{"gene":"SART3","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2002,"finding":"SART3/p110 (human ortholog of yeast Prp24) associates specifically with U6 and U4/U6 snRNPs but not with U4/U5/U6 tri-snRNPs or spliceosomes. Recombinant p110 binds U6 snRNA in vitro requiring an internal U6 region, and p110 functions in the reassembly of U4/U6 snRNP in an in vitro recycling assay, establishing its role as a U4/U6 snRNP recycling factor. Its domain structure comprises an N-terminal region with seven tetratricopeptide repeat (TPR) domains and C-terminal RNA recognition motifs (RRMs).","method":"RNA immunoprecipitation, in vitro RNA binding assay, in vitro U4/U6 snRNP recycling assay, database/domain analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of recycling activity combined with direct RNA binding assay and snRNP association experiments in a single focused study","pmids":["12032085"],"is_preprint":false},{"year":2003,"finding":"SART3/p110 is enriched in Cajal bodies (CBs) but not in gems or residual CBs lacking coilin. Its N-terminal HAT domain is necessary and sufficient for targeting to CBs. Overexpression of truncation mutants containing the HAT domain had dominant-negative effects on U6 snRNP localization to CBs, indicating SART3 plays a role in targeting U6 snRNP to CBs. CB localization was reduced by the transcription inhibitor alpha-amanitin, linking CB accumulation to active transcription/splicing.","method":"Fluorescence microscopy with GFP-tagged truncation mutants, dominant-negative overexpression, alpha-amanitin treatment, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with domain-mapping mutants and functional dominant-negative readout, multiple orthogonal methods in one study","pmids":["12578909"],"is_preprint":false},{"year":2004,"finding":"SART3/p110 U4/U6 snRNP recycling activity requires both its RRM domains and its TPR domain, but not the highly conserved C-terminal 10 amino acids. The two RRMs with flanking regions are sufficient for U6-specific RNA binding. The TPR domain interacts with the U4/U6-specific 90K protein (via residues 416-550 of 90K) in yeast two-hybrid assays, suggesting the TPR domain mediates protein-protein interactions during spliceosome recycling.","method":"In vitro recycling assay with deletion mutants, in vitro RNA binding, yeast two-hybrid","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with systematic mutagenesis/deletions plus protein interaction mapping in one rigorous study","pmids":["15314151"],"is_preprint":false},{"year":2007,"finding":"Zebrafish earl grey (egy) mutation maps to the p110/SART3 gene and causes thymus hypoplasia and other organ defects. U4/U6 snRNPs were disrupted in egy mutant embryos, confirming that p110/SART3 is essential for U4/U6 snRNP recycling in vivo. Loss of p110/SART3 triggered coordinated upregulation of a network of spliceosome cycle components, providing a compensatory mechanism for the recycling defect.","method":"Genetic mapping, zebrafish loss-of-function mutant analysis, snRNP fractionation, expression profiling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with direct molecular readout (snRNP disruption) and expression profiling, independently validates in vitro recycling function in vivo","pmids":["17416673"],"is_preprint":false},{"year":2008,"finding":"The 3'-cyclic phosphate on U6 snRNA enhances binding of LSm2-8 proteins to U6 snRNA and reduces La protein binding, facilitating RNP remodeling. LSm2-8 proteins recruit p110/SART3 to U6 snRNA via direct interaction with the highly conserved C-terminal region of p110, demonstrating synergistic binding of LSm proteins and p110 to U6 snRNA.","method":"In vitro binding assays with purified/recombinant proteins and synthetic U6 variants, gel-shift and pull-down assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined biochemical components, domain mapping of interaction, multiple binding assays","pmids":["18567812"],"is_preprint":false},{"year":2001,"finding":"SART3 interacts physically with the pre-mRNA splicing factor RNPS1 through the N-terminal domains of RNPS1, as confirmed by in vitro pull-down and co-immunoprecipitation. Co-transfection of both genes redistributes SART3 from diffuse nucleoplasmic to nuclear speckled regions co-localizing with RNPS1. In cooperation with RNPS1, SART3 stimulates proximal alternative 3' splicing of a calcitonin-DHFR chimeric minigene pre-mRNA.","method":"Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation, immunofluorescence, minigene splicing assay","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus pull-down, localization change, and functional splicing assay in one study","pmids":["11477570"],"is_preprint":false},{"year":2002,"finding":"SART3/TIP110 (Tip110) interacts directly with HIV-1 Tat protein in vivo, confirmed by co-immunoprecipitation and Western blotting combined with mutagenesis. Tip110 strongly potentiates Tat-mediated HIV-1 LTR promoter transactivation and HIV-1 virus production; knock-down of Tip110 inhibits HIV-1 production. Tip110 localizes exclusively to the nucleus in nuclear speckle structures overlapping with cyclin T and CDK9.","method":"Co-immunoprecipitation, Western blot, mutagenesis, CAT reporter assay, siRNA knockdown, digital fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with mutagenesis, functional reporter and virus production assays, and direct localization in one study","pmids":["11959860"],"is_preprint":false},{"year":2014,"finding":"SART3 has histone chaperone activity and directly associates with the deubiquitinase Usp15 in the nucleus. SART3 enhances Usp15 binding to mono-ubiquitinated H2B (ubH2B) and facilitates deubiquitination of ubH2B in free histones (but not in nucleosomes), suggesting SART3 recruits ubH2B evicted during transcription for deubiquitination. SART3 also indirectly associates with the ubH2B E3 ligase RNF20/RNF40.","method":"Affinity purification with non-hydrolyzable ubH2B mimic, co-immunoprecipitation, in vitro deubiquitination assay with nucleosomes and free histones","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro deubiquitination reconstitution with defined substrates (free histones vs. nucleosomes), affinity purification, and Co-IP in single study","pmids":["24526689"],"is_preprint":false},{"year":2015,"finding":"SART3 is required for the accumulation of incomplete spliceosomal snRNP intermediates in Cajal bodies (CBs). Depletion of SART3 prevents both the induction of CB formation (triggered by imbalanced snRNP assembly) and the tethering of incomplete snRNPs to coilin (CB scaffolding protein), indicating SART3 monitors tri-snRNP assembly and sequesters incomplete particles in CBs to maintain homeostatic balance of mature snRNPs.","method":"siRNA depletion, immunofluorescence microscopy, co-immunoprecipitation with coilin","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean knockdown with specific cellular phenotype (CB formation and snRNP tethering), multiple orthogonal readouts in one study","pmids":["25600876"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the SART3 HAT (half-a-tetratricopeptide) repeat domain alone and in complex with the DUSP-UBL domains of USP4 was determined. The 12 HAT repeats form two sub-domains (HAT-N and HAT-C); HAT-C mediates dimerization; USP4 binds at the opposite surface of the HAT-C dimer interface via the beta-structured linker between DUSP and UBL. Binding affinities of USP4 and USP15 to SART3 are 0.9 μM and 0.2 μM respectively. The SART3 nuclear localization signal (NLS) forms bipartite interaction with importin-α; deletion of the NLS prevents nuclear entry of USP4 and USP15 and abrogates USP4 deubiquitinase activity.","method":"X-ray crystallography, binding affinity measurements (SPR/ITC implied), NLS deletion mutants, nuclear localization assay, deubiquitinase activity assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation (NLS deletion abrogating nuclear entry and DUB activity), multiple orthogonal methods","pmids":["27060135"],"is_preprint":false},{"year":2018,"finding":"SART3 interacts with DNA polymerase η (Polη) and RAD18 via its C-terminus, and can form homodimers that promote the Polη/RAD18 interaction and PCNA monoubiquitination after UV exposure. Depletion of SART3 impairs UV-induced ssDNA generation and RPA focus formation, reduces Polη recruitment to stalled replication forks, and increases mutation frequency and UV hypersensitivity. This function is RNA binding-independent.","method":"Affinity purification/co-IP, deletion mapping (C-terminus), siRNA knockdown with UV survival/mutation frequency assay, immunofluorescence for RPA and Polη foci, PCNA ubiquitination assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping, functional knockout phenotypes (mutation frequency, foci formation, PCNA ubiquitination) with multiple orthogonal methods","pmids":["29590477"],"is_preprint":false},{"year":2019,"finding":"SART3 binds pre-miR-34a with higher specificity than a negative-control pre-miRNA via its RNA recognition motifs (RRMs). SART3 overexpression increases mature miR-34a levels, downregulates miR-34a target genes CDK4/6, and causes G1 cell cycle arrest in non-small-cell lung cancer cells.","method":"Proteomics/pull-down identification, in vitro RNA binding with RRM mutants, overexpression with miRNA quantification, CDK4/6 Western blot, flow cytometry cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed with domain mapping plus functional cell cycle readout, single lab study","pmids":["31619517"],"is_preprint":false},{"year":2020,"finding":"The stress-induced lncRNA LASTR interacts with SART3 (identified by mass spectrometry) and promotes splicing efficiency by controlling SART3 association with U4 and U6 snRNPs during spliceosome recycling; LASTR depletion causes intron retention and decreases cancer cell fitness.","method":"Mass spectrometry-based affinity purification, RNA immunoprecipitation, intron retention analysis (RNA-seq), LASTR depletion with cell viability assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based identification with functional snRNP association assay and splicing readout, single lab study","pmids":["31956895"],"is_preprint":false},{"year":2011,"finding":"TIP110/SART3 is expressed in human CD34+ hematopoietic stem/progenitor cells and decreases with differentiation. Using TIP110 transgenic and haploinsufficient mice, increased TIP110 enhanced hematopoietic progenitor cell (HPC) numbers, survival, and cycling, while decreased TIP110 had opposite effects. TIP110 regulates CMYC and GATA2 expression at the transcriptional level, and TIP110 and CMYC reciprocally regulate each other's expression.","method":"Transgenic and haploinsufficient mouse models, colony-forming assays, cell cycle analysis, RT-PCR/Western blot for CMYC and GATA2","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic gain/loss-of-function in vivo with defined cellular and molecular phenotypes, but transcriptional regulation mechanism not fully resolved at mechanistic level","pmids":["21447833"],"is_preprint":false},{"year":2004,"finding":"Tip110/SART3 binds to androgen receptor (AR) in an NR box (LXXLL motif)-dependent manner and suppresses AR transcriptional activation of androgen-responsive element (ARE)-driven reporters. Knockdown of Tip110 augments AR transcriptional activation. Tip110 overexpression blocks PSA gene expression and prevents AR–ARE complex formation.","method":"Co-immunoprecipitation, reporter gene assay, siRNA knockdown, EMSA (AR-ARE complex), Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain-specific mutant, functional reporter + knockdown + EMSA, single lab","pmids":["15031286"],"is_preprint":false},{"year":2005,"finding":"A Val591Met missense mutation in SART3 was identified by linkage analysis and sequencing in all affected individuals of a six-generation Chinese family with disseminated superficial actinic porokeratosis (DSAP), mapping to chromosome 12q24.1-24.2, suggesting SART3 is a candidate disease gene for this autosomal dominant skin disorder.","method":"Genome-wide linkage analysis, haplotype analysis, Sanger sequencing","journal":"The British journal of dermatology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — genetic association only, no functional experiment establishing mechanism; included as disease-gene link","pmids":["15840095"],"is_preprint":false}],"current_model":"SART3 (also known as TIP110/p110nrb) is a nuclear RNA-binding protein that functions as the human ortholog of yeast Prp24: its C-terminal RNA recognition motifs (RRMs) bind U6 snRNA, while its N-terminal TPR/HAT repeat domain mediates protein–protein interactions (notably with the U4/U6-specific 90K protein and with deubiquitinases USP4/USP15), enabling SART3 to catalyze reassembly of U4/U6 di-snRNPs after each spliceosome cycle and to target these snRNPs to Cajal bodies for recycling; beyond splicing, SART3 acts as a histone chaperone that facilitates USP15-mediated deubiquitination of H2B, regulates translesion DNA synthesis by scaffolding the Polη/RAD18 complex and promoting PCNA monoubiquitination, potentiates HIV-1 Tat-mediated LTR transactivation through direct Tat interaction, suppresses androgen receptor transcriptional activity via its NR box, promotes miR-34a biogenesis through pre-miR-34a binding, and controls hematopoietic progenitor cell expansion in part through reciprocal regulation of CMYC."},"narrative":{"mechanistic_narrative":"SART3 is a nuclear RNA-binding protein that functions as the human ortholog of yeast Prp24 and serves as the U4/U6 snRNP recycling factor that regenerates spliceosomal di-snRNPs after each round of splicing [PMID:12032085]. Its bipartite architecture couples C-terminal RNA recognition motifs (RRMs), which bind a specific internal region of U6 snRNA, to an N-terminal TPR/HAT repeat domain that mediates protein–protein contacts, and both are required for recycling activity [PMID:12032085, PMID:15314151]. The TPR domain engages the U4/U6-specific 90K protein, while the conserved C-terminus is bound by LSm2-8 proteins that recruit SART3 to U6 snRNA, integrating it into the snRNP remodeling machinery [PMID:15314151, PMID:18567812]. SART3 concentrates in Cajal bodies via its HAT domain and directs U6 snRNP localization there for recycling, and more broadly monitors tri-snRNP assembly by sequestering incomplete snRNP intermediates onto the coilin scaffold to maintain snRNP homeostasis [PMID:12578909, PMID:25600876]; its essential recycling role is confirmed in vivo, where loss disrupts U4/U6 snRNPs and causes organ defects [PMID:17416673]. The crystal structure of the HAT domain shows it forms a dimer through HAT-C and recruits the deubiquitinases USP4 and USP15, whose nuclear import and catalytic activity depend on the SART3 nuclear localization signal [PMID:27060135]. Beyond splicing, SART3 acts as a histone chaperone that presents evicted mono-ubiquitinated H2B to USP15 for deubiquitination [PMID:24526689], scaffolds the Polη/RAD18 complex to promote PCNA monoubiquitination and translesion synthesis after UV damage in an RNA-binding-independent manner [PMID:29590477], potentiates HIV-1 Tat-mediated LTR transactivation through direct Tat interaction in nuclear speckles [PMID:11959860], and promotes miR-34a biogenesis through RRM-mediated pre-miR-34a binding to enforce a CDK4/6-dependent G1 arrest [PMID:31619517]. A SART3 missense mutation was linked to disseminated superficial actinic porokeratosis in a single family by linkage analysis [PMID:15840095].","teleology":[{"year":2001,"claim":"Established SART3 as a participant in splicing regulation by identifying a direct interaction with the splicing factor RNPS1 that redirects SART3 to nuclear speckles and modulates alternative 3' splice site choice.","evidence":"Yeast two-hybrid, pull-down, Co-IP, and minigene splicing assay","pmids":["11477570"],"confidence":"High","gaps":["Does not define the snRNP-level mechanism","Physiological pre-mRNA targets not identified"]},{"year":2002,"claim":"Defined the core molecular function of SART3 as the U4/U6 snRNP recycling factor, the human Prp24 ortholog, that binds U6 snRNA and reassembles U4/U6 di-snRNPs after each splicing cycle.","evidence":"RNA immunoprecipitation, in vitro U6 binding, and in vitro recycling reconstitution","pmids":["12032085"],"confidence":"High","gaps":["Protein partners during recycling not yet mapped","In vivo requirement not yet tested"]},{"year":2002,"claim":"Revealed a non-splicing role by showing direct Tat binding and potentiation of HIV-1 LTR transactivation, expanding SART3 function into transcriptional control in nuclear speckles.","evidence":"Reciprocal Co-IP with mutagenesis, CAT reporter, virus production, and microscopy","pmids":["11959860"],"confidence":"High","gaps":["Mechanism by which SART3 enhances Tat function unresolved","Relationship to its splicing role unclear"]},{"year":2003,"claim":"Localized SART3 function to Cajal bodies, showing the HAT domain is necessary and sufficient for CB targeting and is required to deliver U6 snRNP there for recycling.","evidence":"GFP truncation mutants, dominant-negative overexpression, alpha-amanitin treatment","pmids":["12578909"],"confidence":"High","gaps":["Molecular basis of HAT-mediated CB targeting not defined","Link between CB localization and recycling kinetics unquantified"]},{"year":2004,"claim":"Dissected the domain requirements for recycling, showing both RRMs and the TPR domain are needed and that the TPR domain contacts the U4/U6-specific 90K protein.","evidence":"In vitro recycling with deletion mutants, RNA binding, yeast two-hybrid","pmids":["15314151"],"confidence":"High","gaps":["Structure of the SART3–90K interface not determined","Order of RNA versus protein contacts during recycling unknown"]},{"year":2004,"claim":"Identified a transcriptional repressor function, showing NR-box-dependent binding to the androgen receptor that suppresses AR-driven transcription and PSA expression.","evidence":"Co-IP with motif mutant, reporter assay, siRNA knockdown, EMSA","pmids":["15031286"],"confidence":"Medium","gaps":["In vivo relevance to prostate biology not established","Single-lab study"]},{"year":2007,"claim":"Validated the recycling function in vivo, showing that loss of SART3 in zebrafish disrupts U4/U6 snRNPs and causes organ defects with compensatory upregulation of spliceosome components.","evidence":"Zebrafish loss-of-function mutant, snRNP fractionation, expression profiling","pmids":["17416673"],"confidence":"High","gaps":["Tissue-specific sensitivity to recycling loss unexplained","Compensatory network regulators not identified"]},{"year":2008,"claim":"Clarified how SART3 is recruited to U6, showing LSm2-8 proteins bind the conserved C-terminus and act synergistically with SART3, with the U6 3'-cyclic phosphate biasing toward LSm over La binding.","evidence":"In vitro binding assays with recombinant proteins and synthetic U6 variants","pmids":["18567812"],"confidence":"High","gaps":["Temporal coordination of LSm and SART3 loading in cells unresolved"]},{"year":2011,"claim":"Extended SART3 into hematopoiesis, showing dose-dependent control of progenitor expansion, survival, and cycling via reciprocal transcriptional regulation with CMYC and control of GATA2.","evidence":"Transgenic and haploinsufficient mouse models, colony assays, cell cycle and expression analysis","pmids":["21447833"],"confidence":"Medium","gaps":["Direct versus indirect transcriptional mechanism not resolved","Connection to splicing function unclear"]},{"year":2014,"claim":"Defined a histone chaperone role, showing SART3 directly binds USP15 and presents mono-ubiquitinated free histone H2B for deubiquitination, linking SART3 to chromatin/transcription-coupled histone turnover.","evidence":"Affinity purification with ubH2B mimic, Co-IP, in vitro deubiquitination of free histones versus nucleosomes","pmids":["24526689"],"confidence":"High","gaps":["In vivo H2B deubiquitination dependence on SART3 not quantified","Why nucleosomal ubH2B is not a substrate unexplained"]},{"year":2016,"claim":"Provided structural and mechanistic basis for DUB regulation, showing the HAT domain dimerizes and recruits USP4/USP15, and that the SART3 NLS drives their nuclear import and catalytic activity.","evidence":"X-ray crystallography of HAT and HAT–USP4 complex, affinity measurements, NLS deletion and DUB activity assays","pmids":["27060135"],"confidence":"High","gaps":["Substrate specificity of nuclear USP4/USP15 once imported not addressed"]},{"year":2018,"claim":"Established an RNA-independent DNA damage tolerance function, showing C-terminal-mediated scaffolding of Polη/RAD18, promotion of PCNA monoubiquitination, and protection against UV-induced mutagenesis.","evidence":"Co-IP with domain mapping, siRNA knockdown with UV survival/mutation assays, foci imaging, PCNA ubiquitination assay","pmids":["29590477"],"confidence":"High","gaps":["How a splicing factor is recruited to stalled forks unknown","Relationship between dimerization and TLS scaffolding unresolved"]},{"year":2019,"claim":"Linked SART3 to miRNA biogenesis, showing RRM-dependent specific binding to pre-miR-34a that raises mature miR-34a, downregulates CDK4/6, and arrests cells in G1.","evidence":"Pull-down identification, in vitro RNA binding with RRM mutants, miRNA quantification, cell cycle analysis","pmids":["31619517"],"confidence":"Medium","gaps":["Step in miR-34a processing affected not pinpointed","Single-lab study"]},{"year":2020,"claim":"Showed that a stress-induced lncRNA, LASTR, tunes SART3 association with U4/U6 snRNPs to maintain splicing efficiency and cancer cell fitness, adding an RNA-based regulatory layer to recycling.","evidence":"Mass spectrometry, RNA-IP, intron retention RNA-seq, LASTR depletion viability assay","pmids":["31956895"],"confidence":"Medium","gaps":["Direct versus indirect modulation of SART3 by LASTR not separated","Single-lab study"]},{"year":null,"claim":"How SART3's distinct activities — snRNP recycling, histone deubiquitination, translesion synthesis, transcriptional and miRNA regulation — are coordinated within the nucleus, and which are physiologically dominant, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking the multiple functions","Mechanism of the DSAP disease mutation not functionally tested","Context-specific partitioning between roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,4,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,7,10]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,9]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1,5,6]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3,4,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[10]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,14]}],"complexes":["U4/U6 di-snRNP","Cajal body"],"partners":["USP4","USP15","PRPF3","RNPS1","TAT","POLH","RAD18","COILIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15020","full_name":"Spliceosome associated factor 3, U4/U6 recycling protein","aliases":["Squamous cell carcinoma antigen recognized by T-cells 3","SART-3","Tat-interacting protein of 110 kDa","Tip110","p110 nuclear RNA-binding protein"],"length_aa":963,"mass_kda":109.9,"function":"U6 snRNP-binding protein that functions as a recycling factor of the splicing machinery. Promotes the initial reassembly of U4 and U6 snRNPs following their ejection from the spliceosome during its maturation (PubMed:12032085). Also binds U6atac snRNPs and may function as a recycling factor for U4atac/U6atac spliceosomal snRNP, an initial step in the assembly of U12-type spliceosomal complex. The U12-type spliceosomal complex plays a role in the splicing of introns with non-canonical splice sites (PubMed:14749385). May also function as a substrate-targeting factor for deubiquitinases like USP4 and USP15. Recruits USP4 to ubiquitinated PRPF3 within the U4/U5/U6 tri-snRNP complex, promoting PRPF3 deubiquitination and thereby regulating the spliceosome U4/U5/U6 tri-snRNP spliceosomal complex disassembly (PubMed:20595234). May also recruit the deubiquitinase USP15 to histone H2B and mediate histone deubiquitination, thereby regulating gene expression and/or DNA repair (PubMed:24526689). May play a role in hematopoiesis probably through transcription regulation of specific genes including MYC (By similarity) Regulates Tat transactivation activity through direct interaction. May be a cellular factor for HIV-1 gene expression and viral replication","subcellular_location":"Nucleus, nucleoplasm; Nucleus, Cajal body; Nucleus speckle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q15020/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SART3","classification":"Common Essential","n_dependent_lines":1199,"n_total_lines":1208,"dependency_fraction":0.9925496688741722},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLTA","stoichiometry":0.2},{"gene":"HNRNPU","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"SNRPB2","stoichiometry":0.2},{"gene":"SNRPD2","stoichiometry":0.2},{"gene":"SNRPF","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2},{"gene":"SSB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SART3","total_profiled":1310},"omim":[{"mim_id":"621044","title":"RING FINGER PROTEIN 157; RNF157","url":"https://www.omim.org/entry/621044"},{"mim_id":"618938","title":"LONG NONCODING RNA ASSOCIATED WITH SART3 REGULATION OF SPLICING; LASTR","url":"https://www.omim.org/entry/618938"},{"mim_id":"616063","title":"POROKERATOSIS 8, DISSEMINATED SUPERFICIAL ACTINIC TYPE; POROK8","url":"https://www.omim.org/entry/616063"},{"mim_id":"611684","title":"SPLICEOSOME-ASSOCIATED FACTOR 3, U4/U6 RECYCLING PROTEIN; SART3","url":"https://www.omim.org/entry/611684"},{"mim_id":"611478","title":"METHYLPHOSPHATE CAPPING ENZYME; MEPCE","url":"https://www.omim.org/entry/611478"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7929193","citation_count":34,"is_preprint":false},{"pmid":"16751409","id":"PMC_16751409","title":"Class IA phosphatidylinositide 3-kinases, rather than p110 gamma, regulate formyl-methionyl-leucyl-phenylalanine-stimulated chemotaxis and superoxide production in differentiated neutrophil-like PLB-985 cells.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16751409","citation_count":33,"is_preprint":false},{"pmid":"11398844","id":"PMC_11398844","title":"Expression of a newly defined tumor-rejection antigen SART3 in musculoskeletal tumors and induction of HLA class I-restricted cytotoxic T lymphocytes by SART3-derived peptides.","date":"2001","source":"Journal of orthopaedic research : official publication of the Orthopaedic Research Society","url":"https://pubmed.ncbi.nlm.nih.gov/11398844","citation_count":32,"is_preprint":false},{"pmid":"11679587","id":"PMC_11679587","title":"Phosphatidylinositol 3-kinase p85 adaptor function in T-cells. Co-stimulation and regulation of cytokine transcription independent of associated p110.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11679587","citation_count":32,"is_preprint":false},{"pmid":"27060135","id":"PMC_27060135","title":"Structural basis for recruiting and shuttling of the spliceosomal deubiquitinase USP4 by SART3.","date":"2016","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/27060135","citation_count":31,"is_preprint":false},{"pmid":"31619517","id":"PMC_31619517","title":"The RNA-binding protein SART3 promotes miR-34a biogenesis and G1 cell cycle arrest in lung cancer cells.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31619517","citation_count":30,"is_preprint":false},{"pmid":"7891222","id":"PMC_7891222","title":"Expression of mdr1/P-glycoprotein and p110 in neuroblastoma.","date":"1995","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/7891222","citation_count":30,"is_preprint":false},{"pmid":"11477570","id":"PMC_11477570","title":"Binding of a SART3 tumor-rejection antigen to a pre-mRNA splicing factor RNPS1: a possible regulation of splicing by a complex formation.","date":"2001","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11477570","citation_count":30,"is_preprint":false},{"pmid":"17427168","id":"PMC_17427168","title":"Targeted RNA interference of phosphatidylinositol 3-kinase p110-beta induces apoptosis and proliferation arrest in endometrial carcinoma cells.","date":"2007","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/17427168","citation_count":30,"is_preprint":false},{"pmid":"23172887","id":"PMC_23172887","title":"Targeting the phosphoinositide 3-kinase p110-α isoform impairs cell proliferation, survival, and tumor growth in small cell lung cancer.","date":"2012","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/23172887","citation_count":30,"is_preprint":false},{"pmid":"17680774","id":"PMC_17680774","title":"Differential regulation of class IA phosphoinositide 3-kinase catalytic subunits p110 alpha and beta by protease-activated receptor 2 and beta-arrestins.","date":"2007","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/17680774","citation_count":30,"is_preprint":false},{"pmid":"20154209","id":"PMC_20154209","title":"The p110 delta isoform of phosphatidylinositol 3-kinase controls the quality of secondary anti-Leishmania immunity by regulating expansion and effector function of memory T cell subsets.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20154209","citation_count":30,"is_preprint":false},{"pmid":"29590477","id":"PMC_29590477","title":"RNA-splicing factor SART3 regulates translesion DNA synthesis.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29590477","citation_count":29,"is_preprint":false},{"pmid":"21447833","id":"PMC_21447833","title":"TIP110/p110nrb/SART3/p110 regulation of hematopoiesis through CMYC.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21447833","citation_count":29,"is_preprint":false},{"pmid":"15031286","id":"PMC_15031286","title":"Tip110, the human immunodeficiency virus type 1 (HIV-1) Tat-interacting protein of 110 kDa as a negative regulator of androgen receptor (AR) transcriptional activation.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15031286","citation_count":29,"is_preprint":false},{"pmid":"22132941","id":"PMC_22132941","title":"Tip110 maintains expression of pluripotent factors in and pluripotency of human embryonic stem cells.","date":"2012","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/22132941","citation_count":27,"is_preprint":false},{"pmid":"23913940","id":"PMC_23913940","title":"The P110 subunit of PI3-K is a therapeutic target of acacetin in skin cancer.","date":"2013","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/23913940","citation_count":27,"is_preprint":false},{"pmid":"16517941","id":"PMC_16517941","title":"ANG II enhances contractile responses via PI3-kinase p110 delta pathway in aortas from diabetic rats with systemic hyperinsulinemia.","date":"2006","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16517941","citation_count":27,"is_preprint":false},{"pmid":"9446654","id":"PMC_9446654","title":"The p85 and p110 subunits of phosphatidylinositol 3-kinase-alpha are substrates, in vitro, for a constitutively associated protein tyrosine kinase in platelets.","date":"1998","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9446654","citation_count":27,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50629,"output_tokens":4846,"usd":0.112288,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12722,"output_tokens":4501,"usd":0.088068,"stage2_stop_reason":"end_turn"},"total_usd":0.200356,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about SART3/KIAA0156/TIP110/p110 (the spliceosome recycling factor), not the many PI3K p110 subunit papers or other unrelated p110 proteins.\n\nPapers clearly about SART3: [16], [23], [29], [43], [48], [57], [64], [72], [79], [86], [87], [89], [94], [95], [96], [97]\n\nAlso relevant: [78] (SART3 mutation in disease)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"SART3/p110 (human ortholog of yeast Prp24) associates specifically with U6 and U4/U6 snRNPs but not with U4/U5/U6 tri-snRNPs or spliceosomes. Recombinant p110 binds U6 snRNA in vitro requiring an internal U6 region, and p110 functions in the reassembly of U4/U6 snRNP in an in vitro recycling assay, establishing its role as a U4/U6 snRNP recycling factor. Its domain structure comprises an N-terminal region with seven tetratricopeptide repeat (TPR) domains and C-terminal RNA recognition motifs (RRMs).\",\n      \"method\": \"RNA immunoprecipitation, in vitro RNA binding assay, in vitro U4/U6 snRNP recycling assay, database/domain analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of recycling activity combined with direct RNA binding assay and snRNP association experiments in a single focused study\",\n      \"pmids\": [\"12032085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SART3/p110 is enriched in Cajal bodies (CBs) but not in gems or residual CBs lacking coilin. Its N-terminal HAT domain is necessary and sufficient for targeting to CBs. Overexpression of truncation mutants containing the HAT domain had dominant-negative effects on U6 snRNP localization to CBs, indicating SART3 plays a role in targeting U6 snRNP to CBs. CB localization was reduced by the transcription inhibitor alpha-amanitin, linking CB accumulation to active transcription/splicing.\",\n      \"method\": \"Fluorescence microscopy with GFP-tagged truncation mutants, dominant-negative overexpression, alpha-amanitin treatment, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with domain-mapping mutants and functional dominant-negative readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"12578909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SART3/p110 U4/U6 snRNP recycling activity requires both its RRM domains and its TPR domain, but not the highly conserved C-terminal 10 amino acids. The two RRMs with flanking regions are sufficient for U6-specific RNA binding. The TPR domain interacts with the U4/U6-specific 90K protein (via residues 416-550 of 90K) in yeast two-hybrid assays, suggesting the TPR domain mediates protein-protein interactions during spliceosome recycling.\",\n      \"method\": \"In vitro recycling assay with deletion mutants, in vitro RNA binding, yeast two-hybrid\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with systematic mutagenesis/deletions plus protein interaction mapping in one rigorous study\",\n      \"pmids\": [\"15314151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Zebrafish earl grey (egy) mutation maps to the p110/SART3 gene and causes thymus hypoplasia and other organ defects. U4/U6 snRNPs were disrupted in egy mutant embryos, confirming that p110/SART3 is essential for U4/U6 snRNP recycling in vivo. Loss of p110/SART3 triggered coordinated upregulation of a network of spliceosome cycle components, providing a compensatory mechanism for the recycling defect.\",\n      \"method\": \"Genetic mapping, zebrafish loss-of-function mutant analysis, snRNP fractionation, expression profiling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with direct molecular readout (snRNP disruption) and expression profiling, independently validates in vitro recycling function in vivo\",\n      \"pmids\": [\"17416673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The 3'-cyclic phosphate on U6 snRNA enhances binding of LSm2-8 proteins to U6 snRNA and reduces La protein binding, facilitating RNP remodeling. LSm2-8 proteins recruit p110/SART3 to U6 snRNA via direct interaction with the highly conserved C-terminal region of p110, demonstrating synergistic binding of LSm proteins and p110 to U6 snRNA.\",\n      \"method\": \"In vitro binding assays with purified/recombinant proteins and synthetic U6 variants, gel-shift and pull-down assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined biochemical components, domain mapping of interaction, multiple binding assays\",\n      \"pmids\": [\"18567812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SART3 interacts physically with the pre-mRNA splicing factor RNPS1 through the N-terminal domains of RNPS1, as confirmed by in vitro pull-down and co-immunoprecipitation. Co-transfection of both genes redistributes SART3 from diffuse nucleoplasmic to nuclear speckled regions co-localizing with RNPS1. In cooperation with RNPS1, SART3 stimulates proximal alternative 3' splicing of a calcitonin-DHFR chimeric minigene pre-mRNA.\",\n      \"method\": \"Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation, immunofluorescence, minigene splicing assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus pull-down, localization change, and functional splicing assay in one study\",\n      \"pmids\": [\"11477570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SART3/TIP110 (Tip110) interacts directly with HIV-1 Tat protein in vivo, confirmed by co-immunoprecipitation and Western blotting combined with mutagenesis. Tip110 strongly potentiates Tat-mediated HIV-1 LTR promoter transactivation and HIV-1 virus production; knock-down of Tip110 inhibits HIV-1 production. Tip110 localizes exclusively to the nucleus in nuclear speckle structures overlapping with cyclin T and CDK9.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, mutagenesis, CAT reporter assay, siRNA knockdown, digital fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with mutagenesis, functional reporter and virus production assays, and direct localization in one study\",\n      \"pmids\": [\"11959860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SART3 has histone chaperone activity and directly associates with the deubiquitinase Usp15 in the nucleus. SART3 enhances Usp15 binding to mono-ubiquitinated H2B (ubH2B) and facilitates deubiquitination of ubH2B in free histones (but not in nucleosomes), suggesting SART3 recruits ubH2B evicted during transcription for deubiquitination. SART3 also indirectly associates with the ubH2B E3 ligase RNF20/RNF40.\",\n      \"method\": \"Affinity purification with non-hydrolyzable ubH2B mimic, co-immunoprecipitation, in vitro deubiquitination assay with nucleosomes and free histones\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro deubiquitination reconstitution with defined substrates (free histones vs. nucleosomes), affinity purification, and Co-IP in single study\",\n      \"pmids\": [\"24526689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SART3 is required for the accumulation of incomplete spliceosomal snRNP intermediates in Cajal bodies (CBs). Depletion of SART3 prevents both the induction of CB formation (triggered by imbalanced snRNP assembly) and the tethering of incomplete snRNPs to coilin (CB scaffolding protein), indicating SART3 monitors tri-snRNP assembly and sequesters incomplete particles in CBs to maintain homeostatic balance of mature snRNPs.\",\n      \"method\": \"siRNA depletion, immunofluorescence microscopy, co-immunoprecipitation with coilin\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with specific cellular phenotype (CB formation and snRNP tethering), multiple orthogonal readouts in one study\",\n      \"pmids\": [\"25600876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the SART3 HAT (half-a-tetratricopeptide) repeat domain alone and in complex with the DUSP-UBL domains of USP4 was determined. The 12 HAT repeats form two sub-domains (HAT-N and HAT-C); HAT-C mediates dimerization; USP4 binds at the opposite surface of the HAT-C dimer interface via the beta-structured linker between DUSP and UBL. Binding affinities of USP4 and USP15 to SART3 are 0.9 μM and 0.2 μM respectively. The SART3 nuclear localization signal (NLS) forms bipartite interaction with importin-α; deletion of the NLS prevents nuclear entry of USP4 and USP15 and abrogates USP4 deubiquitinase activity.\",\n      \"method\": \"X-ray crystallography, binding affinity measurements (SPR/ITC implied), NLS deletion mutants, nuclear localization assay, deubiquitinase activity assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation (NLS deletion abrogating nuclear entry and DUB activity), multiple orthogonal methods\",\n      \"pmids\": [\"27060135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SART3 interacts with DNA polymerase η (Polη) and RAD18 via its C-terminus, and can form homodimers that promote the Polη/RAD18 interaction and PCNA monoubiquitination after UV exposure. Depletion of SART3 impairs UV-induced ssDNA generation and RPA focus formation, reduces Polη recruitment to stalled replication forks, and increases mutation frequency and UV hypersensitivity. This function is RNA binding-independent.\",\n      \"method\": \"Affinity purification/co-IP, deletion mapping (C-terminus), siRNA knockdown with UV survival/mutation frequency assay, immunofluorescence for RPA and Polη foci, PCNA ubiquitination assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping, functional knockout phenotypes (mutation frequency, foci formation, PCNA ubiquitination) with multiple orthogonal methods\",\n      \"pmids\": [\"29590477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SART3 binds pre-miR-34a with higher specificity than a negative-control pre-miRNA via its RNA recognition motifs (RRMs). SART3 overexpression increases mature miR-34a levels, downregulates miR-34a target genes CDK4/6, and causes G1 cell cycle arrest in non-small-cell lung cancer cells.\",\n      \"method\": \"Proteomics/pull-down identification, in vitro RNA binding with RRM mutants, overexpression with miRNA quantification, CDK4/6 Western blot, flow cytometry cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed with domain mapping plus functional cell cycle readout, single lab study\",\n      \"pmids\": [\"31619517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The stress-induced lncRNA LASTR interacts with SART3 (identified by mass spectrometry) and promotes splicing efficiency by controlling SART3 association with U4 and U6 snRNPs during spliceosome recycling; LASTR depletion causes intron retention and decreases cancer cell fitness.\",\n      \"method\": \"Mass spectrometry-based affinity purification, RNA immunoprecipitation, intron retention analysis (RNA-seq), LASTR depletion with cell viability assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based identification with functional snRNP association assay and splicing readout, single lab study\",\n      \"pmids\": [\"31956895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIP110/SART3 is expressed in human CD34+ hematopoietic stem/progenitor cells and decreases with differentiation. Using TIP110 transgenic and haploinsufficient mice, increased TIP110 enhanced hematopoietic progenitor cell (HPC) numbers, survival, and cycling, while decreased TIP110 had opposite effects. TIP110 regulates CMYC and GATA2 expression at the transcriptional level, and TIP110 and CMYC reciprocally regulate each other's expression.\",\n      \"method\": \"Transgenic and haploinsufficient mouse models, colony-forming assays, cell cycle analysis, RT-PCR/Western blot for CMYC and GATA2\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic gain/loss-of-function in vivo with defined cellular and molecular phenotypes, but transcriptional regulation mechanism not fully resolved at mechanistic level\",\n      \"pmids\": [\"21447833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Tip110/SART3 binds to androgen receptor (AR) in an NR box (LXXLL motif)-dependent manner and suppresses AR transcriptional activation of androgen-responsive element (ARE)-driven reporters. Knockdown of Tip110 augments AR transcriptional activation. Tip110 overexpression blocks PSA gene expression and prevents AR–ARE complex formation.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assay, siRNA knockdown, EMSA (AR-ARE complex), Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain-specific mutant, functional reporter + knockdown + EMSA, single lab\",\n      \"pmids\": [\"15031286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A Val591Met missense mutation in SART3 was identified by linkage analysis and sequencing in all affected individuals of a six-generation Chinese family with disseminated superficial actinic porokeratosis (DSAP), mapping to chromosome 12q24.1-24.2, suggesting SART3 is a candidate disease gene for this autosomal dominant skin disorder.\",\n      \"method\": \"Genome-wide linkage analysis, haplotype analysis, Sanger sequencing\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — genetic association only, no functional experiment establishing mechanism; included as disease-gene link\",\n      \"pmids\": [\"15840095\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SART3 (also known as TIP110/p110nrb) is a nuclear RNA-binding protein that functions as the human ortholog of yeast Prp24: its C-terminal RNA recognition motifs (RRMs) bind U6 snRNA, while its N-terminal TPR/HAT repeat domain mediates protein–protein interactions (notably with the U4/U6-specific 90K protein and with deubiquitinases USP4/USP15), enabling SART3 to catalyze reassembly of U4/U6 di-snRNPs after each spliceosome cycle and to target these snRNPs to Cajal bodies for recycling; beyond splicing, SART3 acts as a histone chaperone that facilitates USP15-mediated deubiquitination of H2B, regulates translesion DNA synthesis by scaffolding the Polη/RAD18 complex and promoting PCNA monoubiquitination, potentiates HIV-1 Tat-mediated LTR transactivation through direct Tat interaction, suppresses androgen receptor transcriptional activity via its NR box, promotes miR-34a biogenesis through pre-miR-34a binding, and controls hematopoietic progenitor cell expansion in part through reciprocal regulation of CMYC.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SART3 is a nuclear RNA-binding protein that functions as the human ortholog of yeast Prp24 and serves as the U4/U6 snRNP recycling factor that regenerates spliceosomal di-snRNPs after each round of splicing [#0]. Its bipartite architecture couples C-terminal RNA recognition motifs (RRMs), which bind a specific internal region of U6 snRNA, to an N-terminal TPR/HAT repeat domain that mediates protein–protein contacts, and both are required for recycling activity [#0, #2]. The TPR domain engages the U4/U6-specific 90K protein, while the conserved C-terminus is bound by LSm2-8 proteins that recruit SART3 to U6 snRNA, integrating it into the snRNP remodeling machinery [#2, #4]. SART3 concentrates in Cajal bodies via its HAT domain and directs U6 snRNP localization there for recycling, and more broadly monitors tri-snRNP assembly by sequestering incomplete snRNP intermediates onto the coilin scaffold to maintain snRNP homeostasis [#1, #8]; its essential recycling role is confirmed in vivo, where loss disrupts U4/U6 snRNPs and causes organ defects [#3]. The crystal structure of the HAT domain shows it forms a dimer through HAT-C and recruits the deubiquitinases USP4 and USP15, whose nuclear import and catalytic activity depend on the SART3 nuclear localization signal [#9]. Beyond splicing, SART3 acts as a histone chaperone that presents evicted mono-ubiquitinated H2B to USP15 for deubiquitination [#7], scaffolds the Polη/RAD18 complex to promote PCNA monoubiquitination and translesion synthesis after UV damage in an RNA-binding-independent manner [#10], potentiates HIV-1 Tat-mediated LTR transactivation through direct Tat interaction in nuclear speckles [#6], and promotes miR-34a biogenesis through RRM-mediated pre-miR-34a binding to enforce a CDK4/6-dependent G1 arrest [#11]. A SART3 missense mutation was linked to disseminated superficial actinic porokeratosis in a single family by linkage analysis [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established SART3 as a participant in splicing regulation by identifying a direct interaction with the splicing factor RNPS1 that redirects SART3 to nuclear speckles and modulates alternative 3' splice site choice.\",\n      \"evidence\": \"Yeast two-hybrid, pull-down, Co-IP, and minigene splicing assay\",\n      \"pmids\": [\"11477570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the snRNP-level mechanism\", \"Physiological pre-mRNA targets not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the core molecular function of SART3 as the U4/U6 snRNP recycling factor, the human Prp24 ortholog, that binds U6 snRNA and reassembles U4/U6 di-snRNPs after each splicing cycle.\",\n      \"evidence\": \"RNA immunoprecipitation, in vitro U6 binding, and in vitro recycling reconstitution\",\n      \"pmids\": [\"12032085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protein partners during recycling not yet mapped\", \"In vivo requirement not yet tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Revealed a non-splicing role by showing direct Tat binding and potentiation of HIV-1 LTR transactivation, expanding SART3 function into transcriptional control in nuclear speckles.\",\n      \"evidence\": \"Reciprocal Co-IP with mutagenesis, CAT reporter, virus production, and microscopy\",\n      \"pmids\": [\"11959860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SART3 enhances Tat function unresolved\", \"Relationship to its splicing role unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Localized SART3 function to Cajal bodies, showing the HAT domain is necessary and sufficient for CB targeting and is required to deliver U6 snRNP there for recycling.\",\n      \"evidence\": \"GFP truncation mutants, dominant-negative overexpression, alpha-amanitin treatment\",\n      \"pmids\": [\"12578909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of HAT-mediated CB targeting not defined\", \"Link between CB localization and recycling kinetics unquantified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Dissected the domain requirements for recycling, showing both RRMs and the TPR domain are needed and that the TPR domain contacts the U4/U6-specific 90K protein.\",\n      \"evidence\": \"In vitro recycling with deletion mutants, RNA binding, yeast two-hybrid\",\n      \"pmids\": [\"15314151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the SART3–90K interface not determined\", \"Order of RNA versus protein contacts during recycling unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified a transcriptional repressor function, showing NR-box-dependent binding to the androgen receptor that suppresses AR-driven transcription and PSA expression.\",\n      \"evidence\": \"Co-IP with motif mutant, reporter assay, siRNA knockdown, EMSA\",\n      \"pmids\": [\"15031286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance to prostate biology not established\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Validated the recycling function in vivo, showing that loss of SART3 in zebrafish disrupts U4/U6 snRNPs and causes organ defects with compensatory upregulation of spliceosome components.\",\n      \"evidence\": \"Zebrafish loss-of-function mutant, snRNP fractionation, expression profiling\",\n      \"pmids\": [\"17416673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific sensitivity to recycling loss unexplained\", \"Compensatory network regulators not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Clarified how SART3 is recruited to U6, showing LSm2-8 proteins bind the conserved C-terminus and act synergistically with SART3, with the U6 3'-cyclic phosphate biasing toward LSm over La binding.\",\n      \"evidence\": \"In vitro binding assays with recombinant proteins and synthetic U6 variants\",\n      \"pmids\": [\"18567812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal coordination of LSm and SART3 loading in cells unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended SART3 into hematopoiesis, showing dose-dependent control of progenitor expansion, survival, and cycling via reciprocal transcriptional regulation with CMYC and control of GATA2.\",\n      \"evidence\": \"Transgenic and haploinsufficient mouse models, colony assays, cell cycle and expression analysis\",\n      \"pmids\": [\"21447833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect transcriptional mechanism not resolved\", \"Connection to splicing function unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a histone chaperone role, showing SART3 directly binds USP15 and presents mono-ubiquitinated free histone H2B for deubiquitination, linking SART3 to chromatin/transcription-coupled histone turnover.\",\n      \"evidence\": \"Affinity purification with ubH2B mimic, Co-IP, in vitro deubiquitination of free histones versus nucleosomes\",\n      \"pmids\": [\"24526689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo H2B deubiquitination dependence on SART3 not quantified\", \"Why nucleosomal ubH2B is not a substrate unexplained\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided structural and mechanistic basis for DUB regulation, showing the HAT domain dimerizes and recruits USP4/USP15, and that the SART3 NLS drives their nuclear import and catalytic activity.\",\n      \"evidence\": \"X-ray crystallography of HAT and HAT–USP4 complex, affinity measurements, NLS deletion and DUB activity assays\",\n      \"pmids\": [\"27060135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate specificity of nuclear USP4/USP15 once imported not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established an RNA-independent DNA damage tolerance function, showing C-terminal-mediated scaffolding of Polη/RAD18, promotion of PCNA monoubiquitination, and protection against UV-induced mutagenesis.\",\n      \"evidence\": \"Co-IP with domain mapping, siRNA knockdown with UV survival/mutation assays, foci imaging, PCNA ubiquitination assay\",\n      \"pmids\": [\"29590477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a splicing factor is recruited to stalled forks unknown\", \"Relationship between dimerization and TLS scaffolding unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked SART3 to miRNA biogenesis, showing RRM-dependent specific binding to pre-miR-34a that raises mature miR-34a, downregulates CDK4/6, and arrests cells in G1.\",\n      \"evidence\": \"Pull-down identification, in vitro RNA binding with RRM mutants, miRNA quantification, cell cycle analysis\",\n      \"pmids\": [\"31619517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Step in miR-34a processing affected not pinpointed\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that a stress-induced lncRNA, LASTR, tunes SART3 association with U4/U6 snRNPs to maintain splicing efficiency and cancer cell fitness, adding an RNA-based regulatory layer to recycling.\",\n      \"evidence\": \"Mass spectrometry, RNA-IP, intron retention RNA-seq, LASTR depletion viability assay\",\n      \"pmids\": [\"31956895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect modulation of SART3 by LASTR not separated\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SART3's distinct activities — snRNP recycling, histone deubiquitination, translesion synthesis, transcriptional and miRNA regulation — are coordinated within the nucleus, and which are physiologically dominant, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking the multiple functions\", \"Mechanism of the DSAP disease mutation not functionally tested\", \"Context-specific partitioning between roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 4, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4, 7, 10]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3, 4, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 14]}\n    ],\n    \"complexes\": [\n      \"U4/U6 di-snRNP\",\n      \"Cajal body\"\n    ],\n    \"partners\": [\n      \"USP4\",\n      \"USP15\",\n      \"PRPF3\",\n      \"RNPS1\",\n      \"Tat\",\n      \"POLH\",\n      \"RAD18\",\n      \"coilin\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}