{"gene":"SNIP1","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2000,"finding":"SNIP1 is a nuclear protein containing an NLS and FHA domain. Its C-terminus interacts with Smad1 and Smad2, while its N-terminus binds both Smad4 and the coactivator CBP/p300. Endogenous SNIP1 co-immunoprecipitates with Smad4 and CBP/p300 in NMuMg cells, and in vitro binding was confirmed. Overexpression of SNIP1 or its N-terminus inhibits Smad4/p300 complex formation and suppresses TGF-β-induced transcriptional activation, identifying SNIP1 as a nuclear inhibitor of CBP/p300-dependent TGF-β signaling.","method":"Yeast two-hybrid, mammalian co-immunoprecipitation (endogenous and overexpression), in vitro binding assay, reporter gene assay, Xenopus developmental rescue experiments","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP at endogenous levels, in vitro binding, multiple orthogonal functional assays, replicated in Xenopus model","pmids":["10887155"],"is_preprint":false},{"year":2001,"finding":"SNIP1 inhibits NF-κB transcriptional activity by competing with the NF-κB subunit RelA/p65 for binding to the C/H1 domain of CBP/p300. This inhibition is mediated by the N-terminal domain of SNIP1 and is selective: SNIP1 does not interfere with p53 (which binds other p300 domains) or CBP/p300-independent factors such as VP16. Immunohistochemistry showed co-localization of SNIP1 with RelA/p65 and p300 in specific tissues.","method":"Reporter gene assay, domain mapping (N-terminal SNIP1 constructs), competitive binding assay, immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — competitive binding mechanism established with domain mapping and multiple transcription factor controls, mechanistically orthogonal to prior TGF-β finding","pmids":["11567019"],"is_preprint":false},{"year":2004,"finding":"siRNA-mediated knockdown of SNIP1 in human cell lines causes G1 cell cycle arrest, reduced cell proliferation, and decreased cyclin D1 mRNA and protein levels. SNIP1 depletion inhibits cyclin D1 promoter activity in a manner dependent on an AP-1 binding site. SNIP1 itself is induced by serum stimulation prior to cyclin D1 expression. An interaction with BRG1, a component of the SWI/SNF chromatin remodelling complex, was detected. These effects were independent of p53 and Rb.","method":"siRNA knockdown, flow cytometry (cell cycle analysis), RT-PCR, reporter gene assay, co-immunoprecipitation (SNIP1-BRG1)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype, multiple orthogonal readouts (proliferation, cell cycle, mRNA, promoter activity), single lab","pmids":["15378006"],"is_preprint":false},{"year":2006,"finding":"SNIP1 associates with c-Myc via its C-terminus binding to the N-terminus of c-Myc, as identified by yeast two-hybrid and confirmed in mammalian cells. SNIP1 enhances c-Myc transcriptional activity by: (1) stabilizing c-Myc against proteasomal degradation, and (2) bridging the c-Myc/p300 complex. SNIP1 synergizes with c-Myc and H-Ras in oncogenic focus formation and anchorage-independent growth assays.","method":"Yeast two-hybrid, co-immunoprecipitation, proteasomal degradation assay, in vitro transformation/focus formation assay, soft agar colony assay, tissue array co-staining","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus mammalian Co-IP plus functional assays (proteasome protection, transformation), single lab with multiple orthogonal methods","pmids":["17157259"],"is_preprint":false},{"year":2007,"finding":"SNIP1 is required for ATR checkpoint kinase-dependent signaling in human U-2 OS cells: SNIP1 depletion impairs p53 induction in response to UV irradiation and selectively reduces phosphorylation of ATR targets including p53, Chk1, and H2AX. SNIP1 is also required for ATR-dependent functions of the p14(ARF) tumor suppressor, including p14(ARF)-mediated modulation of RelA(p65) NF-κB activity. These functions are independent of SNIP1's role in regulating cyclin D1.","method":"siRNA knockdown, immunoblot for phosphorylation of ATR substrates (p53, Chk1, H2AX), UV irradiation treatment, reporter gene assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean loss-of-function with phospho-substrate readouts, single lab, single paper","pmids":["17260016"],"is_preprint":false},{"year":2008,"finding":"The majority of nucleoplasmic SNIP1 resides in a complex (termed SNIP1/SkIP-associated RNA-processing complex, SSRC) containing SkIP, THRAP3, BCLAF1, and Pinin — proteins with roles in RNA processing and transcriptional regulation. SNIP1 does not primarily regulate cyclin D1 transcription but instead stabilizes cyclin D1 mRNA through a cotranscriptional or post-transcriptional mechanism. The SSRC complex is coordinately recruited to the 3' end of the cyclin D1 gene and to cyclin D1 RNA. SNIP1 is required for recruitment of the RNA processing factor U2AF65 to both the cyclin D1 gene and RNA.","method":"Co-immunoprecipitation (complex isolation), RNA co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, mRNA stability assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — complex defined by Co-IP, ChIP and RNA-IP provide orthogonal evidence for co-recruitment, functional U2AF65 recruitment established, single lab","pmids":["18794151"],"is_preprint":false},{"year":2008,"finding":"The yeast ortholog of SNIP1, Pml1, is a component of the RES splicing complex. X-ray crystallography revealed Pml1 consists mainly of an FHA domain. Mutation of the putative phosphothreonine-binding pocket of Pml1's FHA domain does not affect pre-mRNA splicing. Pml1 integrates into the RES complex by binding Snu17, which itself contacts Bud13; mutagenesis and truncation studies demarcated the binding sites within these subunits.","method":"X-ray crystallography, recombinant complex reconstitution, truncation and mutagenesis, alternative splice-site choice assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis plus reconstitution of the complex, single lab but multiple orthogonal methods","pmids":["19033360"],"is_preprint":false},{"year":2011,"finding":"Overexpression of SNIP1-EGFP in HeLa cells shows nuclear localization with characteristic subnuclear distribution in speckles or larger discrete nuclear bodies. Overexpression of SNIP1 in HEK293 or H1299 cells strongly activates the HSE (heat shock element) signaling pathway reporter, and SNIP1 selectively regulates transcription of HSP70A1A and HSP27.","method":"Fluorescence microscopy (EGFP fusion), reporter gene assay (HSE-luciferase), RT-PCR (HSP70A1A, HSP27)","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression reporter assay only, single lab, single method per observation, no endogenous protein studies","pmids":["22020748"],"is_preprint":false},{"year":2018,"finding":"SNIP1 physically interacts with TET2 DNA dioxygenase and bridges TET2 to bind the transcription factor c-MYC, as identified by mammalian two-hybrid screen and confirmed by co-immunoprecipitation. SNIP1 recruits TET2 to promoters of c-MYC target genes including those involved in DNA damage response. TET2-mediated protection from DNA damage-induced apoptosis requires SNIP1.","method":"Mammalian two-hybrid screen, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, apoptosis assays (DNA damage)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two-hybrid plus reciprocal Co-IP plus ChIP establish ternary complex and genomic recruitment, functional epistasis (TET2 protection requires SNIP1), single lab","pmids":["30404004"],"is_preprint":false},{"year":2021,"finding":"SNIP1 inhibits ubiquitination and degradation of c-Myc protein. The lncRNA AFAP1-AS1 interacts with SNIP1 (identified by RNA pull-down and mass spectrometry), and this interaction promotes stabilization of c-Myc, which in turn upregulates ZEB1, ZEB2, and SNAIL to enhance EMT and lung cancer metastasis.","method":"RNA pull-down, mass spectrometry, co-immunoprecipitation, ubiquitination assay, in vivo lung metastasis model","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNA pulldown with MS identification, ubiquitination assay, in vivo model; single lab, mechanistic data on SNIP1 is supportive but SNIP1 mechanism is secondary to lncRNA study","pmids":["34168109"],"is_preprint":false},{"year":2021,"finding":"A biallelic SNIP1 variant (p.Glu366Gly) in the Amish community causes an autosomal recessive neurodevelopmental disorder. Gene transcript studies in affected individuals defined altered expression profiles of molecules with neurodevelopmental roles, confirming SNIP1's role in human spliceosome function and TGF-β signal transduction in vivo.","method":"Human genetic study (biallelic variant identification), gene expression profiling in affected individuals","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — human loss-of-function genetics with transcriptome readout; confirms spliceosome/TGF-β roles but molecular mechanism detail limited to expression changes","pmids":["34570759"],"is_preprint":false},{"year":2022,"finding":"SNIP1 is a non-histone substrate of the lysine methyltransferase KMT5A. KMT5A mono-methylates SNIP1 at K301. This methylation releases the histone acetyltransferase KAT2A from SNIP1, promotes interaction of c-MYC with KAT2A, and recruits the c-MYC/KAT2A complex to promoters of c-MYC targets. This cascade inhibits the Hippo kinase pathway and transcriptionally activates MARK4 to enhance TNBC metastasis.","method":"In vitro methylation assay, mass spectrometry (methylation site identification), co-immunoprecipitation, ChIP, site-directed mutagenesis (K301), xenograft mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro methylation assay with site-specific mutagenesis, Co-IP, ChIP, and in vivo validation; multiple orthogonal methods, single lab","pmids":["35449131"],"is_preprint":false},{"year":2023,"finding":"SNIP1 is required for recruitment of PRC2 to target gene loci and for H3K27me3 turnover in neural progenitor cells. SNIP1-depleted mouse brains exhibit dysplasia with robust caspase 9-dependent apoptosis. Depletion of PRC2 is sufficient to reduce apoptosis and brain dysplasia in SNIP1-depleted brains, establishing a genetic epistasis where SNIP1 normally restricts PRC2 activity at survival/neurogenesis gene loci.","method":"Conditional knockout (in vivo), ChIP-seq (PRC2/H3K27me3 occupancy), epistasis (double depletion of SNIP1 and PRC2), caspase 9 apoptosis assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with ChIP-seq and genetic epistasis (PRC2 rescue of SNIP1-KO phenotype), multiple orthogonal methods, single lab","pmids":["37553330"],"is_preprint":false},{"year":2023,"finding":"MKRN1 (an E3 ubiquitin ligase) ubiquitinates and degrades SNIP1. Loss of SNIP1 protein de-represses TGF-β signaling, promoting EMT in colorectal cancer cells. Intestinal conditional knockout of MKRN1 in mice reduces intestinal lesions and metastatic liver microlesions, consistent with the MKRN1/SNIP1/TGF-β axis driving metastasis.","method":"Ubiquitination assay, quantitative proteomics, ubiquitination modification omics, co-immunoprecipitation, conditional knockout mouse model, in vitro proliferation/invasion assays","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay with proteomics, in vivo conditional KO, epistasis (SNIP1 rescue of MKRN1-driven EMT), multiple orthogonal methods","pmids":["37620897"],"is_preprint":false},{"year":2023,"finding":"SNIP1 forms a ternary complex with c-MYC and lncRNA BCAN-AS1 (via SNIP1 recognizing N6-methyladenosine modification on BCAN-AS1). This complex blocks SKP2-mediated ubiquitination and degradation of c-MYC, thereby stabilizing c-MYC protein in pancreatic cancer cells.","method":"RNA pull-down, co-immunoprecipitation, m6A modification detection, ubiquitination assay, mass spectrometry","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNA pulldown plus Co-IP plus ubiquitination assay; SNIP1 role as m6A reader is a new claim supported by single lab","pmids":["37726400"],"is_preprint":false},{"year":2024,"finding":"SNIP1 SUMOylation is regulated by SENP1 deSUMOylation activity. The lncRNA MSC-AS1 binds SENP1 and blocks its deSUMOylation of SNIP1, thereby inhibiting SNIP1 activity and promoting EMT and intestinal fibrosis in Crohn's disease.","method":"Co-immunoprecipitation (MSC-AS1/SENP1/SNIP1), SUMOylation assay, siRNA knockdown, in vivo mouse model (TNBS-induced colitis)","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — SUMOylation assay and Co-IP support the mechanism, single lab, SNIP1 SUMOylation as novel PTM is a new claim","pmids":["38309408"],"is_preprint":false},{"year":2025,"finding":"TET2 forms an inhibitory complex with HDAC1/2 and SNIP1 to suppress RUNX2 transcription at its P2 promoter in vascular smooth muscle cells; this function is independent of TET2's catalytic demethylase activity. SNIP1 is indispensable for TET2's interaction with HDAC1/2 (i.e., SNIP1 bridges TET2 to HDAC1/2), and knockdown of SNIP1 accelerates vascular calcification in mice. TET2 deacetylates H3K27ac at the RUNX2 P2 promoter through this complex.","method":"Co-immunoprecipitation (TET2/HDAC1/2/SNIP1 complex), enzymatic loss-of-function mutation of TET2, ChIP (H3K27ac), siRNA knockdown, in vivo mouse models (vitamin D3 and CKD diet)","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of ternary complex, catalytic mutant controls, ChIP, and in vivo epistasis (SNIP1 KD accelerates VC), multiple orthogonal methods, single lab","pmids":["40067382"],"is_preprint":false},{"year":2026,"finding":"The FHA domain of SNIP1 directly recognizes phosphorylated SF3B1 (P-SF3B1), phosphorylated by CDK11 during spliceosome activation. This interaction promotes recruitment of the RES (retention and splicing) complex during spliceosome activation. Acute SNIP1 depletion disrupts RES complex incorporation into spliceosomes, causes widespread splicing defects, promotes hyperphosphorylation of SF3B1 by CDK11, and impairs cell viability. The neurodevelopmental disorder-associated SNIP1 E366G variant impairs P-SF3B1 binding, pre-mRNA splicing, and cell viability.","method":"Quantitative proteomics of chromatin-associated spliceosomes, iCLIP-seq, CDK11 inhibitor (OTS964) treatment, FHA domain mutagenesis (including E366G disease variant), acute SNIP1 depletion, splicing assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative proteomics plus iCLIP-seq plus domain mutagenesis plus disease variant functional validation; multiple orthogonal methods, single study","pmids":["41904131"],"is_preprint":false}],"current_model":"SNIP1 is a nuclear FHA domain-containing protein that functions as a multi-pathway transcriptional regulator: its N-terminus competitively inhibits TGF-β (Smad4) and NF-κB (RelA/p65) signaling by blocking their access to the C/H1 domain of CBP/p300, while its C-terminus interacts with c-MYC to stabilize it against proteasomal/SKP2-mediated degradation and bridge it to p300/KAT2A coactivators; SNIP1 also resides in the SSRC RNA-processing complex (with SkIP, THRAP3, BCLAF1, Pinin) that recruits U2AF65 to stabilize cyclin D1 mRNA, and in the spliceosome where its FHA domain reads phospho-SF3B1 (phosphorylated by CDK11) to recruit the RES complex; SNIP1 is post-translationally regulated by KMT5A-mediated K301 mono-methylation, MKRN1-mediated ubiquitin-proteasomal degradation, and SENP1-regulated SUMOylation; and SNIP1 acts as a scaffold bridging TET2 to HDAC1/2 and c-MYC at specific gene promoters, with loss-of-function in the Amish E366G variant causing autosomal recessive neurodevelopmental disease."},"narrative":{"mechanistic_narrative":"SNIP1 is a nuclear FHA-domain protein that integrates transcriptional control, mRNA processing, and chromatin regulation, originally identified as a competitive inhibitor of CBP/p300-dependent signaling [PMID:10887155]. Through its N-terminus it binds the C/H1 domain of CBP/p300 and blocks coactivator access for both Smad4-dependent TGF-β signaling and the NF-κB subunit RelA/p65, while sparing p300 targets that engage other domains [PMID:10887155, PMID:11567019]. Conversely, its C-terminus binds c-MYC, stabilizing the oncoprotein against proteasomal and SKP2-mediated ubiquitination and bridging it to p300/KAT2A coactivators to enhance c-MYC-driven transcription and oncogenic transformation [PMID:17157259, PMID:37726400]. SNIP1 also acts as a chromatin scaffold, bridging the dioxygenase TET2 to c-MYC target promoters and to HDAC1/2 to repress specific genes, and restricting PRC2 recruitment and H3K27me3 turnover during neurogenesis [PMID:30404004, PMID:37553330, PMID:40067382]. In RNA processing, SNIP1 is a core subunit of the SSRC complex (with SkIP, THRAP3, BCLAF1, Pinin) that recruits U2AF65 to stabilize cyclin D1 mRNA, and its FHA domain reads CDK11-phosphorylated SF3B1 to recruit the RES complex during spliceosome activation [PMID:18794151, PMID:41904131]. SNIP1 abundance and activity are tuned by KMT5A-mediated K301 mono-methylation, MKRN1-mediated ubiquitin-proteasomal degradation, and SENP1-regulated SUMOylation [PMID:35449131, PMID:37620897, PMID:38309408]. A biallelic E366G variant in the FHA domain causes an autosomal recessive neurodevelopmental disorder by impairing phospho-SF3B1 binding and pre-mRNA splicing [PMID:34570759, PMID:41904131].","teleology":[{"year":2000,"claim":"Established the founding mechanism: how a nuclear factor could selectively dampen TGF-β transcriptional output, by showing SNIP1 sequesters CBP/p300 from Smad4.","evidence":"Yeast two-hybrid, endogenous reciprocal Co-IP, in vitro binding, reporter assays and Xenopus rescue in NMuMg cells","pmids":["10887155"],"confidence":"High","gaps":["Did not address whether the same competition operates on other p300-dependent pathways","No structural basis for the N-terminus/CBP interaction"]},{"year":2001,"claim":"Generalized the competitive-inhibition model to a second pathway, showing SNIP1 also blocks RelA/p65 access to the C/H1 domain of CBP/p300, defining it as a selective coactivator-sequestering regulator rather than a TGF-β-specific factor.","evidence":"Domain mapping, competitive binding assays, reporter assays with transcription-factor controls, immunohistochemistry","pmids":["11567019"],"confidence":"High","gaps":["Selectivity rules for which p300-binding factors are inhibited not fully defined","In vivo relevance to NF-κB-driven programs untested"]},{"year":2004,"claim":"Connected SNIP1 to cell-cycle progression, showing its loss arrests cells in G1 with loss of cyclin D1 and linking it to SWI/SNF (BRG1) chromatin remodeling.","evidence":"siRNA knockdown, flow cytometry, RT-PCR, cyclin D1 promoter reporter, Co-IP with BRG1 in human cell lines","pmids":["15378006"],"confidence":"High","gaps":["Whether cyclin D1 control was transcriptional vs post-transcriptional was unresolved (later revised)","BRG1 interaction not functionally dissected"]},{"year":2006,"claim":"Reframed SNIP1 as a pro-oncogenic c-MYC cofactor, showing its C-terminus stabilizes c-MYC against degradation and bridges c-MYC to p300, cooperating in transformation.","evidence":"Yeast two-hybrid, Co-IP, proteasomal degradation assay, focus formation and soft-agar assays, tissue arrays","pmids":["17157259"],"confidence":"High","gaps":["E3 ligase opposed by SNIP1 not identified at this stage","Mechanism of degradation protection unresolved"]},{"year":2007,"claim":"Linked SNIP1 to genome-stability signaling, showing it is required for ATR-dependent phosphorylation of p53, Chk1 and H2AX and for p14ARF function, independent of its cyclin D1 role.","evidence":"siRNA knockdown, phospho-substrate immunoblots after UV, reporter assays in U-2 OS cells","pmids":["17260016"],"confidence":"Medium","gaps":["Direct molecular role of SNIP1 in the ATR pathway not defined","Single lab, not independently confirmed"]},{"year":2008,"claim":"Revised the cyclin D1 mechanism: rather than acting at the promoter, SNIP1 stabilizes cyclin D1 mRNA as part of the SSRC RNA-processing complex that recruits U2AF65, establishing a co/post-transcriptional function.","evidence":"Co-IP complex isolation, RNA-IP, ChIP, siRNA, mRNA stability assays","pmids":["18794151"],"confidence":"High","gaps":["Generality of SSRC-stabilized transcripts beyond cyclin D1 unknown","How SSRC selects target RNAs not defined"]},{"year":2008,"claim":"Provided the structural and complex-context basis for SNIP1's FHA domain via its yeast ortholog Pml1, showing it is a near-pure FHA domain that integrates into the RES splicing complex through Snu17/Bud13 contacts.","evidence":"X-ray crystallography, recombinant RES reconstitution, truncation/mutagenesis, splice-site assays in yeast","pmids":["19033360"],"confidence":"High","gaps":["FHA phosphopeptide-binding pocket appeared dispensable in yeast, leaving its functional role open (resolved later in human)","Human RES architecture inferred from yeast"]},{"year":2011,"claim":"Reported SNIP1 subnuclear speckle localization and a candidate role in activating heat-shock gene transcription.","evidence":"EGFP fusion microscopy, HSE-luciferase reporter, RT-PCR for HSP70A1A/HSP27 in HeLa/HEK293/H1299 (overexpression)","pmids":["22020748"],"confidence":"Low","gaps":["Overexpression reporter only, no endogenous validation","Mechanism of HSE activation undefined"]},{"year":2018,"claim":"Defined SNIP1 as a chromatin scaffold bridging TET2 to c-MYC target promoters, coupling it to DNA-damage-response gene regulation and apoptosis protection.","evidence":"Mammalian two-hybrid, reciprocal Co-IP, ChIP, siRNA, DNA-damage apoptosis assays","pmids":["30404004"],"confidence":"High","gaps":["Whether TET2 catalytic activity is required at these loci not addressed here","Genome-wide scope of the ternary complex limited"]},{"year":2021,"claim":"Showed an lncRNA-directed route to c-MYC stabilization, with AFAP1-AS1 binding SNIP1 to suppress c-MYC ubiquitination and drive EMT/metastasis.","evidence":"RNA pull-down/MS, Co-IP, ubiquitination assay, in vivo lung metastasis model","pmids":["34168109"],"confidence":"Medium","gaps":["SNIP1 mechanism secondary to the lncRNA focus","Direct lncRNA-SNIP1 interface not mapped"]},{"year":2021,"claim":"Provided human in vivo proof of essentiality: a biallelic SNIP1 E366G variant causes autosomal recessive neurodevelopmental disease with altered neurodevelopmental gene expression.","evidence":"Human genetic study and transcriptome profiling in affected Amish individuals","pmids":["34570759"],"confidence":"Medium","gaps":["Molecular consequence of E366G not resolved at this stage (later linked to phospho-SF3B1 binding)","Mechanism limited to expression changes"]},{"year":2022,"claim":"Identified a methylation switch controlling SNIP1 cofactor partner choice, with KMT5A mono-methylating K301 to release KAT2A and route the c-MYC/KAT2A complex to pro-metastatic targets.","evidence":"In vitro methylation, MS site mapping, K301 mutagenesis, Co-IP, ChIP, xenograft model","pmids":["35449131"],"confidence":"High","gaps":["Demethylase reversing K301 not identified","Breadth of methylation-controlled target genes limited"]},{"year":2023,"claim":"Established SNIP1 as a restrictor of PRC2 activity in neurogenesis, with its loss causing PRC2-dependent caspase-9 apoptosis and brain dysplasia rescued by PRC2 depletion.","evidence":"Conditional knockout, ChIP-seq for PRC2/H3K27me3, genetic epistasis, apoptosis assays in mouse brain","pmids":["37553330"],"confidence":"High","gaps":["How SNIP1 mechanistically limits PRC2 occupancy unresolved","Link to splicing role not integrated"]},{"year":2023,"claim":"Defined a degradation arm regulating SNIP1, with MKRN1 ubiquitinating SNIP1 to de-repress TGF-β signaling and promote colorectal cancer EMT/metastasis.","evidence":"Ubiquitination assay, quantitative/ubiquitination proteomics, Co-IP, conditional KO mouse, invasion assays","pmids":["37620897"],"confidence":"High","gaps":["Signals controlling MKRN1 activity toward SNIP1 unknown","Ubiquitination site on SNIP1 not mapped"]},{"year":2023,"claim":"Extended SNIP1's c-MYC-stabilizing function to an m6A-reader role, forming a ternary complex with c-MYC and m6A-modified BCAN-AS1 to block SKP2-mediated c-MYC degradation.","evidence":"RNA pull-down, Co-IP, m6A detection, ubiquitination assay, MS in pancreatic cancer cells","pmids":["37726400"],"confidence":"Medium","gaps":["m6A-reader claim from a single lab","Structural basis of m6A recognition by SNIP1 unknown"]},{"year":2024,"claim":"Added SUMOylation as a third PTM layer, with SENP1 deSUMOylating SNIP1 and MSC-AS1 sequestering SENP1 to inhibit SNIP1 and promote EMT/intestinal fibrosis.","evidence":"Co-IP, SUMOylation assay, siRNA, TNBS colitis mouse model","pmids":["38309408"],"confidence":"Medium","gaps":["SNIP1 SUMOylation site and functional consequence not fully defined","Novel PTM claim from single lab"]},{"year":2025,"claim":"Generalized the TET2 scaffold function to repressive chromatin, showing SNIP1 is indispensable for bridging TET2 to HDAC1/2 to deacetylate H3K27ac and silence RUNX2, with SNIP1 loss accelerating vascular calcification.","evidence":"Co-IP of ternary complex, TET2 catalytic-dead mutant, ChIP for H3K27ac, siRNA, in vivo calcification models","pmids":["40067382"],"confidence":"High","gaps":["How SNIP1 selects TET2/HDAC target loci unknown","Relationship to SNIP1's c-MYC/TET2 role not unified"]},{"year":2026,"claim":"Resolved the long-open FHA function and the disease mechanism, showing the FHA domain reads CDK11-phosphorylated SF3B1 to recruit the RES complex during spliceosome activation, with the E366G variant abrogating this binding.","evidence":"Quantitative spliceosome proteomics, iCLIP-seq, CDK11 inhibition, FHA/E366G mutagenesis, acute depletion and splicing assays","pmids":["41904131"],"confidence":"High","gaps":["How splicing role mechanistically connects to SNIP1's transcriptional/chromatin functions","Full set of SNIP1-dependent splicing events not catalogued"]},{"year":null,"claim":"It remains unresolved how SNIP1's distinct activities — CBP/p300 sequestration, c-MYC stabilization, TET2/PRC2 chromatin scaffolding, and phospho-SF3B1/RES-dependent splicing — are coordinated within one protein and which is primary to its essential and neurodevelopmental roles.","evidence":"","pmids":[],"confidence":"High","gaps":["No integrated model linking the splicing and transcriptional/chromatin functions","PTM crosstalk (methylation, ubiquitination, SUMOylation) governing function-switching not mapped","Structure of human SNIP1 in complex with partners beyond the FHA domain lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,14]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,9,14]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[17]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,7]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5,17]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[8,12,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,13,15]}],"complexes":["SSRC complex","RES complex"],"partners":["CBP/P300","SMAD4","RELA","MYC","TET2","HDAC1","SF3B1","KAT2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TAD8","full_name":"Smad nuclear-interacting protein 1","aliases":["FHA domain-containing protein SNIP1"],"length_aa":396,"mass_kda":45.8,"function":"Required for pre-mRNA splicing as component of the spliceosome (PubMed:29360106). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). Down-regulates NF-kappa-B signaling by competing with RELA for CREBBP/EP300 binding. Involved in the microRNA (miRNA) biogenesis. 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","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8TAD8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SNIP1","classification":"Common Essential","n_dependent_lines":1029,"n_total_lines":1208,"dependency_fraction":0.8518211920529801},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SNRPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SNIP1","total_profiled":1310},"omim":[{"mim_id":"614501","title":"NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, CRANIOFACIAL ABNORMALITIES, AND SEIZURES; NEDHCS","url":"https://www.omim.org/entry/614501"},{"mim_id":"608241","title":"SMAD NUCLEAR INTERACTING PROTEIN 1; SNIP1","url":"https://www.omim.org/entry/608241"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNIP1"},"hgnc":{"alias_symbol":["PML1"],"prev_symbol":[]},"alphafold":{"accession":"Q8TAD8","domains":[{"cath_id":"2.60.200.20","chopping":"246-374","consensus_level":"high","plddt":93.8245,"start":246,"end":374}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAD8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAD8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAD8-F1-predicted_aligned_error_v6.png","plddt_mean":66.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNIP1","jax_strain_url":"https://www.jax.org/strain/search?query=SNIP1"},"sequence":{"accession":"Q8TAD8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TAD8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TAD8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAD8"}},"corpus_meta":[{"pmid":"10887155","id":"PMC_10887155","title":"A novel smad nuclear interacting 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Part A, Ecological genetics and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25678477","citation_count":7,"is_preprint":false},{"pmid":"17189184","id":"PMC_17189184","title":"SNIP1: Myc's new helper in transcriptional activation.","date":"2006","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/17189184","citation_count":6,"is_preprint":false},{"pmid":"40067382","id":"PMC_40067382","title":"TET2 suppresses vascular calcification by forming an inhibitory complex with HDAC1/2 and SNIP1 independent of demethylation.","date":"2025","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/40067382","citation_count":5,"is_preprint":false},{"pmid":"32902407","id":"PMC_32902407","title":"Modafinil ameliorated pancreatic injury and inflammation through upregulating SNIP1.","date":"2020","source":"General physiology and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/32902407","citation_count":5,"is_preprint":false},{"pmid":"37553330","id":"PMC_37553330","title":"SNIP1 and PRC2 coordinate cell fates of neural progenitors during brain development.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37553330","citation_count":4,"is_preprint":false},{"pmid":"39503492","id":"PMC_39503492","title":"Acidification-based mineral weathering mechanism involves a glucose/methanol/choline oxidoreductase in Caballeronia mineralivorans PML1(12).","date":"2024","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39503492","citation_count":4,"is_preprint":false},{"pmid":"38304835","id":"PMC_38304835","title":"The clinical utilization of SNIP1 and its pathophysiological mechanisms in disease.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38304835","citation_count":2,"is_preprint":false},{"pmid":"37720048","id":"PMC_37720048","title":"The PML1-WDR5 axis regulates H3K4me3 marks and promotes stemness of estrogen receptor-positive breast cancer.","date":"2023","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/37720048","citation_count":2,"is_preprint":false},{"pmid":"23897559","id":"PMC_23897559","title":"Silencing of the Smad nuclear interacting protein 1 (SNIP1) by siRNA inhibits proliferation and induces apoptosis in pituitary adenoma cells.","date":"2013","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23897559","citation_count":1,"is_preprint":false},{"pmid":"40463196","id":"PMC_40463196","title":"PML1-Mediated Feedforward Loop Through PI3K and MAPK Axes Drives Endocrine Resistance.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40463196","citation_count":0,"is_preprint":false},{"pmid":"41904131","id":"PMC_41904131","title":"Phosphorylation of SF3B1 by CDK11 orchestrates spliceosome activation via SNIP1-dependent RES complex recruitment.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41904131","citation_count":0,"is_preprint":false},{"pmid":"42260104","id":"PMC_42260104","title":"A PML1-CCL5-PI3K/MAPK feedback loop governs survival of endocrine-resistant breast cancer cells.","date":"2026","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/42260104","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21343,"output_tokens":6194,"usd":0.078469,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14009,"output_tokens":5755,"usd":0.10696,"stage2_stop_reason":"end_turn"},"total_usd":0.185429,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully classify each paper before extracting discoveries.\n\n**Classification notes:**\n- Papers [1]-[8], [10]-[11], [13], [17]-[25], [27], [30]-[32], [34], [36], [38]: About SNIP1 (Smad Nuclear Interacting Protein 1) — the canonical query gene. INCLUDE.\n- Papers [14], [15], [16], [35], [37], [39]: Need careful review.\n  - [14], [35], [37], [39]: About PML1 (Promyelocytic Leukemia isoform 1) — this is a different gene (PML gene isoform), NOT SNIP1. The HGNC alias \"PML1\" listed in the query refers to an older alias for SNIP1, but papers [14], [35], [37], [39] clearly describe the PML gene isoform in breast cancer, which is a completely different protein. EXCLUDE as alias collision.\n  - [16]: Same — PML gene isoform. EXCLUDE.\n  - [15]: SnIP1 in barley/plants interacting with SnRK1 — plant protein, symbol collision. EXCLUDE.\n  - [9]: Yeast Pml1 — this is the yeast ortholog of SNIP1 (RES complex, FHA domain, splicing). INCLUDE as ortholog.\n  - [12]: Lactobacillus brevis PML1 — bacterial strain name. EXCLUDE.\n  - [26], [33]: Caballeronia mineralivorans PML1(12) — bacterial strain name. EXCLUDE.\n  - [28]: Crayfish SNIP1 ortholog — INCLUDE.\n  - [29]: Commentary on SNIP1/Myc paper. INCLUDE if mechanistic.\n  - [19]: lncRNA H19/miR-29a-3p/SNIP1/c-myc axis — involves SNIP1 mechanistically. INCLUDE.\n  - [3]: AFAP1-AS1/SNIP1 — lncRNA study but SNIP1 mechanism is described. INCLUDE.\n  - [13]: BCAN-AS1/SNIP1/c-Myc — SNIP1 mechanism described. INCLUDE.\n  - [25]: MSC-AS1/SENP1/SNIP1 SUMOylation. INCLUDE.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"SNIP1 is a nuclear protein containing an NLS and FHA domain. Its C-terminus interacts with Smad1 and Smad2, while its N-terminus binds both Smad4 and the coactivator CBP/p300. Endogenous SNIP1 co-immunoprecipitates with Smad4 and CBP/p300 in NMuMg cells, and in vitro binding was confirmed. Overexpression of SNIP1 or its N-terminus inhibits Smad4/p300 complex formation and suppresses TGF-β-induced transcriptional activation, identifying SNIP1 as a nuclear inhibitor of CBP/p300-dependent TGF-β signaling.\",\n      \"method\": \"Yeast two-hybrid, mammalian co-immunoprecipitation (endogenous and overexpression), in vitro binding assay, reporter gene assay, Xenopus developmental rescue experiments\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP at endogenous levels, in vitro binding, multiple orthogonal functional assays, replicated in Xenopus model\",\n      \"pmids\": [\"10887155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SNIP1 inhibits NF-κB transcriptional activity by competing with the NF-κB subunit RelA/p65 for binding to the C/H1 domain of CBP/p300. This inhibition is mediated by the N-terminal domain of SNIP1 and is selective: SNIP1 does not interfere with p53 (which binds other p300 domains) or CBP/p300-independent factors such as VP16. Immunohistochemistry showed co-localization of SNIP1 with RelA/p65 and p300 in specific tissues.\",\n      \"method\": \"Reporter gene assay, domain mapping (N-terminal SNIP1 constructs), competitive binding assay, immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — competitive binding mechanism established with domain mapping and multiple transcription factor controls, mechanistically orthogonal to prior TGF-β finding\",\n      \"pmids\": [\"11567019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"siRNA-mediated knockdown of SNIP1 in human cell lines causes G1 cell cycle arrest, reduced cell proliferation, and decreased cyclin D1 mRNA and protein levels. SNIP1 depletion inhibits cyclin D1 promoter activity in a manner dependent on an AP-1 binding site. SNIP1 itself is induced by serum stimulation prior to cyclin D1 expression. An interaction with BRG1, a component of the SWI/SNF chromatin remodelling complex, was detected. These effects were independent of p53 and Rb.\",\n      \"method\": \"siRNA knockdown, flow cytometry (cell cycle analysis), RT-PCR, reporter gene assay, co-immunoprecipitation (SNIP1-BRG1)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype, multiple orthogonal readouts (proliferation, cell cycle, mRNA, promoter activity), single lab\",\n      \"pmids\": [\"15378006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SNIP1 associates with c-Myc via its C-terminus binding to the N-terminus of c-Myc, as identified by yeast two-hybrid and confirmed in mammalian cells. SNIP1 enhances c-Myc transcriptional activity by: (1) stabilizing c-Myc against proteasomal degradation, and (2) bridging the c-Myc/p300 complex. SNIP1 synergizes with c-Myc and H-Ras in oncogenic focus formation and anchorage-independent growth assays.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, proteasomal degradation assay, in vitro transformation/focus formation assay, soft agar colony assay, tissue array co-staining\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus mammalian Co-IP plus functional assays (proteasome protection, transformation), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17157259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SNIP1 is required for ATR checkpoint kinase-dependent signaling in human U-2 OS cells: SNIP1 depletion impairs p53 induction in response to UV irradiation and selectively reduces phosphorylation of ATR targets including p53, Chk1, and H2AX. SNIP1 is also required for ATR-dependent functions of the p14(ARF) tumor suppressor, including p14(ARF)-mediated modulation of RelA(p65) NF-κB activity. These functions are independent of SNIP1's role in regulating cyclin D1.\",\n      \"method\": \"siRNA knockdown, immunoblot for phosphorylation of ATR substrates (p53, Chk1, H2AX), UV irradiation treatment, reporter gene assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean loss-of-function with phospho-substrate readouts, single lab, single paper\",\n      \"pmids\": [\"17260016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The majority of nucleoplasmic SNIP1 resides in a complex (termed SNIP1/SkIP-associated RNA-processing complex, SSRC) containing SkIP, THRAP3, BCLAF1, and Pinin — proteins with roles in RNA processing and transcriptional regulation. SNIP1 does not primarily regulate cyclin D1 transcription but instead stabilizes cyclin D1 mRNA through a cotranscriptional or post-transcriptional mechanism. The SSRC complex is coordinately recruited to the 3' end of the cyclin D1 gene and to cyclin D1 RNA. SNIP1 is required for recruitment of the RNA processing factor U2AF65 to both the cyclin D1 gene and RNA.\",\n      \"method\": \"Co-immunoprecipitation (complex isolation), RNA co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, mRNA stability assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex defined by Co-IP, ChIP and RNA-IP provide orthogonal evidence for co-recruitment, functional U2AF65 recruitment established, single lab\",\n      \"pmids\": [\"18794151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The yeast ortholog of SNIP1, Pml1, is a component of the RES splicing complex. X-ray crystallography revealed Pml1 consists mainly of an FHA domain. Mutation of the putative phosphothreonine-binding pocket of Pml1's FHA domain does not affect pre-mRNA splicing. Pml1 integrates into the RES complex by binding Snu17, which itself contacts Bud13; mutagenesis and truncation studies demarcated the binding sites within these subunits.\",\n      \"method\": \"X-ray crystallography, recombinant complex reconstitution, truncation and mutagenesis, alternative splice-site choice assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis plus reconstitution of the complex, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19033360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of SNIP1-EGFP in HeLa cells shows nuclear localization with characteristic subnuclear distribution in speckles or larger discrete nuclear bodies. Overexpression of SNIP1 in HEK293 or H1299 cells strongly activates the HSE (heat shock element) signaling pathway reporter, and SNIP1 selectively regulates transcription of HSP70A1A and HSP27.\",\n      \"method\": \"Fluorescence microscopy (EGFP fusion), reporter gene assay (HSE-luciferase), RT-PCR (HSP70A1A, HSP27)\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression reporter assay only, single lab, single method per observation, no endogenous protein studies\",\n      \"pmids\": [\"22020748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNIP1 physically interacts with TET2 DNA dioxygenase and bridges TET2 to bind the transcription factor c-MYC, as identified by mammalian two-hybrid screen and confirmed by co-immunoprecipitation. SNIP1 recruits TET2 to promoters of c-MYC target genes including those involved in DNA damage response. TET2-mediated protection from DNA damage-induced apoptosis requires SNIP1.\",\n      \"method\": \"Mammalian two-hybrid screen, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, apoptosis assays (DNA damage)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two-hybrid plus reciprocal Co-IP plus ChIP establish ternary complex and genomic recruitment, functional epistasis (TET2 protection requires SNIP1), single lab\",\n      \"pmids\": [\"30404004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNIP1 inhibits ubiquitination and degradation of c-Myc protein. The lncRNA AFAP1-AS1 interacts with SNIP1 (identified by RNA pull-down and mass spectrometry), and this interaction promotes stabilization of c-Myc, which in turn upregulates ZEB1, ZEB2, and SNAIL to enhance EMT and lung cancer metastasis.\",\n      \"method\": \"RNA pull-down, mass spectrometry, co-immunoprecipitation, ubiquitination assay, in vivo lung metastasis model\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNA pulldown with MS identification, ubiquitination assay, in vivo model; single lab, mechanistic data on SNIP1 is supportive but SNIP1 mechanism is secondary to lncRNA study\",\n      \"pmids\": [\"34168109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A biallelic SNIP1 variant (p.Glu366Gly) in the Amish community causes an autosomal recessive neurodevelopmental disorder. Gene transcript studies in affected individuals defined altered expression profiles of molecules with neurodevelopmental roles, confirming SNIP1's role in human spliceosome function and TGF-β signal transduction in vivo.\",\n      \"method\": \"Human genetic study (biallelic variant identification), gene expression profiling in affected individuals\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — human loss-of-function genetics with transcriptome readout; confirms spliceosome/TGF-β roles but molecular mechanism detail limited to expression changes\",\n      \"pmids\": [\"34570759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SNIP1 is a non-histone substrate of the lysine methyltransferase KMT5A. KMT5A mono-methylates SNIP1 at K301. This methylation releases the histone acetyltransferase KAT2A from SNIP1, promotes interaction of c-MYC with KAT2A, and recruits the c-MYC/KAT2A complex to promoters of c-MYC targets. This cascade inhibits the Hippo kinase pathway and transcriptionally activates MARK4 to enhance TNBC metastasis.\",\n      \"method\": \"In vitro methylation assay, mass spectrometry (methylation site identification), co-immunoprecipitation, ChIP, site-directed mutagenesis (K301), xenograft mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro methylation assay with site-specific mutagenesis, Co-IP, ChIP, and in vivo validation; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35449131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SNIP1 is required for recruitment of PRC2 to target gene loci and for H3K27me3 turnover in neural progenitor cells. SNIP1-depleted mouse brains exhibit dysplasia with robust caspase 9-dependent apoptosis. Depletion of PRC2 is sufficient to reduce apoptosis and brain dysplasia in SNIP1-depleted brains, establishing a genetic epistasis where SNIP1 normally restricts PRC2 activity at survival/neurogenesis gene loci.\",\n      \"method\": \"Conditional knockout (in vivo), ChIP-seq (PRC2/H3K27me3 occupancy), epistasis (double depletion of SNIP1 and PRC2), caspase 9 apoptosis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with ChIP-seq and genetic epistasis (PRC2 rescue of SNIP1-KO phenotype), multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37553330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MKRN1 (an E3 ubiquitin ligase) ubiquitinates and degrades SNIP1. Loss of SNIP1 protein de-represses TGF-β signaling, promoting EMT in colorectal cancer cells. Intestinal conditional knockout of MKRN1 in mice reduces intestinal lesions and metastatic liver microlesions, consistent with the MKRN1/SNIP1/TGF-β axis driving metastasis.\",\n      \"method\": \"Ubiquitination assay, quantitative proteomics, ubiquitination modification omics, co-immunoprecipitation, conditional knockout mouse model, in vitro proliferation/invasion assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay with proteomics, in vivo conditional KO, epistasis (SNIP1 rescue of MKRN1-driven EMT), multiple orthogonal methods\",\n      \"pmids\": [\"37620897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SNIP1 forms a ternary complex with c-MYC and lncRNA BCAN-AS1 (via SNIP1 recognizing N6-methyladenosine modification on BCAN-AS1). This complex blocks SKP2-mediated ubiquitination and degradation of c-MYC, thereby stabilizing c-MYC protein in pancreatic cancer cells.\",\n      \"method\": \"RNA pull-down, co-immunoprecipitation, m6A modification detection, ubiquitination assay, mass spectrometry\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNA pulldown plus Co-IP plus ubiquitination assay; SNIP1 role as m6A reader is a new claim supported by single lab\",\n      \"pmids\": [\"37726400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNIP1 SUMOylation is regulated by SENP1 deSUMOylation activity. The lncRNA MSC-AS1 binds SENP1 and blocks its deSUMOylation of SNIP1, thereby inhibiting SNIP1 activity and promoting EMT and intestinal fibrosis in Crohn's disease.\",\n      \"method\": \"Co-immunoprecipitation (MSC-AS1/SENP1/SNIP1), SUMOylation assay, siRNA knockdown, in vivo mouse model (TNBS-induced colitis)\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — SUMOylation assay and Co-IP support the mechanism, single lab, SNIP1 SUMOylation as novel PTM is a new claim\",\n      \"pmids\": [\"38309408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TET2 forms an inhibitory complex with HDAC1/2 and SNIP1 to suppress RUNX2 transcription at its P2 promoter in vascular smooth muscle cells; this function is independent of TET2's catalytic demethylase activity. SNIP1 is indispensable for TET2's interaction with HDAC1/2 (i.e., SNIP1 bridges TET2 to HDAC1/2), and knockdown of SNIP1 accelerates vascular calcification in mice. TET2 deacetylates H3K27ac at the RUNX2 P2 promoter through this complex.\",\n      \"method\": \"Co-immunoprecipitation (TET2/HDAC1/2/SNIP1 complex), enzymatic loss-of-function mutation of TET2, ChIP (H3K27ac), siRNA knockdown, in vivo mouse models (vitamin D3 and CKD diet)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of ternary complex, catalytic mutant controls, ChIP, and in vivo epistasis (SNIP1 KD accelerates VC), multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40067382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The FHA domain of SNIP1 directly recognizes phosphorylated SF3B1 (P-SF3B1), phosphorylated by CDK11 during spliceosome activation. This interaction promotes recruitment of the RES (retention and splicing) complex during spliceosome activation. Acute SNIP1 depletion disrupts RES complex incorporation into spliceosomes, causes widespread splicing defects, promotes hyperphosphorylation of SF3B1 by CDK11, and impairs cell viability. The neurodevelopmental disorder-associated SNIP1 E366G variant impairs P-SF3B1 binding, pre-mRNA splicing, and cell viability.\",\n      \"method\": \"Quantitative proteomics of chromatin-associated spliceosomes, iCLIP-seq, CDK11 inhibitor (OTS964) treatment, FHA domain mutagenesis (including E366G disease variant), acute SNIP1 depletion, splicing assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative proteomics plus iCLIP-seq plus domain mutagenesis plus disease variant functional validation; multiple orthogonal methods, single study\",\n      \"pmids\": [\"41904131\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNIP1 is a nuclear FHA domain-containing protein that functions as a multi-pathway transcriptional regulator: its N-terminus competitively inhibits TGF-β (Smad4) and NF-κB (RelA/p65) signaling by blocking their access to the C/H1 domain of CBP/p300, while its C-terminus interacts with c-MYC to stabilize it against proteasomal/SKP2-mediated degradation and bridge it to p300/KAT2A coactivators; SNIP1 also resides in the SSRC RNA-processing complex (with SkIP, THRAP3, BCLAF1, Pinin) that recruits U2AF65 to stabilize cyclin D1 mRNA, and in the spliceosome where its FHA domain reads phospho-SF3B1 (phosphorylated by CDK11) to recruit the RES complex; SNIP1 is post-translationally regulated by KMT5A-mediated K301 mono-methylation, MKRN1-mediated ubiquitin-proteasomal degradation, and SENP1-regulated SUMOylation; and SNIP1 acts as a scaffold bridging TET2 to HDAC1/2 and c-MYC at specific gene promoters, with loss-of-function in the Amish E366G variant causing autosomal recessive neurodevelopmental disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNIP1 is a nuclear FHA-domain protein that integrates transcriptional control, mRNA processing, and chromatin regulation, originally identified as a competitive inhibitor of CBP/p300-dependent signaling [#0]. Through its N-terminus it binds the C/H1 domain of CBP/p300 and blocks coactivator access for both Smad4-dependent TGF-\\u03b2 signaling and the NF-\\u03baB subunit RelA/p65, while sparing p300 targets that engage other domains [#0, #1]. Conversely, its C-terminus binds c-MYC, stabilizing the oncoprotein against proteasomal and SKP2-mediated ubiquitination and bridging it to p300/KAT2A coactivators to enhance c-MYC-driven transcription and oncogenic transformation [#3, #14]. SNIP1 also acts as a chromatin scaffold, bridging the dioxygenase TET2 to c-MYC target promoters and to HDAC1/2 to repress specific genes, and restricting PRC2 recruitment and H3K27me3 turnover during neurogenesis [#8, #12, #16]. In RNA processing, SNIP1 is a core subunit of the SSRC complex (with SkIP, THRAP3, BCLAF1, Pinin) that recruits U2AF65 to stabilize cyclin D1 mRNA, and its FHA domain reads CDK11-phosphorylated SF3B1 to recruit the RES complex during spliceosome activation [#5, #17]. SNIP1 abundance and activity are tuned by KMT5A-mediated K301 mono-methylation, MKRN1-mediated ubiquitin-proteasomal degradation, and SENP1-regulated SUMOylation [#11, #13, #15]. A biallelic E366G variant in the FHA domain causes an autosomal recessive neurodevelopmental disorder by impairing phospho-SF3B1 binding and pre-mRNA splicing [#10, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the founding mechanism: how a nuclear factor could selectively dampen TGF-\\u03b2 transcriptional output, by showing SNIP1 sequesters CBP/p300 from Smad4.\",\n      \"evidence\": \"Yeast two-hybrid, endogenous reciprocal Co-IP, in vitro binding, reporter assays and Xenopus rescue in NMuMg cells\",\n      \"pmids\": [\"10887155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether the same competition operates on other p300-dependent pathways\", \"No structural basis for the N-terminus/CBP interaction\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Generalized the competitive-inhibition model to a second pathway, showing SNIP1 also blocks RelA/p65 access to the C/H1 domain of CBP/p300, defining it as a selective coactivator-sequestering regulator rather than a TGF-\\u03b2-specific factor.\",\n      \"evidence\": \"Domain mapping, competitive binding assays, reporter assays with transcription-factor controls, immunohistochemistry\",\n      \"pmids\": [\"11567019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity rules for which p300-binding factors are inhibited not fully defined\", \"In vivo relevance to NF-\\u03baB-driven programs untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected SNIP1 to cell-cycle progression, showing its loss arrests cells in G1 with loss of cyclin D1 and linking it to SWI/SNF (BRG1) chromatin remodeling.\",\n      \"evidence\": \"siRNA knockdown, flow cytometry, RT-PCR, cyclin D1 promoter reporter, Co-IP with BRG1 in human cell lines\",\n      \"pmids\": [\"15378006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cyclin D1 control was transcriptional vs post-transcriptional was unresolved (later revised)\", \"BRG1 interaction not functionally dissected\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Reframed SNIP1 as a pro-oncogenic c-MYC cofactor, showing its C-terminus stabilizes c-MYC against degradation and bridges c-MYC to p300, cooperating in transformation.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, proteasomal degradation assay, focus formation and soft-agar assays, tissue arrays\",\n      \"pmids\": [\"17157259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase opposed by SNIP1 not identified at this stage\", \"Mechanism of degradation protection unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked SNIP1 to genome-stability signaling, showing it is required for ATR-dependent phosphorylation of p53, Chk1 and H2AX and for p14ARF function, independent of its cyclin D1 role.\",\n      \"evidence\": \"siRNA knockdown, phospho-substrate immunoblots after UV, reporter assays in U-2 OS cells\",\n      \"pmids\": [\"17260016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular role of SNIP1 in the ATR pathway not defined\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revised the cyclin D1 mechanism: rather than acting at the promoter, SNIP1 stabilizes cyclin D1 mRNA as part of the SSRC RNA-processing complex that recruits U2AF65, establishing a co/post-transcriptional function.\",\n      \"evidence\": \"Co-IP complex isolation, RNA-IP, ChIP, siRNA, mRNA stability assays\",\n      \"pmids\": [\"18794151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of SSRC-stabilized transcripts beyond cyclin D1 unknown\", \"How SSRC selects target RNAs not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided the structural and complex-context basis for SNIP1's FHA domain via its yeast ortholog Pml1, showing it is a near-pure FHA domain that integrates into the RES splicing complex through Snu17/Bud13 contacts.\",\n      \"evidence\": \"X-ray crystallography, recombinant RES reconstitution, truncation/mutagenesis, splice-site assays in yeast\",\n      \"pmids\": [\"19033360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FHA phosphopeptide-binding pocket appeared dispensable in yeast, leaving its functional role open (resolved later in human)\", \"Human RES architecture inferred from yeast\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Reported SNIP1 subnuclear speckle localization and a candidate role in activating heat-shock gene transcription.\",\n      \"evidence\": \"EGFP fusion microscopy, HSE-luciferase reporter, RT-PCR for HSP70A1A/HSP27 in HeLa/HEK293/H1299 (overexpression)\",\n      \"pmids\": [\"22020748\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Overexpression reporter only, no endogenous validation\", \"Mechanism of HSE activation undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined SNIP1 as a chromatin scaffold bridging TET2 to c-MYC target promoters, coupling it to DNA-damage-response gene regulation and apoptosis protection.\",\n      \"evidence\": \"Mammalian two-hybrid, reciprocal Co-IP, ChIP, siRNA, DNA-damage apoptosis assays\",\n      \"pmids\": [\"30404004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TET2 catalytic activity is required at these loci not addressed here\", \"Genome-wide scope of the ternary complex limited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed an lncRNA-directed route to c-MYC stabilization, with AFAP1-AS1 binding SNIP1 to suppress c-MYC ubiquitination and drive EMT/metastasis.\",\n      \"evidence\": \"RNA pull-down/MS, Co-IP, ubiquitination assay, in vivo lung metastasis model\",\n      \"pmids\": [\"34168109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SNIP1 mechanism secondary to the lncRNA focus\", \"Direct lncRNA-SNIP1 interface not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided human in vivo proof of essentiality: a biallelic SNIP1 E366G variant causes autosomal recessive neurodevelopmental disease with altered neurodevelopmental gene expression.\",\n      \"evidence\": \"Human genetic study and transcriptome profiling in affected Amish individuals\",\n      \"pmids\": [\"34570759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular consequence of E366G not resolved at this stage (later linked to phospho-SF3B1 binding)\", \"Mechanism limited to expression changes\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a methylation switch controlling SNIP1 cofactor partner choice, with KMT5A mono-methylating K301 to release KAT2A and route the c-MYC/KAT2A complex to pro-metastatic targets.\",\n      \"evidence\": \"In vitro methylation, MS site mapping, K301 mutagenesis, Co-IP, ChIP, xenograft model\",\n      \"pmids\": [\"35449131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demethylase reversing K301 not identified\", \"Breadth of methylation-controlled target genes limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established SNIP1 as a restrictor of PRC2 activity in neurogenesis, with its loss causing PRC2-dependent caspase-9 apoptosis and brain dysplasia rescued by PRC2 depletion.\",\n      \"evidence\": \"Conditional knockout, ChIP-seq for PRC2/H3K27me3, genetic epistasis, apoptosis assays in mouse brain\",\n      \"pmids\": [\"37553330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SNIP1 mechanistically limits PRC2 occupancy unresolved\", \"Link to splicing role not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a degradation arm regulating SNIP1, with MKRN1 ubiquitinating SNIP1 to de-repress TGF-\\u03b2 signaling and promote colorectal cancer EMT/metastasis.\",\n      \"evidence\": \"Ubiquitination assay, quantitative/ubiquitination proteomics, Co-IP, conditional KO mouse, invasion assays\",\n      \"pmids\": [\"37620897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling MKRN1 activity toward SNIP1 unknown\", \"Ubiquitination site on SNIP1 not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended SNIP1's c-MYC-stabilizing function to an m6A-reader role, forming a ternary complex with c-MYC and m6A-modified BCAN-AS1 to block SKP2-mediated c-MYC degradation.\",\n      \"evidence\": \"RNA pull-down, Co-IP, m6A detection, ubiquitination assay, MS in pancreatic cancer cells\",\n      \"pmids\": [\"37726400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A-reader claim from a single lab\", \"Structural basis of m6A recognition by SNIP1 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added SUMOylation as a third PTM layer, with SENP1 deSUMOylating SNIP1 and MSC-AS1 sequestering SENP1 to inhibit SNIP1 and promote EMT/intestinal fibrosis.\",\n      \"evidence\": \"Co-IP, SUMOylation assay, siRNA, TNBS colitis mouse model\",\n      \"pmids\": [\"38309408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SNIP1 SUMOylation site and functional consequence not fully defined\", \"Novel PTM claim from single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Generalized the TET2 scaffold function to repressive chromatin, showing SNIP1 is indispensable for bridging TET2 to HDAC1/2 to deacetylate H3K27ac and silence RUNX2, with SNIP1 loss accelerating vascular calcification.\",\n      \"evidence\": \"Co-IP of ternary complex, TET2 catalytic-dead mutant, ChIP for H3K27ac, siRNA, in vivo calcification models\",\n      \"pmids\": [\"40067382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SNIP1 selects TET2/HDAC target loci unknown\", \"Relationship to SNIP1's c-MYC/TET2 role not unified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved the long-open FHA function and the disease mechanism, showing the FHA domain reads CDK11-phosphorylated SF3B1 to recruit the RES complex during spliceosome activation, with the E366G variant abrogating this binding.\",\n      \"evidence\": \"Quantitative spliceosome proteomics, iCLIP-seq, CDK11 inhibition, FHA/E366G mutagenesis, acute depletion and splicing assays\",\n      \"pmids\": [\"41904131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How splicing role mechanistically connects to SNIP1's transcriptional/chromatin functions\", \"Full set of SNIP1-dependent splicing events not catalogued\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how SNIP1's distinct activities — CBP/p300 sequestration, c-MYC stabilization, TET2/PRC2 chromatin scaffolding, and phospho-SF3B1/RES-dependent splicing — are coordinated within one protein and which is primary to its essential and neurodevelopmental roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No integrated model linking the splicing and transcriptional/chromatin functions\", \"PTM crosstalk (methylation, ubiquitination, SUMOylation) governing function-switching not mapped\", \"Structure of human SNIP1 in complex with partners beyond the FHA domain lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 9, 14]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 17]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [8, 12, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 13, 15]}\n    ],\n    \"complexes\": [\"SSRC complex\", \"RES complex\"],\n    \"partners\": [\"CBP/p300\", \"Smad4\", \"RELA\", \"MYC\", \"TET2\", \"HDAC1\", \"SF3B1\", \"KAT2A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}