{"gene":"SART1","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2025,"finding":"SART1 localizes uniquely to the distal surface of mitotic centrosomes along the spindle axis, forming a structure called the 'SART1 cap'. SART1 functions as a mitosis-specific microtubule-associated protein; its N-terminus is the microtubule-binding region. SART1 downregulation causes spindle assembly defects with reduced microtubule dynamics, end-on attachment defects, and checkpoint activation in human cells. SART1 depletion does not affect centriole duplication or γ-tubulin accumulation but reduces selective PCM proteins such as ninein. Depletion from frog egg extracts disrupts spindle pole assembly in both centrosomal and acentrosomal contexts. Immunoprecipitation consistently identifies centrosomal proteins as SART1 interaction partners.","method":"RNAi knockdown in human cells, immunostaining, live imaging, immunoprecipitation, Xenopus egg extract spindle assembly assay, N-terminal truncation/mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (cell depletion, extract reconstitution, mutagenesis of binding domain, immunoprecipitation, live imaging) in a single rigorous study establishing a direct mitotic function","pmids":["40320072"],"is_preprint":false},{"year":2024,"finding":"SART1 promotes DNA double-strand break (DSB) end resection, an essential first step of homologous recombination (HR). This function requires phosphorylation of SART1 at threonine 430 and 695 by ATM/ATR. SART1 is recruited to DSB sites in a manner dependent on active transcription and its RS domain. SART1 is epistatic with BRCA1 in promoting resection, particularly transcription-associated resection in G2 phase. SART1 and BRCA1 accumulate at DSB sites interdependently and epistatically counteract the resection blockade by 53BP1 and RIF1. SART1 and BRCA1 epistatically suppress genomic alterations from DSB misrepair in G2.","method":"siRNA knockdown, epistasis analysis, phospho-mutant constructs, chromatin recruitment assays (live imaging/foci), chromosome aberration analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by double knockdown, ATM/ATR phospho-site mutagenesis, recruitment assays, and chromosome analysis; multiple orthogonal methods in one study","pmids":["39117746"],"is_preprint":false},{"year":2024,"finding":"SART1 silencing leads to increased poly-ADP ribosylation and increased chromatin-bound PARP1. SART1 is recruited to chromatin following DNA damage and limits PARP1 chromatin retention and activity. The N-terminus of SART1 (containing an RGG/RG box) is sufficient to regulate PAR chain accumulation and PARP1 chromatin retention. Silencing of SART1 increases cellular sensitivity to IR-induced DNA damage and to PARP inhibitors specifically in the absence of BRCA1.","method":"siRNA knockdown, chromatin fractionation, PAR chain quantification, PARP1 chromatin localization assays, N-terminal truncation constructs, drug sensitivity assays","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical fractionation, domain mapping, functional drug-sensitivity assays) in a single focused study","pmids":["39569366"],"is_preprint":false},{"year":2021,"finding":"SART1 suppresses HBV cccDNA transcription by directly downregulating hepatocyte nuclear factor 4α (HNF4α) expression. ChIP assays demonstrated that SART1 associates with the HNF4α proximal P1 promoter element. This anti-HBV activity is independent of Janus kinase signaling. Knockdown of SART1 markedly enhanced HBV RNA, antigen expression, and progeny virus production, while overexpression inhibited HBV transcription and replication in cell culture and in AAV-HBV mice.","method":"siRNA knockdown, lentiviral/AAV overexpression, luciferase reporter assays, chromatin immunoprecipitation (ChIP), in vivo mouse models","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP establishes direct promoter binding, complemented by reporter assays, in vitro knockdown/OE, and in vivo mouse validation; multiple orthogonal methods","pmids":["34242702"],"is_preprint":false},{"year":2014,"finding":"SART1 exerts its anti-HCV action through mRNA splicing. SART1 knockdown identified 419 differentially expressed genes and revealed that SART1 regulates antiviral interferon effector genes (IEGs) by direct transcriptional regulation for some ISGs (e.g. MX1, OAS3) and by promoting alternative mRNA splicing for others including EIF4G3, GORASP2, ZFAND6, and RAB6A. SART1 does not affect the JAK-STAT pathway or IFN receptor signaling. EIF4G3 and GORASP2 were confirmed to have anti-HCV effects.","method":"siRNA knockdown, mRNA-sequencing, qRT-PCR, Western blot, HCV replicon model","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq with functional validation of specific splicing targets in HCV model, single lab","pmids":["25481564"],"is_preprint":false},{"year":2010,"finding":"SART1 (as the 110 kDa U4/U6.U5 tri-snRNP component) is SUMOylated at lysines 94 and 141 in vivo. In vitro sumoylation confirmed preferential conjugation of SUMO-2 monomers and multimers at Lys94 and Lys141. Positively charged amino acids flanking the sumoylation consensus tetramer at Lys94 enhance sumoylation efficiency. Mutation of Lys94 and Lys141 reduces SART1 sumoylation in HeLa cells.","method":"In vitro SUMO conjugation assay with recombinant SART1, MALDI-ToF/FT-ICR/nanoLC-MS/MS, site-directed mutagenesis (K94R/K141R), in vivo sumoylation in HeLa cells","journal":"Journal of proteomics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of SUMOylation with mass spectrometry site identification and mutational validation in cells; single lab but two orthogonal systems","pmids":["20346425"],"is_preprint":false},{"year":2009,"finding":"HAF (SART1) is an oxygen-independent E3 ubiquitin ligase for HIF-1α that degrades HIF-1α but not HIF-2α, providing isoform-specific regulation of HIF pathway members.","method":"Described as summary of prior experimental work; ubiquitin ligase activity and substrate specificity established by prior biochemical assays (referenced in this review)","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review summarizing prior experimental findings on E3 ligase activity; underlying experiments not fully described in this abstract alone","pmids":["19377289"],"is_preprint":false},{"year":2014,"finding":"HAF (SART1) SUMOylation is induced by hypoxia and is required for HAF to complex with HIF2α at DNA to promote HIF2-dependent transcription in clear-cell renal cell carcinoma. In contrast, HAF-mediated HIF1α degradation is SUMOylation-independent. HAF overexpression in mice increased CRCC growth and metastasis.","method":"Co-IP/ChIP of HAF-HIF2α complex at DNA, SUMOylation mutant constructs, in vivo mouse model, Western blot","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP establishes HAF:HIF2α complex at DNA, SUMOylation mutant separates two distinct mechanisms, in vivo validation; multiple orthogonal methods","pmids":["25421578"],"is_preprint":false},{"year":2016,"finding":"HAF (SART1) acts as a tumor suppressor in immune cells by preventing inappropriate HIF-1α activation. In SART1+/- male mice, HIF-1α is upregulated in circulating and liver-infiltrating immune cells, driving HIF-1-dependent RANTES (CCL5) production from Kupffer cells and increased neutrophilic liver infiltration. SART1-/- mice are embryonic lethal. Neutralization of RANTES decreased neutrophilic infiltration and attenuated HCC in SART1+/- mice.","method":"Germline SART1 knockout/heterozygous mouse model, cytokine measurement, RANTES neutralization in vivo, cell-type-specific HIF-1α analysis","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model with specific pathway readouts (HIF-1α, RANTES), neutralization rescue experiment, and multiple cell-type analyses","pmids":["26799785"],"is_preprint":false},{"year":2019,"finding":"HAF (SART1) promotes ubiquitination and proteasomal degradation of neurofibromin (NF1), independently of oxygen and pVHL, resulting in Ras-ERK pathway activation. Hypoxia enhanced HAF:neurofibromin binding independently of HAF-SUMOylation. HAF knockdown increased neurofibromin levels primarily in hypoxia. HAF-mediated resistance to sorafenib/sunitinib was HIF-2α-dependent in normoxia but HIF-2α-independent in hypoxia, indicating two mechanistic pathways.","method":"Co-IP (HAF:neurofibromin), ubiquitination assay, HAF knockdown, p-ERK measurement, drug resistance assays, HIF-2α siRNA epistasis","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, epistasis with HIF-2α, HAF knockdown with defined readouts; multiple orthogonal methods in one study","pmids":["30705246"],"is_preprint":false},{"year":2024,"finding":"HAF (SART1) regulates NF-κB activity in hepatocytes by controlling transcription of TRADD and RIPK1. Hepatocyte-specific SART1 deletion (hepS-/-) causes decreased phospho-p65 and phospho-p50 (NF-κB components) and triggers apoptosis, leading to HCC in both male and female mice. HAF siRNA in vitro recapitulates these effects. High-fat diet suppresses HAF and NF-κB components in early-stage disease but they are upregulated in HCC.","method":"Conditional hepatocyte-specific Cre/lox SART1 knockout (Alb-Cre), Western blot for NF-κB components, HAF siRNA in vitro, high-fat diet model, myeloid-specific knockout as control","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic deletion with defined molecular readouts (NF-κB phosphorylation, apoptosis markers), in vitro siRNA recapitulation, and dietary model validation","pmids":["39255518"],"is_preprint":false},{"year":2011,"finding":"Silencing of SART1 sensitizes colorectal cancer cells to 5-FU and SN38 by inducing caspase-8-dependent apoptosis. SART1 knockdown downregulates c-FLIP (a caspase-8 inhibitor), identifying SART1 as a regulator of c-FLIP expression and drug-induced caspase-8 activation.","method":"siRNA knockdown in 5 colorectal cancer cell lines, caspase-8 inhibitor rescue, Western blot for c-FLIP, drug sensitivity assays","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA in multiple cell lines, pharmacological rescue of caspase-8 activation, c-FLIP Western blot; single lab","pmids":["22027693"],"is_preprint":false},{"year":2005,"finding":"Overexpression of SART-1 via adenoviral transduction inhibits cell growth, induces cell cycle arrest, and activates apoptosis pathways in A549 and MCF-7 cancer cells.","method":"Recombinant adenovirus-mediated gene transduction, Trypan Blue exclusion, flow cytometry, Western blot for apoptosis markers","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined cellular phenotype (cell cycle arrest, apoptosis) with molecular confirmation by Western blot, but single lab, single method per endpoint","pmids":["16158934"],"is_preprint":false},{"year":2020,"finding":"In zebrafish, a point mutation in exon 12 of sart1 causes upregulation of sart1, increased apoptosis (activated caspase-3) in brain and eye, downregulation of vision-related genes, and developmental defects in the central nervous system. sart1 expression is restricted to the brain in zebrafish.","method":"Forward genetic screen, whole-exome sequencing, RNA-Seq, immunostaining for activated caspase-3, in situ expression analysis","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model with RNA-Seq and immunostaining; multiple methods but single lab in a model organism","pmids":["33105605"],"is_preprint":false},{"year":2024,"finding":"In Saccharomyces cerevisiae, the phosphatase Psr1 binds and dephosphorylates the core splicing factor Snu66 (SART1 ortholog). Psr1 deletion or tethering of catalytic-dead Psr1 to Snu66 results in splicing defects of introns with non-canonical 5' splice sites. Hub1 can displace Psr1 from Snu66, linking two regulatory inputs on this spliceosomal component.","method":"Genetic deletion (PSR1 knockout), catalytic mutant tethering, splicing assays, protein interaction assays","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and binding/splicing assays in yeast; ortholog of SART1, single lab","pmids":["39484844"],"is_preprint":false},{"year":2015,"finding":"In ccRCC cells expressing mutant VHL, HIF1α undergoes proteasome-dependent degradation mediated by the E3 ubiquitin ligase SART1 under hypoxic conditions. Mutant VHL can protect HIF1α from SART1-dependent degradation in normoxia, but this protection is lost in hypoxia. SART1-mediated HIF1α degradation favors ccRCC proliferation.","method":"siRNA inhibition of SART1 and VHL, proteasome inhibitor rescue, HIF1α protein level assays, proliferation assays in RCC4 and RCC10 cell lines","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with proteasome inhibitor validation in multiple cell lines; single lab","pmids":["25915846"],"is_preprint":false},{"year":2021,"finding":"Suppression of SART1 by siRNA in macrophages attenuates M2 macrophage polarization. In a bleomycin-induced pulmonary fibrosis mouse model, SART1 siRNA-loaded liposomes accumulated in macrophages and reduced M2 macrophage infiltration and fibrosis.","method":"siRNA knockdown, liposome delivery in vivo, bleomycin mouse model, macrophage polarization assays","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo knockdown with specific macrophage polarization readout; single lab","pmids":["33391530"],"is_preprint":false}],"current_model":"SART1 (also known as HAF/SNRNP110/Snu66) is a multifunctional nuclear protein that serves as a core U4/U6·U5 tri-snRNP component regulating pre-mRNA splicing, acts as an oxygen-independent E3 ubiquitin ligase selectively targeting HIF-1α (but not HIF-2α) for degradation, functions as a mitosis-specific microtubule-associated protein that localizes to a novel centrosomal 'cap' structure to recruit PCM proteins for spindle pole assembly, promotes BRCA1-dependent homologous recombination at DSBs via ATM/ATR-dependent phosphorylation and epistatic counteraction of 53BP1/RIF1, limits PARP1 chromatin retention and PAR chain accumulation through its N-terminal RGG/RG box, suppresses HBV cccDNA transcription by directly binding the HNF4α promoter, and regulates NF-κB activity in hepatocytes by controlling TRADD and RIPK1 transcription to suppress apoptosis."},"narrative":{"mechanistic_narrative":"SART1 is a multifunctional nuclear protein with distinct roles in pre-mRNA splicing, genome maintenance, mitotic spindle assembly, and oxygen-independent control of the HIF pathway [PMID:40320072, PMID:39117746, PMID:25421578, PMID:39484844]. As a core U4/U6·U5 tri-snRNP component (the 110 kDa subunit; yeast Snu66), it governs alternative mRNA splicing, and in yeast its ortholog is dephosphorylated by the phosphatase Psr1 to enable splicing of introns with non-canonical 5' splice sites [PMID:39484844]; this splicing activity underlies its regulation of antiviral effector genes [PMID:25481564]. SART1 is SUMOylated at Lys94 and Lys141, with hypoxia-induced SUMOylation required to form a HAF:HIF2α complex on DNA that drives HIF2-dependent transcription [PMID:20346425, PMID:25421578]. Independently of SUMOylation and of oxygen, SART1/HAF functions as an E3 ubiquitin ligase that selectively targets HIF-1α (but not HIF-2α) and neurofibromin (NF1) for proteasomal degradation, the latter activating Ras-ERK signaling [PMID:19377289, PMID:30705246, PMID:25915846]. In genome maintenance, SART1 is recruited to DNA double-strand breaks in a transcription- and RS-domain-dependent manner and, following ATM/ATR phosphorylation at Thr430 and Thr695, acts epistatically with BRCA1 to promote end resection and counteract the 53BP1/RIF1 resection blockade, while its N-terminal RGG/RG box limits PARP1 chromatin retention and PAR chain accumulation [PMID:39117746, PMID:39569366]. During mitosis it acts as a microtubule-associated protein via its N-terminus, localizing to a distal centrosomal 'SART1 cap' to recruit PCM proteins such as ninein for spindle pole assembly [PMID:40320072]. In hepatocytes SART1/HAF controls TRADD and RIPK1 transcription to sustain NF-κB activity and suppress apoptosis, and prevents inappropriate HIF-1α activation in immune cells, with germline loss being embryonic lethal and tissue-specific loss promoting hepatocellular carcinoma [PMID:26799785, PMID:39255518]. It additionally suppresses HBV cccDNA transcription by directly binding the HNF4α P1 promoter [PMID:34242702].","teleology":[{"year":2005,"claim":"Established that SART1 overexpression has growth-suppressive consequences, providing the first functional handle on its cellular role.","evidence":"adenoviral SART-1 overexpression in A549/MCF-7 cells with cell cycle and apoptosis readouts","pmids":["16158934"],"confidence":"Medium","gaps":["No molecular mechanism for growth arrest defined","Single method per endpoint, single lab","Overexpression phenotype not tied to a defined biochemical activity"]},{"year":2009,"claim":"Identified SART1/HAF as an oxygen-independent E3 ubiquitin ligase with isoform-selective targeting, distinguishing it from canonical pVHL-based HIF regulation.","evidence":"review summarizing prior biochemical ubiquitin ligase/substrate-specificity assays for HIF-1α vs HIF-2α","pmids":["19377289"],"confidence":"Medium","gaps":["Underlying experiments not detailed in this source","Catalytic mechanism and any RING/HECT domain not defined","Substrate recognition determinants unknown"]},{"year":2010,"claim":"Defined SART1 as a SUMOylation target, identifying the modified residues that would later prove functionally separable from its ligase activity.","evidence":"in vitro SUMO conjugation with MS site mapping and K94R/K141R mutagenesis in HeLa cells","pmids":["20346425"],"confidence":"High","gaps":["SUMO E3 ligase responsible in vivo not identified","Functional consequence of SUMOylation not addressed in this study"]},{"year":2014,"claim":"Resolved that SART1 SUMOylation is hypoxia-induced and required specifically for HIF2α transactivation while HIF1α degradation is SUMOylation-independent, separating two HAF mechanisms.","evidence":"Co-IP/ChIP of HAF:HIF2α at DNA, SUMO-mutant constructs, and ccRCC mouse models","pmids":["25421578"],"confidence":"High","gaps":["How SUMOylation enables DNA-bound complex formation structurally unknown","Genome-wide HIF2 target set not mapped"]},{"year":2014,"claim":"Connected SART1's splicing function to antiviral output, showing it regulates interferon effector genes via both transcription and alternative splicing.","evidence":"siRNA knockdown with mRNA-seq and validation of splicing targets in HCV replicon model","pmids":["25481564"],"confidence":"Medium","gaps":["Direct splice-site interactions for target transcripts not demonstrated","Mechanism distinguishing direct transcriptional vs splicing targets unclear"]},{"year":2015,"claim":"Provided cellular evidence that SART1-mediated HIF1α degradation proceeds under hypoxia even in VHL-mutant ccRCC, supporting a pVHL-independent degradation route.","evidence":"siRNA of SART1/VHL with proteasome inhibitor rescue and proliferation assays in RCC lines","pmids":["25915846"],"confidence":"Medium","gaps":["Direct ubiquitination by SART1 not shown in this study","How mutant VHL protects HIF1α in normoxia mechanistically unresolved"]},{"year":2016,"claim":"Used genetic loss to establish SART1 as essential for development and as a suppressor of inappropriate HIF-1α activation in immune cells driving liver pathology.","evidence":"germline SART1 knockout/heterozygous mice, cytokine measurement, RANTES neutralization rescue","pmids":["26799785"],"confidence":"High","gaps":["Cause of embryonic lethality not defined","Cell-intrinsic vs systemic contribution to HCC not fully separated"]},{"year":2019,"claim":"Extended SART1/HAF ligase activity beyond HIF, identifying neurofibromin as a substrate and linking HAF to Ras-ERK activation and targeted-therapy resistance.","evidence":"reciprocal Co-IP, ubiquitination assay, HAF knockdown, p-ERK readouts, HIF-2α epistasis","pmids":["30705246"],"confidence":"High","gaps":["Structural basis of HAF:neurofibromin recognition unknown","Whether other substrates exist not addressed"]},{"year":2021,"claim":"Showed SART1 directly represses HBV transcription by binding the HNF4α promoter, defining a JAK-independent antiviral mechanism.","evidence":"ChIP, luciferase reporters, knockdown/overexpression, AAV-HBV mouse model","pmids":["34242702"],"confidence":"High","gaps":["DNA-binding domain of SART1 mediating promoter association not mapped","Whether SART1 binds the HNF4α promoter directly or via partners not resolved"]},{"year":2021,"claim":"Implicated SART1 in macrophage M2 polarization and fibrosis, broadening its physiological reach to inflammatory contexts.","evidence":"siRNA knockdown, liposomal delivery in bleomycin pulmonary fibrosis model","pmids":["33391530"],"confidence":"Medium","gaps":["Molecular pathway linking SART1 to polarization not defined","Whether splicing or transcriptional activity drives the effect unknown"]},{"year":2024,"claim":"Defined a phosphorylation-dependent DSB repair role, placing SART1 in the BRCA1 resection pathway and counteracting 53BP1/RIF1.","evidence":"siRNA, ATM/ATR phospho-mutants, recruitment foci, epistasis, chromosome aberration analysis","pmids":["39117746"],"confidence":"High","gaps":["Direct molecular target of SART1 at resection sites unknown","How transcription-dependence couples to recruitment unresolved"]},{"year":2024,"claim":"Identified the SART1 N-terminal RGG/RG box as a limiter of PARP1 chromatin retention and PAR accumulation, explaining BRCA1-context PARP-inhibitor sensitivity.","evidence":"siRNA, chromatin fractionation, PAR quantification, N-terminal truncations, drug sensitivity assays","pmids":["39569366"],"confidence":"High","gaps":["Whether SART1 directly binds PARP1 or PAR not established","Relationship between this N-terminal function and its resection role unclear"]},{"year":2024,"claim":"Established hepatocyte SART1/HAF as a transcriptional controller of TRADD and RIPK1 sustaining NF-κB and suppressing apoptosis-driven HCC.","evidence":"hepatocyte-specific Cre/lox knockout, NF-κB Western blots, siRNA recapitulation, high-fat diet model","pmids":["39255518"],"confidence":"High","gaps":["Whether SART1 binds TRADD/RIPK1 promoters directly not shown","Mechanistic link to its splicing or ligase activities unresolved"]},{"year":2024,"claim":"Defined a regulatory input on the spliceosomal function via the yeast ortholog Snu66, showing phosphatase Psr1 and Hub1 modulate splicing of non-canonical 5' splice sites.","evidence":"PSR1 deletion, catalytic-dead Psr1 tethering, splicing and interaction assays in S. cerevisiae","pmids":["39484844"],"confidence":"Medium","gaps":["Conservation of Psr1/Hub1 regulation in human SART1 not tested","Phosphosites on Snu66 not mapped"]},{"year":2025,"claim":"Revealed a mitosis-specific microtubule-associated function, with SART1 forming a centrosomal 'cap' that recruits PCM for spindle pole assembly.","evidence":"RNAi, immunostaining, live imaging, Xenopus extract spindle assembly, N-terminal MT-binding mapping, IP","pmids":["40320072"],"confidence":"High","gaps":["How a splicing factor is repurposed to centrosomes during mitosis unknown","Specific centrosomal interactors mediating cap formation not fully identified"]},{"year":null,"claim":"How SART1's distinct activities—spliceosomal subunit, oxygen-independent E3 ligase, DSB-repair factor, mitotic MAP, and transcriptional regulator—are coordinated within one protein, and whether shared domains or modifications switch between them, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified structural/domain model integrating the activities","Catalytic mechanism of the E3 ligase function not biochemically resolved in the corpus","Determinants partitioning SART1 between nucleus, chromatin, and centrosome unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[6,9,15]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[4,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,7]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,14]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,10]}],"complexes":["U4/U6·U5 tri-snRNP"],"partners":["HIF1A","HIF2A","NF1","BRCA1","PARP1","PSR1","HUB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43290","full_name":"U4/U6.U5 tri-snRNP-associated protein 1","aliases":["SNU66 homolog","hSnu66","Squamous cell carcinoma antigen recognized by T-cells 1","SART-1","hSART-1","U4/U6.U5 tri-snRNP-associated 110 kDa protein"],"length_aa":800,"mass_kda":90.3,"function":"Plays a role in mRNA splicing as a component of the U4/U6-U5 tri-snRNP, one of the building blocks of the spliceosome. May also bind to DNA","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O43290/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SART1","classification":"Common Essential","n_dependent_lines":1189,"n_total_lines":1208,"dependency_fraction":0.984271523178808},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PRPF4B","stoichiometry":10.0},{"gene":"PRPF8","stoichiometry":4.0},{"gene":"SNRNP40","stoichiometry":4.0},{"gene":"CD2BP2","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"EFTUD2","stoichiometry":0.2},{"gene":"EPN1","stoichiometry":0.2},{"gene":"RBM17","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SART1","total_profiled":1310},"omim":[{"mim_id":"617031","title":"PRE-mRNA-PROCESSING FACTOR 38A; PRPF38A","url":"https://www.omim.org/entry/617031"},{"mim_id":"607795","title":"PRE-mRNA-PROCESSING FACTOR 4; PRPF4","url":"https://www.omim.org/entry/607795"},{"mim_id":"605942","title":"DERMATAN SULFATE EPIMERASE; DSE","url":"https://www.omim.org/entry/605942"},{"mim_id":"605941","title":"SPLICEOSOME-ASSOCIATED FACTOR 1, RECRUITER OF U4/U6.U5 tri-snRNP; SART1","url":"https://www.omim.org/entry/605941"},{"mim_id":"147050","title":"IgE RESPONSIVENESS, ATOPIC; IGER","url":"https://www.omim.org/entry/147050"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear speckles","reliability":"Enhanced"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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SART1 functions as a mitosis-specific microtubule-associated protein; its N-terminus is the microtubule-binding region. SART1 downregulation causes spindle assembly defects with reduced microtubule dynamics, end-on attachment defects, and checkpoint activation in human cells. SART1 depletion does not affect centriole duplication or γ-tubulin accumulation but reduces selective PCM proteins such as ninein. Depletion from frog egg extracts disrupts spindle pole assembly in both centrosomal and acentrosomal contexts. Immunoprecipitation consistently identifies centrosomal proteins as SART1 interaction partners.\",\n      \"method\": \"RNAi knockdown in human cells, immunostaining, live imaging, immunoprecipitation, Xenopus egg extract spindle assembly assay, N-terminal truncation/mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (cell depletion, extract reconstitution, mutagenesis of binding domain, immunoprecipitation, live imaging) in a single rigorous study establishing a direct mitotic function\",\n      \"pmids\": [\"40320072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SART1 promotes DNA double-strand break (DSB) end resection, an essential first step of homologous recombination (HR). This function requires phosphorylation of SART1 at threonine 430 and 695 by ATM/ATR. SART1 is recruited to DSB sites in a manner dependent on active transcription and its RS domain. SART1 is epistatic with BRCA1 in promoting resection, particularly transcription-associated resection in G2 phase. SART1 and BRCA1 accumulate at DSB sites interdependently and epistatically counteract the resection blockade by 53BP1 and RIF1. SART1 and BRCA1 epistatically suppress genomic alterations from DSB misrepair in G2.\",\n      \"method\": \"siRNA knockdown, epistasis analysis, phospho-mutant constructs, chromatin recruitment assays (live imaging/foci), chromosome aberration analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by double knockdown, ATM/ATR phospho-site mutagenesis, recruitment assays, and chromosome analysis; multiple orthogonal methods in one study\",\n      \"pmids\": [\"39117746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SART1 silencing leads to increased poly-ADP ribosylation and increased chromatin-bound PARP1. SART1 is recruited to chromatin following DNA damage and limits PARP1 chromatin retention and activity. The N-terminus of SART1 (containing an RGG/RG box) is sufficient to regulate PAR chain accumulation and PARP1 chromatin retention. Silencing of SART1 increases cellular sensitivity to IR-induced DNA damage and to PARP inhibitors specifically in the absence of BRCA1.\",\n      \"method\": \"siRNA knockdown, chromatin fractionation, PAR chain quantification, PARP1 chromatin localization assays, N-terminal truncation constructs, drug sensitivity assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical fractionation, domain mapping, functional drug-sensitivity assays) in a single focused study\",\n      \"pmids\": [\"39569366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SART1 suppresses HBV cccDNA transcription by directly downregulating hepatocyte nuclear factor 4α (HNF4α) expression. ChIP assays demonstrated that SART1 associates with the HNF4α proximal P1 promoter element. This anti-HBV activity is independent of Janus kinase signaling. Knockdown of SART1 markedly enhanced HBV RNA, antigen expression, and progeny virus production, while overexpression inhibited HBV transcription and replication in cell culture and in AAV-HBV mice.\",\n      \"method\": \"siRNA knockdown, lentiviral/AAV overexpression, luciferase reporter assays, chromatin immunoprecipitation (ChIP), in vivo mouse models\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP establishes direct promoter binding, complemented by reporter assays, in vitro knockdown/OE, and in vivo mouse validation; multiple orthogonal methods\",\n      \"pmids\": [\"34242702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SART1 exerts its anti-HCV action through mRNA splicing. SART1 knockdown identified 419 differentially expressed genes and revealed that SART1 regulates antiviral interferon effector genes (IEGs) by direct transcriptional regulation for some ISGs (e.g. MX1, OAS3) and by promoting alternative mRNA splicing for others including EIF4G3, GORASP2, ZFAND6, and RAB6A. SART1 does not affect the JAK-STAT pathway or IFN receptor signaling. EIF4G3 and GORASP2 were confirmed to have anti-HCV effects.\",\n      \"method\": \"siRNA knockdown, mRNA-sequencing, qRT-PCR, Western blot, HCV replicon model\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq with functional validation of specific splicing targets in HCV model, single lab\",\n      \"pmids\": [\"25481564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SART1 (as the 110 kDa U4/U6.U5 tri-snRNP component) is SUMOylated at lysines 94 and 141 in vivo. In vitro sumoylation confirmed preferential conjugation of SUMO-2 monomers and multimers at Lys94 and Lys141. Positively charged amino acids flanking the sumoylation consensus tetramer at Lys94 enhance sumoylation efficiency. Mutation of Lys94 and Lys141 reduces SART1 sumoylation in HeLa cells.\",\n      \"method\": \"In vitro SUMO conjugation assay with recombinant SART1, MALDI-ToF/FT-ICR/nanoLC-MS/MS, site-directed mutagenesis (K94R/K141R), in vivo sumoylation in HeLa cells\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of SUMOylation with mass spectrometry site identification and mutational validation in cells; single lab but two orthogonal systems\",\n      \"pmids\": [\"20346425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HAF (SART1) is an oxygen-independent E3 ubiquitin ligase for HIF-1α that degrades HIF-1α but not HIF-2α, providing isoform-specific regulation of HIF pathway members.\",\n      \"method\": \"Described as summary of prior experimental work; ubiquitin ligase activity and substrate specificity established by prior biochemical assays (referenced in this review)\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review summarizing prior experimental findings on E3 ligase activity; underlying experiments not fully described in this abstract alone\",\n      \"pmids\": [\"19377289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HAF (SART1) SUMOylation is induced by hypoxia and is required for HAF to complex with HIF2α at DNA to promote HIF2-dependent transcription in clear-cell renal cell carcinoma. In contrast, HAF-mediated HIF1α degradation is SUMOylation-independent. HAF overexpression in mice increased CRCC growth and metastasis.\",\n      \"method\": \"Co-IP/ChIP of HAF-HIF2α complex at DNA, SUMOylation mutant constructs, in vivo mouse model, Western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP establishes HAF:HIF2α complex at DNA, SUMOylation mutant separates two distinct mechanisms, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"25421578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HAF (SART1) acts as a tumor suppressor in immune cells by preventing inappropriate HIF-1α activation. In SART1+/- male mice, HIF-1α is upregulated in circulating and liver-infiltrating immune cells, driving HIF-1-dependent RANTES (CCL5) production from Kupffer cells and increased neutrophilic liver infiltration. SART1-/- mice are embryonic lethal. Neutralization of RANTES decreased neutrophilic infiltration and attenuated HCC in SART1+/- mice.\",\n      \"method\": \"Germline SART1 knockout/heterozygous mouse model, cytokine measurement, RANTES neutralization in vivo, cell-type-specific HIF-1α analysis\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model with specific pathway readouts (HIF-1α, RANTES), neutralization rescue experiment, and multiple cell-type analyses\",\n      \"pmids\": [\"26799785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HAF (SART1) promotes ubiquitination and proteasomal degradation of neurofibromin (NF1), independently of oxygen and pVHL, resulting in Ras-ERK pathway activation. Hypoxia enhanced HAF:neurofibromin binding independently of HAF-SUMOylation. HAF knockdown increased neurofibromin levels primarily in hypoxia. HAF-mediated resistance to sorafenib/sunitinib was HIF-2α-dependent in normoxia but HIF-2α-independent in hypoxia, indicating two mechanistic pathways.\",\n      \"method\": \"Co-IP (HAF:neurofibromin), ubiquitination assay, HAF knockdown, p-ERK measurement, drug resistance assays, HIF-2α siRNA epistasis\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, epistasis with HIF-2α, HAF knockdown with defined readouts; multiple orthogonal methods in one study\",\n      \"pmids\": [\"30705246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HAF (SART1) regulates NF-κB activity in hepatocytes by controlling transcription of TRADD and RIPK1. Hepatocyte-specific SART1 deletion (hepS-/-) causes decreased phospho-p65 and phospho-p50 (NF-κB components) and triggers apoptosis, leading to HCC in both male and female mice. HAF siRNA in vitro recapitulates these effects. High-fat diet suppresses HAF and NF-κB components in early-stage disease but they are upregulated in HCC.\",\n      \"method\": \"Conditional hepatocyte-specific Cre/lox SART1 knockout (Alb-Cre), Western blot for NF-κB components, HAF siRNA in vitro, high-fat diet model, myeloid-specific knockout as control\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic deletion with defined molecular readouts (NF-κB phosphorylation, apoptosis markers), in vitro siRNA recapitulation, and dietary model validation\",\n      \"pmids\": [\"39255518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Silencing of SART1 sensitizes colorectal cancer cells to 5-FU and SN38 by inducing caspase-8-dependent apoptosis. SART1 knockdown downregulates c-FLIP (a caspase-8 inhibitor), identifying SART1 as a regulator of c-FLIP expression and drug-induced caspase-8 activation.\",\n      \"method\": \"siRNA knockdown in 5 colorectal cancer cell lines, caspase-8 inhibitor rescue, Western blot for c-FLIP, drug sensitivity assays\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA in multiple cell lines, pharmacological rescue of caspase-8 activation, c-FLIP Western blot; single lab\",\n      \"pmids\": [\"22027693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Overexpression of SART-1 via adenoviral transduction inhibits cell growth, induces cell cycle arrest, and activates apoptosis pathways in A549 and MCF-7 cancer cells.\",\n      \"method\": \"Recombinant adenovirus-mediated gene transduction, Trypan Blue exclusion, flow cytometry, Western blot for apoptosis markers\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined cellular phenotype (cell cycle arrest, apoptosis) with molecular confirmation by Western blot, but single lab, single method per endpoint\",\n      \"pmids\": [\"16158934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In zebrafish, a point mutation in exon 12 of sart1 causes upregulation of sart1, increased apoptosis (activated caspase-3) in brain and eye, downregulation of vision-related genes, and developmental defects in the central nervous system. sart1 expression is restricted to the brain in zebrafish.\",\n      \"method\": \"Forward genetic screen, whole-exome sequencing, RNA-Seq, immunostaining for activated caspase-3, in situ expression analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model with RNA-Seq and immunostaining; multiple methods but single lab in a model organism\",\n      \"pmids\": [\"33105605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Saccharomyces cerevisiae, the phosphatase Psr1 binds and dephosphorylates the core splicing factor Snu66 (SART1 ortholog). Psr1 deletion or tethering of catalytic-dead Psr1 to Snu66 results in splicing defects of introns with non-canonical 5' splice sites. Hub1 can displace Psr1 from Snu66, linking two regulatory inputs on this spliceosomal component.\",\n      \"method\": \"Genetic deletion (PSR1 knockout), catalytic mutant tethering, splicing assays, protein interaction assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and binding/splicing assays in yeast; ortholog of SART1, single lab\",\n      \"pmids\": [\"39484844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In ccRCC cells expressing mutant VHL, HIF1α undergoes proteasome-dependent degradation mediated by the E3 ubiquitin ligase SART1 under hypoxic conditions. Mutant VHL can protect HIF1α from SART1-dependent degradation in normoxia, but this protection is lost in hypoxia. SART1-mediated HIF1α degradation favors ccRCC proliferation.\",\n      \"method\": \"siRNA inhibition of SART1 and VHL, proteasome inhibitor rescue, HIF1α protein level assays, proliferation assays in RCC4 and RCC10 cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with proteasome inhibitor validation in multiple cell lines; single lab\",\n      \"pmids\": [\"25915846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Suppression of SART1 by siRNA in macrophages attenuates M2 macrophage polarization. In a bleomycin-induced pulmonary fibrosis mouse model, SART1 siRNA-loaded liposomes accumulated in macrophages and reduced M2 macrophage infiltration and fibrosis.\",\n      \"method\": \"siRNA knockdown, liposome delivery in vivo, bleomycin mouse model, macrophage polarization assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo knockdown with specific macrophage polarization readout; single lab\",\n      \"pmids\": [\"33391530\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SART1 (also known as HAF/SNRNP110/Snu66) is a multifunctional nuclear protein that serves as a core U4/U6·U5 tri-snRNP component regulating pre-mRNA splicing, acts as an oxygen-independent E3 ubiquitin ligase selectively targeting HIF-1α (but not HIF-2α) for degradation, functions as a mitosis-specific microtubule-associated protein that localizes to a novel centrosomal 'cap' structure to recruit PCM proteins for spindle pole assembly, promotes BRCA1-dependent homologous recombination at DSBs via ATM/ATR-dependent phosphorylation and epistatic counteraction of 53BP1/RIF1, limits PARP1 chromatin retention and PAR chain accumulation through its N-terminal RGG/RG box, suppresses HBV cccDNA transcription by directly binding the HNF4α promoter, and regulates NF-κB activity in hepatocytes by controlling TRADD and RIPK1 transcription to suppress apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SART1 is a multifunctional nuclear protein with distinct roles in pre-mRNA splicing, genome maintenance, mitotic spindle assembly, and oxygen-independent control of the HIF pathway [#0, #1, #7, #14]. As a core U4/U6\\u00b7U5 tri-snRNP component (the 110 kDa subunit; yeast Snu66), it governs alternative mRNA splicing, and in yeast its ortholog is dephosphorylated by the phosphatase Psr1 to enable splicing of introns with non-canonical 5' splice sites [#14]; this splicing activity underlies its regulation of antiviral effector genes [#4]. SART1 is SUMOylated at Lys94 and Lys141, with hypoxia-induced SUMOylation required to form a HAF:HIF2\\u03b1 complex on DNA that drives HIF2-dependent transcription [#5, #7]. Independently of SUMOylation and of oxygen, SART1/HAF functions as an E3 ubiquitin ligase that selectively targets HIF-1\\u03b1 (but not HIF-2\\u03b1) and neurofibromin (NF1) for proteasomal degradation, the latter activating Ras-ERK signaling [#6, #9, #15]. In genome maintenance, SART1 is recruited to DNA double-strand breaks in a transcription- and RS-domain-dependent manner and, following ATM/ATR phosphorylation at Thr430 and Thr695, acts epistatically with BRCA1 to promote end resection and counteract the 53BP1/RIF1 resection blockade, while its N-terminal RGG/RG box limits PARP1 chromatin retention and PAR chain accumulation [#1, #2]. During mitosis it acts as a microtubule-associated protein via its N-terminus, localizing to a distal centrosomal 'SART1 cap' to recruit PCM proteins such as ninein for spindle pole assembly [#0]. In hepatocytes SART1/HAF controls TRADD and RIPK1 transcription to sustain NF-\\u03baB activity and suppress apoptosis, and prevents inappropriate HIF-1\\u03b1 activation in immune cells, with germline loss being embryonic lethal and tissue-specific loss promoting hepatocellular carcinoma [#8, #10]. It additionally suppresses HBV cccDNA transcription by directly binding the HNF4\\u03b1 P1 promoter [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that SART1 overexpression has growth-suppressive consequences, providing the first functional handle on its cellular role.\",\n      \"evidence\": \"adenoviral SART-1 overexpression in A549/MCF-7 cells with cell cycle and apoptosis readouts\",\n      \"pmids\": [\"16158934\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No molecular mechanism for growth arrest defined\", \"Single method per endpoint, single lab\", \"Overexpression phenotype not tied to a defined biochemical activity\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified SART1/HAF as an oxygen-independent E3 ubiquitin ligase with isoform-selective targeting, distinguishing it from canonical pVHL-based HIF regulation.\",\n      \"evidence\": \"review summarizing prior biochemical ubiquitin ligase/substrate-specificity assays for HIF-1\\u03b1 vs HIF-2\\u03b1\",\n      \"pmids\": [\"19377289\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Underlying experiments not detailed in this source\", \"Catalytic mechanism and any RING/HECT domain not defined\", \"Substrate recognition determinants unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined SART1 as a SUMOylation target, identifying the modified residues that would later prove functionally separable from its ligase activity.\",\n      \"evidence\": \"in vitro SUMO conjugation with MS site mapping and K94R/K141R mutagenesis in HeLa cells\",\n      \"pmids\": [\"20346425\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"SUMO E3 ligase responsible in vivo not identified\", \"Functional consequence of SUMOylation not addressed in this study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved that SART1 SUMOylation is hypoxia-induced and required specifically for HIF2\\u03b1 transactivation while HIF1\\u03b1 degradation is SUMOylation-independent, separating two HAF mechanisms.\",\n      \"evidence\": \"Co-IP/ChIP of HAF:HIF2\\u03b1 at DNA, SUMO-mutant constructs, and ccRCC mouse models\",\n      \"pmids\": [\"25421578\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How SUMOylation enables DNA-bound complex formation structurally unknown\", \"Genome-wide HIF2 target set not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected SART1's splicing function to antiviral output, showing it regulates interferon effector genes via both transcription and alternative splicing.\",\n      \"evidence\": \"siRNA knockdown with mRNA-seq and validation of splicing targets in HCV replicon model\",\n      \"pmids\": [\"25481564\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct splice-site interactions for target transcripts not demonstrated\", \"Mechanism distinguishing direct transcriptional vs splicing targets unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided cellular evidence that SART1-mediated HIF1\\u03b1 degradation proceeds under hypoxia even in VHL-mutant ccRCC, supporting a pVHL-independent degradation route.\",\n      \"evidence\": \"siRNA of SART1/VHL with proteasome inhibitor rescue and proliferation assays in RCC lines\",\n      \"pmids\": [\"25915846\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct ubiquitination by SART1 not shown in this study\", \"How mutant VHL protects HIF1\\u03b1 in normoxia mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Used genetic loss to establish SART1 as essential for development and as a suppressor of inappropriate HIF-1\\u03b1 activation in immune cells driving liver pathology.\",\n      \"evidence\": \"germline SART1 knockout/heterozygous mice, cytokine measurement, RANTES neutralization rescue\",\n      \"pmids\": [\"26799785\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Cause of embryonic lethality not defined\", \"Cell-intrinsic vs systemic contribution to HCC not fully separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended SART1/HAF ligase activity beyond HIF, identifying neurofibromin as a substrate and linking HAF to Ras-ERK activation and targeted-therapy resistance.\",\n      \"evidence\": \"reciprocal Co-IP, ubiquitination assay, HAF knockdown, p-ERK readouts, HIF-2\\u03b1 epistasis\",\n      \"pmids\": [\"30705246\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of HAF:neurofibromin recognition unknown\", \"Whether other substrates exist not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed SART1 directly represses HBV transcription by binding the HNF4\\u03b1 promoter, defining a JAK-independent antiviral mechanism.\",\n      \"evidence\": \"ChIP, luciferase reporters, knockdown/overexpression, AAV-HBV mouse model\",\n      \"pmids\": [\"34242702\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"DNA-binding domain of SART1 mediating promoter association not mapped\", \"Whether SART1 binds the HNF4\\u03b1 promoter directly or via partners not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated SART1 in macrophage M2 polarization and fibrosis, broadening its physiological reach to inflammatory contexts.\",\n      \"evidence\": \"siRNA knockdown, liposomal delivery in bleomycin pulmonary fibrosis model\",\n      \"pmids\": [\"33391530\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular pathway linking SART1 to polarization not defined\", \"Whether splicing or transcriptional activity drives the effect unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a phosphorylation-dependent DSB repair role, placing SART1 in the BRCA1 resection pathway and counteracting 53BP1/RIF1.\",\n      \"evidence\": \"siRNA, ATM/ATR phospho-mutants, recruitment foci, epistasis, chromosome aberration analysis\",\n      \"pmids\": [\"39117746\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular target of SART1 at resection sites unknown\", \"How transcription-dependence couples to recruitment unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the SART1 N-terminal RGG/RG box as a limiter of PARP1 chromatin retention and PAR accumulation, explaining BRCA1-context PARP-inhibitor sensitivity.\",\n      \"evidence\": \"siRNA, chromatin fractionation, PAR quantification, N-terminal truncations, drug sensitivity assays\",\n      \"pmids\": [\"39569366\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether SART1 directly binds PARP1 or PAR not established\", \"Relationship between this N-terminal function and its resection role unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established hepatocyte SART1/HAF as a transcriptional controller of TRADD and RIPK1 sustaining NF-\\u03baB and suppressing apoptosis-driven HCC.\",\n      \"evidence\": \"hepatocyte-specific Cre/lox knockout, NF-\\u03baB Western blots, siRNA recapitulation, high-fat diet model\",\n      \"pmids\": [\"39255518\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether SART1 binds TRADD/RIPK1 promoters directly not shown\", \"Mechanistic link to its splicing or ligase activities unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a regulatory input on the spliceosomal function via the yeast ortholog Snu66, showing phosphatase Psr1 and Hub1 modulate splicing of non-canonical 5' splice sites.\",\n      \"evidence\": \"PSR1 deletion, catalytic-dead Psr1 tethering, splicing and interaction assays in S. cerevisiae\",\n      \"pmids\": [\"39484844\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Conservation of Psr1/Hub1 regulation in human SART1 not tested\", \"Phosphosites on Snu66 not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a mitosis-specific microtubule-associated function, with SART1 forming a centrosomal 'cap' that recruits PCM for spindle pole assembly.\",\n      \"evidence\": \"RNAi, immunostaining, live imaging, Xenopus extract spindle assembly, N-terminal MT-binding mapping, IP\",\n      \"pmids\": [\"40320072\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How a splicing factor is repurposed to centrosomes during mitosis unknown\", \"Specific centrosomal interactors mediating cap formation not fully identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SART1's distinct activities\\u2014spliceosomal subunit, oxygen-independent E3 ligase, DSB-repair factor, mitotic MAP, and transcriptional regulator\\u2014are coordinated within one protein, and whether shared domains or modifications switch between them, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified structural/domain model integrating the activities\", \"Catalytic mechanism of the E3 ligase function not biochemically resolved in the corpus\", \"Determinants partitioning SART1 between nucleus, chromatin, and centrosome unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [6, 9, 15]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [4, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 14]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [\n      \"U4/U6\\u00b7U5 tri-snRNP\"\n    ],\n    \"partners\": [\n      \"HIF1A\",\n      \"HIF2A\",\n      \"NF1\",\n      \"BRCA1\",\n      \"PARP1\",\n      \"Psr1\",\n      \"Hub1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}