomics, co-IP, domain mapping, RNAi, apoptosis assay\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding mapped to domains plus cellular phenotype; single lab\",\n      \"pmids\": [\"25450007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"UV cross-linking of purified yeast Bact spliceosomes shows that Prp45 (SNW1 ortholog) contacts nucleotides surrounding the branch-site upon step 1 catalysis; this interaction is enhanced relative to earlier spliceosomal complexes, indicating dynamic Prp45-pre-mRNA contacts during catalytic activation.\",\n      \"method\": \"UV cross-linking of purified spliceosomal complexes, site-specifically labeled pre-mRNA\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted purified spliceosomal complexes with site-specific labeling; direct contact demonstrated\",\n      \"pmids\": [\"26393790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNW1 detaches from its splicing complex (formed with SNRNP200 and SNRNP220) upon NF-κB activation, binds to the NF-κB heterodimer in the nucleus, and recruits p-TEFb to facilitate transcriptional elongation of NF-κB target genes (IL-8, TNF); SNW1 does not regulate cytoplasmic NF-κB pathway components.\",\n      \"method\": \"Genome-wide RNAi screen, co-IP, ChIP, RNAi knockdown with target gene expression readout\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide functional screen plus co-IP and ChIP defining pathway position; multiple orthogonal methods\",\n      \"pmids\": [\"30397075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNW1 acts as a novel RBPJ-interacting partner and regulates expression of Notch target genes in neuroblastoma; silencing RBPJ prevents SNW1-mediated Notch gene expression, placing SNW1 in the RBPJ-dependent Notch transcriptional complex.\",\n      \"method\": \"Co-IP, RNAi, reporter assay, gene expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus epistasis RNAi; single lab, single publication\",\n      \"pmids\": [\"30642633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Drosophila Bx42 (SNW1 ortholog) is essential for development of many tissues; RNAi-mediated knockdown of Bx42 produces phenotypes resembling Notch mutants, and target genes of Notch signaling (cut, E(spl)m8) are suppressed; the wing phenotype from Suppressor of Hairless overexpression is strongly enhanced by simultaneous Bx42 RNAi, placing Bx42/SNW1 in the Notch pathway downstream of Notch signaling.\",\n      \"method\": \"Inducible RNAi in Drosophila, genetic epistasis with Notch pathway components, in situ target gene expression\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo RNAi with genetic epistasis in Drosophila ortholog; supports conserved Notch pathway role\",\n      \"pmids\": [\"12204255\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNW1/SKIP is a conserved nuclear protein that functions dually as an essential spliceosome component (residing in the U5 snRNP/activated spliceosome and contacting pre-mRNA branch-site nucleotides via its SNW domain) and as a transcriptional coregulator that bridges multiple signaling pathways—including Notch/RBPJ, VDR, RAR, Wnt/β-catenin, NF-κB, and Ski/pRb—by competing with corepressor complexes (SMRT/HDAC) for contacts on DNA-binding proteins and by recruiting elongation factors (P-TEFb/CDK9) and chromatin regulators (c-Myc, Menin, TRRAP) to promoters; its spliceosomal role is mechanistically critical for mitosis because SNW1-dependent splicing of sororin and APC2 pre-mRNAs is required for sister chromatid cohesion, and its N-terminal disordered region mediates a disorder-to-order transition upon binding the cyclophilin PPIL1 to facilitate spliceosome activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SNW1 (also called SKIP/NCoA-62) is a conserved nuclear protein that functions both as an essential spliceosome component and as a transcriptional coregulator linking multiple signaling pathways to RNA polymerase II elongation. Within the spliceosome, SNW1 resides in the U5 snRNP and activated (Bact) complex, directly contacts pre-mRNA branch-site nucleotides via its SNW domain, interacts with core splicing factors PRPF8, SNRNP200/Brr2, and EFTUD2/Snu114, and undergoes a disorder-to-order transition upon binding the cyclophilin PPIL1 through an N-terminal disordered region [PMID:26393790, PMID:16595688, PMID:25450007, PMID:25257309]. Its spliceosomal activity is mechanistically required for sister chromatid cohesion, as SNW1 depletion causes intron retention in sororin and APC2 pre-mRNAs, and simultaneous expression of intron-less cDNAs rescues the cohesion defect [PMID:25257309]. As a transcriptional coregulator, SNW1 bridges DNA-bound factors—including VDR, RAR, Notch/RBPJ, LEF1/β-catenin, and NF-κB—to P-TEFb (CycT1:CDK9), c-Myc, Menin, and TRRAP, while competing with corepressor complexes (SMRT/HDAC) for binding on the same transcription factors [PMID:9632709, PMID:10713164, PMID:15905409, PMID:19818711, PMID:30397075, PMID:20103590].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"The initial identification of SNW1/SKIP as a nuclear coactivator for the vitamin D receptor and as a Ski oncoprotein-interacting partner established its dual identity as a transcriptional coregulator connected to nuclear receptor signaling and oncogenic pathways.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, and transient transcription assays in mammalian cells; independent nuclear localization by immunofluorescence\",\n      \"pmids\": [\"9632709\", \"9569025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which SKIP activates transcription (direct chromatin contact vs. bridging factor) was unknown\",\n        \"Whether SKIP had signaling-pathway-specific or general coactivator function was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstration that SNW1 binds both NotchIC and the corepressor SMRT in a mutually exclusive manner on CBF1 revealed a competitive switching mechanism by which SNW1 converts CBF1 from a repressor to an activator during Notch signaling, and extended its coregulator role to Notch and EBNA2 viral transactivation.\",\n      \"evidence\": \"GST pull-down competition, antisense loss-of-function blocking Notch-dependent muscle differentiation inhibition, reporter assays; EBNA2 binding mapped to a distinct SKIP region\",\n      \"pmids\": [\"10713164\", \"10644367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SKIP displaces SMRT or is displaced by SMRT in vivo was not kinetically resolved\",\n        \"Whether SKIP's splicing and transcriptional coregulator roles are functionally separable remained unknown\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Domain mapping established the SNW domain as the hub for transcriptional activation, VDR ternary complex formation with SRC coactivators, interactions with pRb, Ski, and HPV E7 oncoprotein, while the fission yeast ortholog linked SNW1 to the spliceosome via U2AF interaction and showed essentiality.\",\n      \"evidence\": \"Deletion/mutagenesis, ternary complex reconstitution, LXXLL peptide competition, yeast two-hybrid with U2AF23, gene deletion lethality in S. pombe\",\n      \"pmids\": [\"11522815\", \"11514567\", \"11414703\", \"12466551\", \"11753645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How SNW1 could simultaneously participate in splicing and transcription was mechanistically unclear\",\n        \"No structural information on the SNW domain itself was available\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Cross-species complementation (human SNW1 rescuing yeast PRP45 deletion) proved SNW1 is a bona fide splicing factor, while ChIP showed ligand-dependent recruitment to VDR-responsive promoters at a late step after VDR/SRC entry, and its association with U5 snRNP components Prp8 and the 200-kDa helicase was demonstrated.\",\n      \"evidence\": \"Genetic complementation in S. cerevisiae, ChIP at endogenous promoters, co-IP with U5 components, nuclear matrix fractionation\",\n      \"pmids\": [\"15194481\", \"15225769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SNW1's splicing and transcriptional roles are exerted on the same gene simultaneously was unknown\",\n        \"No direct RNA contact by SNW1 had been demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The discovery that SNW1 recruits P-TEFb (CycT1:CDK9) to promote transcriptional elongation—demonstrated in the context of HIV-1 Tat transactivation—provided the first mechanistic explanation for how SNW1 activates transcription: by coupling elongation factor recruitment to DNA-bound activators and to alternative splice-site selection.\",\n      \"evidence\": \"Co-IP from nuclear extracts, in vitro transcription elongation assay showing stimulation of elongation but not initiation, RNAi, ChIP, alternative splice-site assay\",\n      \"pmids\": [\"15905409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether P-TEFb recruitment by SNW1 occurs in non-HIV transcriptional contexts was not yet shown\",\n        \"How SNW1 coordinates elongation factor delivery with its spliceosomal activity was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"NMR structural determination of the PPIL1–SKIP complex revealed that a disordered N-terminal region of SKIP (residues 59–129) undergoes a disorder-to-order transition upon binding PPIL1, forming a hook-like structure; this interaction occurs at a site distinct from the PPIase active site, leaving PPIL1 catalytically competent within the activated spliceosome.\",\n      \"evidence\": \"NMR structure, SPR (Kd = 1.25 × 10⁻⁷ M), chemical shift perturbation, GST pull-down; confirmed by subsequent crystallography and peptide array\",\n      \"pmids\": [\"16595688\", \"20007319\", \"20368803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of PPIL1 isomerase activity while bound to SKIP was not identified\",\n        \"Whether the disorder-to-order transition is required for spliceosome catalytic activation was not tested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic interaction mapping of yeast Prp45 with NTC components and second-step splicing factors established SNW1 as critical for the second catalytic step, especially for non-consensus splice sites, while in mammalian cells SNW1 was shown to recruit c-Myc, Menin, and TRRAP downstream of P-TEFb to chromatin.\",\n      \"evidence\": \"Synthetic lethality screen with NTC/step-2 factors, spliceosome purification, co-IP/RNAi-ChIP for c-Myc/Menin/TRRAP at HIV-1 promoter\",\n      \"pmids\": [\"19016306\", \"19818711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether c-Myc/TRRAP recruitment is specific to viral promoters or general to SNW1-dependent genes was unknown\",\n        \"The structural basis for Prp45/SNW1 contacts at the catalytic center was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of SNW1 as a component of a LEF1–HDAC1 ternary complex that mediates both transcriptional repression and Wnt-induced activation of target genes extended SNW1's coregulator function to the Wnt/β-catenin pathway, with C-terminal truncation stabilizing β-catenin.\",\n      \"evidence\": \"Co-IP, reporter assay, morpholino knockdown and overexpression in Xenopus embryos affecting neural crest induction\",\n      \"pmids\": [\"20103590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SNW1 directly contacts β-catenin was not demonstrated\",\n        \"The relationship between SNW1's splicing role and its Wnt signaling role in neural crest was not dissected\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"In vivo epistasis experiments in Xenopus and zebrafish demonstrated that SNW1 regulates a specific domain of BMP signaling (phospho-Smad1) at the neural plate border required for neural crest specification, with BMP overexpression rescuing the SNW1 morphant phenotype.\",\n      \"evidence\": \"Morpholino knockdown in two organisms, pSmad1 immunostaining, BMP reporter transgenic, tissue explant assays, epistasis rescue\",\n      \"pmids\": [\"21358802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SNW1 regulates BMP signaling through its splicing or transcriptional coregulator function was not resolved\",\n        \"No direct interaction between SNW1 and BMP pathway components was shown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Transcriptome-wide splicing analysis after SNW1 depletion revealed that its spliceosomal role is specifically required for sister chromatid cohesion through splicing of sororin and APC2 pre-mRNAs; simultaneous expression of intron-less cDNAs rescued cohesion, establishing a causal chain from splicing to mitotic fidelity.\",\n      \"evidence\": \"RNAi, RNA-seq, cohesin chromatin fractionation, intron-less cDNA rescue, live-cell imaging; domain-mapped interactions with EFTUD2 and SNRNP200\",\n      \"pmids\": [\"25257309\", \"25450007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"What feature of sororin/APC2 introns makes them particularly SNW1-dependent was not determined\",\n        \"Whether other mitotic phenotypes arise from SNW1-dependent splicing of additional transcripts was unexplored\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"UV cross-linking of purified Bact spliceosomes demonstrated that yeast Prp45 directly contacts nucleotides surrounding the branch site during catalytic activation, providing the first evidence that SNW1 physically engages the pre-mRNA substrate at the catalytic center.\",\n      \"evidence\": \"UV cross-linking with site-specifically labeled pre-mRNA in purified Bact complexes\",\n      \"pmids\": [\"26393790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SNW1/Prp45 branch-site contact is catalytic or structural was not distinguished\",\n        \"No high-resolution structure of SNW1 within the intact spliceosome was available at this time\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A genome-wide RNAi screen identified SNW1 as an NF-κB transcriptional coactivator that detaches from its spliceosomal complex upon NF-κB activation to bind the NF-κB heterodimer and recruit P-TEFb for elongation of inflammatory target genes, providing a signal-dependent mechanism for toggling between splicing and transcription functions.\",\n      \"evidence\": \"Genome-wide RNAi screen, co-IP showing dissociation from SNRNP200/SNRNP220, ChIP at IL-8/TNF promoters\",\n      \"pmids\": [\"30397075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The signal that triggers SNW1 release from the spliceosomal complex upon NF-κB activation was not identified\",\n        \"Whether this switching mechanism operates for other signaling pathways (Notch, VDR) was not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A central unresolved question is how SNW1 partitions between its spliceosomal and transcriptional coregulator functions at the molecular level—whether these activities are temporally or spatially separated, and whether co-transcriptional splicing provides a unified context for both roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of human SNW1 in the spliceosomal context has been published in the timeline\",\n        \"Whether distinct SNW1 pools exist for splicing versus transcription has not been quantified\",\n        \"The full set of SNW1-dependent splice-sensitive transcripts beyond sororin/APC2 is not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [14, 15, 16, 25]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 5, 14, 18, 26]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 7, 20, 26]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 14, 18, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 8, 12, 26]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [8, 12, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0008953854\", \"supporting_discovery_ids\": [6, 13, 14, 15, 16, 17, 23, 25]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 13, 14, 15, 16, 17, 23, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 5, 14, 18, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 20, 22, 27]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"complexes\": [\n      \"U5 snRNP\",\n      \"Activated spliceosome (Bact)\",\n      \"P-TEFb (CycT1:CDK9)\"\n    ],\n    \"partners\": [\n      \"PPIL1\",\n      \"PRPF8\",\n      \"SNRNP200\",\n      \"EFTUD2\",\n      \"CDK9\",\n      \"RBPJ\",\n      \"VDR\",\n      \"SMRT\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}