{"gene":"SLU7","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":1992,"finding":"SLU7 is required for second catalytic step of pre-mRNA splicing and mediates 3' splice site choice; mutations in SLU7 eliminate the normal 20-fold preference for 3' splice sites located >22 nucleotides downstream of the branchpoint. SLU7 contains a zinc knuckle motif (similar to retroviral nucleocapsid proteins) that influences the efficiency, but not sequence specificity, of 3' splice site selection. SLU7 is an essential gene in yeast.","method":"Genetic analysis of SLU7 mutants; competing 3' splice site assays; mutational analysis of zinc knuckle motif","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — functional mutagenesis combined with in vivo and in vitro splicing assays; foundational study replicated by multiple subsequent labs","pmids":["1427075"],"is_preprint":false},{"year":1995,"finding":"SLU7 protein acts during the PRP16-dependent step of splicing and can function after PRP16 in the splicing pathway. SLU7 and a novel factor SSF1 are required in concert with PRP16 to promote progression through the second catalytic step of splicing.","method":"Glycerol gradient sedimentation of spliceosomes; in vitro reconstitution with purified proteins; differential ATP requirement assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified factors and biochemical ordering of SLU7 after PRP16","pmids":["7664739"],"is_preprint":false},{"year":1996,"finding":"SLU7 is only required for splicing when the interval between the branchpoint and the 3' splice site is greater than 7 nucleotides; it is dispensable for splicing of RNAs with short branchpoint-to-3'SS distances. SLU7 is a spliceosome component (shown by immunoprecipitation), its recruitment is greatly enhanced by prior addition of PRP16, and SLU7 remains bound to the excised intron and spliced mRNA after step 2 until spliceosome disassembly (ATP-dependent).","method":"In vitro splicing assays with natural and model pre-mRNAs; anti-SLU7 immunoprecipitation of spliceosomal complexes","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro assay with multiple substrates plus direct immunoprecipitation of spliceosomal SLU7; replicated in subsequent studies","pmids":["8756413"],"is_preprint":false},{"year":1997,"finding":"SLU7 physically interacts with Prp18; the Prp18 interaction domain maps to residues 200–224 of Slu7. Excess Slu7 can bypass the need for Prp18 in vitro, indicating they function in a concerted manner. Prp18 requirement is also dictated by branchpoint-to-3'SS distance (<12 nt makes Prp18 dispensable), paralleling SLU7 requirements.","method":"Two-hybrid assay; in vitro splicing bypass experiments; deletion mutagenesis of SLU7","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — two-hybrid interaction confirmed by in vitro functional bypass, replicated and extended in the 2002 study","pmids":["9153314"],"is_preprint":false},{"year":2002,"finding":"Slu7 contains two functionally important domains: a zinc knuckle (residues 122–135) and a Prp18-interaction domain (residues 215–224). Zinc knuckle mutations (C122A, H130A, C135A) make Slu7 spliceosome binding dependent on Prp18. Alanine mutations in the Prp18-interaction domain abrogate binding to Prp18 in two-hybrid and in vitro assays but do not impair splicing alone; compound mutations in both domains are lethal and abolish splicing. Second-step factors are recruited in the order Slu7 → Prp18 → Prp22, and all three are released after step 2 concomitant with mRNA release.","method":"Alanine cluster mutagenesis; two-hybrid assay; in vitro splicing reconstitution; depletion/reconstitution immunoprecipitations","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (mutagenesis, two-hybrid, in vitro reconstitution, immunoprecipitation) in a single rigorous study","pmids":["12212850"],"is_preprint":false},{"year":2013,"finding":"Fission yeast SpSlu7 has widespread intron-specific splicing functions; a missense mutant reveals global splicing derangements. Features including branchpoint-to-3'SS distance, intron length, and A/U content at the intron 5' end determine SpSlu7 dependence. Unexpectedly, an early splicing arrest in the spslu7-2 mutant reveals a role before catalysis. SpSlu7 shows a salt-stable association with U5 snRNP and genetic interactions with spprp1+ (homolog of human U5-102k), suggesting a role in facilitating spliceosome transitions that promote catalysis.","method":"Missense mutant analysis; global splicing assays; co-fractionation/salt-stability assay with U5 snRNP; genetic interaction analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal methods (mutant analysis, co-fractionation, genetics) but no in vitro reconstitution","pmids":["23754748"],"is_preprint":false},{"year":2014,"finding":"Human SLU7 knockdown in liver cells and mouse liver causes profound changes in pre-mRNA splicing and gene expression, impairs glucose and lipid metabolism, increases proliferation, and reverts hepatocytes to a fetal-like gene expression pattern. SLU7 governs splicing and/or expression of SRSF3 and HNF4α, key hepatocellular differentiation genes, and is critical for cAMP-regulated gene transcription.","method":"siRNA knockdown in human liver cells and mouse liver; RNA-seq; gene expression analysis","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD in cells and in vivo mouse model with defined splicing and functional phenotypes; single lab","pmids":["24865429"],"is_preprint":false},{"year":2016,"finding":"SLU7 binds the C13orf25 primary transcript that encodes the miR-17-92 cluster and is required for its processing and expression. SLU7 knockdown alters splicing of C13orf25, reducing miR-17, miR-20, and miR-92a levels, leading to upregulation of CDKN1A (p21) and BCL2L11 (BIM). Rescue with miR-17 mimic reversed oxidative stress, autophagy and apoptosis upon SLU7 KD in HCC cells.","method":"RNA binding/co-immunoprecipitation of SLU7 with C13orf25 transcript; splicing analysis; miRNA expression; miR-17 mimic rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct binding shown by pulldown, functional consequences confirmed by rescue experiment; single lab","pmids":["26804174"],"is_preprint":false},{"year":2019,"finding":"SLU7 knockdown results in R-loop formation, DNA damage, cell-cycle arrest, and severe mitotic derangements including loss of sister chromatid cohesion (SCC). SLU7 controls generation of truncated SRSF3 (SRSF3-TR); SRSF3-TR acts as a dominant negative/gain-of-function to impair splicing of SRSF1 and the SCC protein sororin, linking SLU7 to genome integrity through a SLU7→SRSF3 splicing→SRSF1/sororin pathway.","method":"siRNA knockdown; R-loop detection; DNA damage assays; mitotic analysis; splicing analysis; epistasis/pathway placement","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placed by multiple orthogonal readouts (R-loops, mitotic phenotypes, splicing) in cells and mouse liver; single lab","pmids":["30657957"],"is_preprint":false},{"year":2021,"finding":"SLU7 is required to maintain DNMT1 protein stability and correct DNA methylation. SLU7 is part of the chromatome complex with DNMT1, its adaptor UHRF1, and histone methyltransferase G9a. Mechanistically, SLU7 prevents DNMT1 acetylation and degradation by facilitating DNMT1 interaction with HDAC1 and the deubiquitinase USP7.","method":"Mass spectrometry (chromatome); co-immunoprecipitation; SLU7 knockdown/KO in multiple cell lines and in vivo liver proliferation models; DNA methylation assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and MS identifying complex, functional validation in multiple cell lines and in vivo; single lab","pmids":["34331453"],"is_preprint":false},{"year":2021,"finding":"SLU7 protects HNF4α1 protein stability against oxidative stress-induced degradation, thereby preserving hepatic differentiation. SLU7 is identified as a key component of the stress granule proteome (by mass spectrometry of the SLU7 interactome), placing it in the cell's antioxidant machinery. SLU7 haploinsufficiency in mice increases sensitivity to chronic (CCl4) and acute (acetaminophen) liver injury, with enhanced oxidative stress and impaired hepatic function; AAV-SLU7 delivery prevents injury and dedifferentiation.","method":"Mass spectrometry of SLU7 interactome; Slu7+/- mouse model; AAV-SLU7 rescue; western blotting for HNF4α protein stability","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interactome MS, in vivo haploinsufficient mouse model, and AAV rescue; single lab, multiple orthogonal approaches","pmids":["34170569"],"is_preprint":false},{"year":2023,"finding":"SLU7 interacts with G3BP1 to form a complex with PABPC1 and eIF4G1 that stabilizes the closed-loop structure of class IA PI3K mRNAs, facilitating their translation and stabilization, thereby activating PI3K/Akt signaling to downregulate MHC-I expression in bladder cancer cells.","method":"Co-immunoprecipitation; pulldown assays; SLU7 knockdown in bladder cancer cells; PI3K/Akt pathway activity assays; MHC-I expression analysis","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP identifying complex components plus functional KD experiments; single lab","pmids":["38084438"],"is_preprint":false},{"year":2024,"finding":"SLU7 interacts with the NMD effector UPF1 and preserves UPF1 protein levels, and SLU7 is required for correct nonsense-mediated mRNA decay (NMD). Caspases activated during liver damage cleave and degrade SLU7, mechanistically linking apoptotic signaling to SLU7 downregulation and NMD inhibition.","method":"Co-immunoprecipitation of SLU7 with UPF1; SLU7 knockdown NMD assays; animal models of liver injury; western blotting for caspase-mediated cleavage","journal":"JHEP reports : innovation in hepatology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP, functional NMD assay, and in vivo liver injury models; single lab","pmids":["39105183"],"is_preprint":false},{"year":2025,"finding":"THRAP3 recruits SLU7 to facilitate GIT2 Exon14 skipping, promoting ferroptosis resistance in AML cells. Inhibition of GIT2 Exon14 skipping reverses THRAP3-induced ferroptosis resistance.","method":"Co-immunoprecipitation of THRAP3 with SLU7; SLU7 knockdown/overexpression; GIT2 splicing analysis; ferroptosis assays in vitro and in vivo","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP, functional splicing analysis, and in vivo tumor models; single lab","pmids":["41326370"],"is_preprint":false},{"year":2026,"finding":"NAA50 catalyzes N-terminal acetylation of SLU7, preventing its ubiquitin-proteasomal degradation and sustaining SLU7 stability. SLU7 directly binds MAP3K3 mRNA and promotes its nuclear export (a non-canonical, splicing-independent function), activating p38 MAPK signaling and driving cisplatin resistance in bladder cancer.","method":"Mass spectrometry; co-immunoprecipitation; RIP-qPCR (SLU7-MAP3K3 mRNA binding); RNA-FISH and nucleocytoplasmic fractionation; NAA50 pharmacological inhibition; xenograft models","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MS, co-IP, RIP-qPCR, fractionation, in vivo); single lab","pmids":["42151695"],"is_preprint":false},{"year":2018,"finding":"In the context of alcoholic liver disease, SLU7 knockdown increased SIRT1 full-length expression while repressing splicing of SIRT1 into the SIRT1-ΔExon8 isoform. SLU7 knockdown also ameliorated splicing of lipin-1 and SRSF3, inhibited NF-κB activity, and reduced oxidative stress.","method":"Adenovirus-mediated SLU7 shRNA knockdown in mice; isoform-specific RT-PCR; NF-κB activity assays; oxidative stress markers","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse KD model with specific splicing isoform readouts; single lab","pmids":["29870742"],"is_preprint":false}],"current_model":"SLU7 is an essential splicing factor that promotes 3' splice site choice during the second catalytic step of pre-mRNA splicing by acting after PRP16, requiring its zinc knuckle domain for spliceosome association and a distinct domain for physical interaction with Prp18; beyond splicing, mammalian SLU7 also regulates genome integrity (suppressing R-loops and maintaining sister chromatid cohesion via SRSF3 splicing), preserves DNMT1 stability and DNA methylation by facilitating DNMT1 interaction with HDAC1 and USP7, protects HNF4α from oxidative degradation as part of the stress granule proteome, supports NMD by stabilizing UPF1, and can promote mRNA nuclear export in a non-canonical splicing-independent manner; its expression is downregulated by caspase-mediated cleavage during liver injury, and it is stabilized by NAA50-mediated N-terminal acetylation."},"narrative":{"mechanistic_narrative":"SLU7 is an essential pre-mRNA splicing factor that governs 3' splice site selection during the second catalytic step of spliceosome action [PMID:1427075]. It functions downstream of the ATPase PRP16: SLU7 recruitment to the spliceosome is enhanced by prior PRP16 action, and it remains bound to the excised intron and spliced mRNA until ATP-dependent spliceosome disassembly [PMID:7664739, PMID:8756413]. Its requirement is dictated by the geometry of the intron, being dispensable when the branchpoint-to-3' splice site distance is short [PMID:8756413]. SLU7 uses two functionally distinct modules: a zinc knuckle motif that supports efficient spliceosome association and 3' splice site selection, and a separate domain (residues ~200–224) that physically binds Prp18; second-step factors are recruited in the order Slu7 → Prp18 → Prp22 [PMID:9153314, PMID:12212850]. Beyond core splicing, mammalian SLU7 has acquired roles in genome integrity, where its control of SRSF3 splicing suppresses R-loop formation and preserves sister chromatid cohesion via sororin [PMID:30657957], and in epigenetic maintenance, where it stabilizes DNMT1 and correct DNA methylation by promoting DNMT1 association with HDAC1 and the deubiquitinase USP7 within a chromatome complex with UHRF1 and G9a [PMID:34331453]. As a component of the stress granule proteome, SLU7 protects HNF4α from oxidative degradation to maintain hepatocyte differentiation [PMID:34170569], supports nonsense-mediated decay by interacting with and stabilizing UPF1 [PMID:39105183], and can drive mRNA nuclear export in a splicing-independent manner [PMID:42151695]. SLU7 levels are controlled by caspase-mediated cleavage during liver injury [PMID:39105183] and by NAA50-catalyzed N-terminal acetylation that blocks its proteasomal degradation [PMID:42151695].","teleology":[{"year":1992,"claim":"Established SLU7 as an essential factor that enforces correct 3' splice site choice, defining its place in the second catalytic step rather than in initial spliceosome assembly.","evidence":"Genetic and competing 3' splice site assays with zinc knuckle mutagenesis in yeast","pmids":["1427075"],"confidence":"High","gaps":["Did not order SLU7 relative to other second-step factors","Mechanism of zinc knuckle contribution to spliceosome binding not resolved"]},{"year":1995,"claim":"Placed SLU7 biochemically downstream of PRP16, showing it acts after the PRP16-dependent transition to complete the second step.","evidence":"Glycerol gradient sedimentation and in vitro reconstitution with purified factors","pmids":["7664739"],"confidence":"High","gaps":["Physical basis of PRP16-dependent recruitment not defined","Role of co-factor SSF1 relative to SLU7 unclear"]},{"year":1996,"claim":"Defined SLU7 as a substrate-geometry-dependent spliceosome component, required only when branchpoint-to-3'SS distance exceeds ~7 nt, and showed it persists on products until disassembly.","evidence":"In vitro splicing with model substrates and anti-SLU7 immunoprecipitation of spliceosomal complexes","pmids":["8756413"],"confidence":"High","gaps":["Structural basis for distance dependence not determined","How SLU7 dissociation is coupled to disassembly unknown"]},{"year":1997,"claim":"Identified Prp18 as a direct SLU7 partner and mapped the interaction domain, showing the two factors act in concert at the second step.","evidence":"Two-hybrid mapping and in vitro splicing bypass with deletion mutants","pmids":["9153314"],"confidence":"High","gaps":["Structure of the SLU7–Prp18 interface not solved","Why excess Slu7 bypasses Prp18 mechanistically unresolved"]},{"year":2002,"claim":"Dissected SLU7 into separable zinc knuckle and Prp18-binding domains and ordered the second-step factor assembly Slu7→Prp18→Prp22, clarifying functional division of labor.","evidence":"Alanine cluster mutagenesis, two-hybrid, in vitro reconstitution, and depletion/reconstitution IPs in yeast","pmids":["12212850"],"confidence":"High","gaps":["High-resolution structure of these domains in the spliceosome lacking","How the two domains cooperate during catalysis not detailed"]},{"year":2013,"claim":"Extended SLU7 function to genome-wide intron-specific splicing and revealed an unexpected pre-catalytic role and U5 snRNP association in fission yeast.","evidence":"Missense mutant analysis, global splicing assays, salt-stable co-fractionation with U5 snRNP, and genetic interactions","pmids":["23754748"],"confidence":"Medium","gaps":["Pre-catalytic role not reconstituted in vitro","Direct contacts with U5 snRNP not mapped"]},{"year":2014,"claim":"Established mammalian SLU7 as a regulator of hepatocyte differentiation and metabolism through control of SRSF3 and HNF4α, expanding its biology beyond core splicing.","evidence":"siRNA knockdown in human liver cells and mouse liver with RNA-seq","pmids":["24865429"],"confidence":"Medium","gaps":["Direct vs indirect targets not fully separated","Single lab; mechanism of SRSF3/HNF4α selectivity unclear"]},{"year":2016,"claim":"Showed SLU7 directly binds and processes the miR-17-92 host transcript, linking it to oncogenic miRNA biogenesis and stress survival.","evidence":"RNA pulldown/co-IP of SLU7 with C13orf25, miRNA quantification, and miR-17 mimic rescue in HCC cells","pmids":["26804174"],"confidence":"Medium","gaps":["Splicing vs processing mechanism not distinguished","Single lab; binding site on the transcript not mapped"]},{"year":2018,"claim":"Connected SLU7 to alcoholic liver disease pathways through isoform-specific control of SIRT1, lipin-1, and SRSF3 affecting NF-κB and oxidative stress.","evidence":"Adenoviral shRNA knockdown in mice with isoform-specific RT-PCR and stress/NF-κB readouts","pmids":["29870742"],"confidence":"Medium","gaps":["Direct SLU7 targets among these transcripts not confirmed by binding","Single lab; disease relevance correlative"]},{"year":2019,"claim":"Defined a SLU7→SRSF3→SRSF1/sororin axis that suppresses R-loops and maintains sister chromatid cohesion, tying SLU7 to genome integrity.","evidence":"siRNA knockdown with R-loop detection, DNA damage and mitotic assays, and splicing epistasis","pmids":["30657957"],"confidence":"Medium","gaps":["Direct evidence of SLU7 binding the implicated transcripts limited","Single lab; SRSF3-TR dominant-negative mechanism not structurally defined"]},{"year":2021,"claim":"Revealed a non-splicing chromatin role: SLU7 stabilizes DNMT1 and preserves DNA methylation by promoting DNMT1 association with HDAC1 and USP7 within a chromatome complex.","evidence":"Chromatome mass spectrometry, co-IP, and knockdown/KO with methylation assays in cells and liver models","pmids":["34331453"],"confidence":"Medium","gaps":["Direct vs scaffolded interactions within the complex not separated","Single lab; stoichiometry and dynamics unknown"]},{"year":2021,"claim":"Placed SLU7 in the stress granule proteome where it protects HNF4α from oxidative degradation, establishing a cytoprotective antioxidant function in liver.","evidence":"Interactome mass spectrometry, Slu7+/- mouse model, and AAV-SLU7 rescue of liver injury","pmids":["34170569"],"confidence":"Medium","gaps":["Mechanism by which SLU7 stabilizes HNF4α not molecularly defined","Single lab; stress granule role overlap with splicing unresolved"]},{"year":2023,"claim":"Identified a translational role in which SLU7 with G3BP1, PABPC1 and eIF4G1 stabilizes PI3K mRNA closed-loop structure, activating PI3K/Akt and modulating MHC-I in bladder cancer.","evidence":"Co-IP, pulldown, knockdown, and pathway/MHC-I assays in bladder cancer cells","pmids":["38084438"],"confidence":"Medium","gaps":["Direct RNA contacts vs complex-mediated effects not separated","Single lab; generality beyond bladder cancer untested"]},{"year":2024,"claim":"Showed SLU7 supports nonsense-mediated decay by binding and stabilizing UPF1, and that caspase cleavage links apoptotic liver injury to SLU7 loss and NMD inhibition.","evidence":"Co-IP with UPF1, NMD assays, liver injury models, and western blotting of caspase cleavage","pmids":["39105183"],"confidence":"Medium","gaps":["Caspase cleavage sites and resulting fragments not mapped","Single lab; direct vs indirect UPF1 stabilization unclear"]},{"year":2025,"claim":"Demonstrated THRAP3-directed recruitment of SLU7 to drive GIT2 exon14 skipping, conferring ferroptosis resistance in AML.","evidence":"Co-IP, knockdown/overexpression, GIT2 splicing analysis, and ferroptosis assays in vitro and in vivo","pmids":["41326370"],"confidence":"Medium","gaps":["Mechanism of THRAP3-mediated recruitment not detailed","Single lab; breadth of THRAP3-SLU7 splicing targets unknown"]},{"year":2026,"claim":"Established a splicing-independent mRNA export function for SLU7 (MAP3K3 mRNA, p38 MAPK activation) and identified NAA50 N-terminal acetylation as a stabilizing post-translational control.","evidence":"Mass spectrometry, co-IP, RIP-qPCR, RNA-FISH/fractionation, NAA50 inhibition, and xenografts","pmids":["42151695"],"confidence":"Medium","gaps":["Export machinery engaged by SLU7 not identified","Single lab; relationship between acetylation and splicing function untested"]},{"year":null,"claim":"How SLU7's conserved core second-step splicing activity is mechanistically partitioned from its many mammalian moonlighting roles (DNA methylation, NMD, mRNA export, translation, genome integrity) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of mammalian SLU7 in or out of the spliceosome","Domain requirements for non-splicing functions undefined","Whether moonlighting functions are independent or splicing-dependent unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7,11,14]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,14]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2]}],"complexes":["spliceosome (second-step complex)","stress granule","chromatome complex (with DNMT1/UHRF1/G9a)"],"partners":["PRP18","DNMT1","HDAC1","USP7","UPF1","G3BP1","THRAP3","NAA50"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95391","full_name":"Pre-mRNA-splicing factor SLU7","aliases":[],"length_aa":586,"mass_kda":68.4,"function":"Required for pre-mRNA splicing as component of the spliceosome (PubMed:10197984, PubMed:28502770, PubMed:30705154). Participates in the second catalytic step of pre-mRNA splicing, when the free hydroxyl group of exon I attacks the 3'-splice site to generate spliced mRNA and the excised lariat intron. Required for holding exon 1 properly in the spliceosome and for correct AG identification when more than one possible AG exists in 3'-splicing site region. May be involved in the activation of proximal AG. Probably also involved in alternative splicing regulation","subcellular_location":"Nucleus; Nucleus speckle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O95391/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SLU7","classification":"Common Essential","n_dependent_lines":1193,"n_total_lines":1208,"dependency_fraction":0.9875827814569537},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLU7","total_profiled":1310},"omim":[{"mim_id":"605974","title":"SLU7 HOMOLOG, SPLICING FACTOR; SLU7","url":"https://www.omim.org/entry/605974"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLU7"},"hgnc":{"alias_symbol":["9G8"],"prev_symbol":[]},"alphafold":{"accession":"O95391","domains":[{"cath_id":"-","chopping":"31-92","consensus_level":"medium","plddt":80.8695,"start":31,"end":92},{"cath_id":"-","chopping":"251-319","consensus_level":"medium","plddt":77.5112,"start":251,"end":319},{"cath_id":"-","chopping":"326-409","consensus_level":"medium","plddt":87.8442,"start":326,"end":409},{"cath_id":"-","chopping":"410-474","consensus_level":"medium","plddt":78.0525,"start":410,"end":474},{"cath_id":"-","chopping":"524-586","consensus_level":"medium","plddt":79.1286,"start":524,"end":586}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95391","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95391-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95391-F1-predicted_aligned_error_v6.png","plddt_mean":75.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLU7","jax_strain_url":"https://www.jax.org/strain/search?query=SLU7"},"sequence":{"accession":"O95391","fasta_url":"https://rest.uniprot.org/uniprotkb/O95391.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95391/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95391"}},"corpus_meta":[{"pmid":"1427075","id":"PMC_1427075","title":"An essential splicing factor, SLU7, mediates 3' splice site choice in yeast.","date":"1992","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/1427075","citation_count":143,"is_preprint":false},{"pmid":"7664739","id":"PMC_7664739","title":"SLU7 and a novel activity, SSF1, act during the PRP16-dependent step of yeast pre-mRNA splicing.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7664739","citation_count":116,"is_preprint":false},{"pmid":"12212850","id":"PMC_12212850","title":"How Slu7 and Prp18 cooperate in the second step of yeast pre-mRNA splicing.","date":"2002","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12212850","citation_count":83,"is_preprint":false},{"pmid":"8756413","id":"PMC_8756413","title":"Requirement for SLU7 in yeast pre-mRNA splicing is dictated by the distance between the branchpoint and the 3' splice site.","date":"1996","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8756413","citation_count":78,"is_preprint":false},{"pmid":"24865429","id":"PMC_24865429","title":"Splicing regulator SLU7 is essential for maintaining liver homeostasis.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24865429","citation_count":63,"is_preprint":false},{"pmid":"9153314","id":"PMC_9153314","title":"Functional and physical interaction between the yeast splicing factors Slu7 and Prp18.","date":"1997","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9153314","citation_count":62,"is_preprint":false},{"pmid":"30657957","id":"PMC_30657957","title":"Splicing events in the control of genome integrity: role of SLU7 and truncated SRSF3 proteins.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/30657957","citation_count":57,"is_preprint":false},{"pmid":"38084438","id":"PMC_38084438","title":"G3BP1 and SLU7 Jointly Promote Immune Evasion by Downregulating MHC-I via PI3K/Akt Activation in Bladder Cancer.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38084438","citation_count":30,"is_preprint":false},{"pmid":"26804174","id":"PMC_26804174","title":"Splicing regulator SLU7 preserves survival of hepatocellular carcinoma cells and other solid tumors via oncogenic miR-17-92 cluster expression.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/26804174","citation_count":25,"is_preprint":false},{"pmid":"34170569","id":"PMC_34170569","title":"Splicing Factor SLU7 Prevents Oxidative Stress-Mediated Hepatocyte Nuclear Factor 4α Degradation, Preserving Hepatic Differentiation and Protecting From Liver Damage.","date":"2021","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/34170569","citation_count":20,"is_preprint":false},{"pmid":"29870742","id":"PMC_29870742","title":"Hepatic Knockdown of Splicing Regulator Slu7 Ameliorates Inflammation and Attenuates Liver Injury in Ethanol-Fed Mice.","date":"2018","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29870742","citation_count":9,"is_preprint":false},{"pmid":"34331453","id":"PMC_34331453","title":"The splicing regulator SLU7 is required to preserve DNMT1 protein stability and DNA methylation.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34331453","citation_count":7,"is_preprint":false},{"pmid":"23754748","id":"PMC_23754748","title":"Splicing functions and global dependency on fission yeast slu7 reveal diversity in spliceosome assembly.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23754748","citation_count":6,"is_preprint":false},{"pmid":"39105183","id":"PMC_39105183","title":"Caspases compromise SLU7 and UPF1 stability and NMD activity during 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target","date":"2025-08-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.25.672085","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12240,"output_tokens":4545,"usd":0.052448,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12461,"output_tokens":4729,"usd":0.090265,"stage2_stop_reason":"end_turn"},"total_usd":0.142713,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"SLU7 is required for second catalytic step of pre-mRNA splicing and mediates 3' splice site choice; mutations in SLU7 eliminate the normal 20-fold preference for 3' splice sites located >22 nucleotides downstream of the branchpoint. SLU7 contains a zinc knuckle motif (similar to retroviral nucleocapsid proteins) that influences the efficiency, but not sequence specificity, of 3' splice site selection. SLU7 is an essential gene in yeast.\",\n      \"method\": \"Genetic analysis of SLU7 mutants; competing 3' splice site assays; mutational analysis of zinc knuckle motif\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — functional mutagenesis combined with in vivo and in vitro splicing assays; foundational study replicated by multiple subsequent labs\",\n      \"pmids\": [\"1427075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SLU7 protein acts during the PRP16-dependent step of splicing and can function after PRP16 in the splicing pathway. SLU7 and a novel factor SSF1 are required in concert with PRP16 to promote progression through the second catalytic step of splicing.\",\n      \"method\": \"Glycerol gradient sedimentation of spliceosomes; in vitro reconstitution with purified proteins; differential ATP requirement assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified factors and biochemical ordering of SLU7 after PRP16\",\n      \"pmids\": [\"7664739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SLU7 is only required for splicing when the interval between the branchpoint and the 3' splice site is greater than 7 nucleotides; it is dispensable for splicing of RNAs with short branchpoint-to-3'SS distances. SLU7 is a spliceosome component (shown by immunoprecipitation), its recruitment is greatly enhanced by prior addition of PRP16, and SLU7 remains bound to the excised intron and spliced mRNA after step 2 until spliceosome disassembly (ATP-dependent).\",\n      \"method\": \"In vitro splicing assays with natural and model pre-mRNAs; anti-SLU7 immunoprecipitation of spliceosomal complexes\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro assay with multiple substrates plus direct immunoprecipitation of spliceosomal SLU7; replicated in subsequent studies\",\n      \"pmids\": [\"8756413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SLU7 physically interacts with Prp18; the Prp18 interaction domain maps to residues 200–224 of Slu7. Excess Slu7 can bypass the need for Prp18 in vitro, indicating they function in a concerted manner. Prp18 requirement is also dictated by branchpoint-to-3'SS distance (<12 nt makes Prp18 dispensable), paralleling SLU7 requirements.\",\n      \"method\": \"Two-hybrid assay; in vitro splicing bypass experiments; deletion mutagenesis of SLU7\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two-hybrid interaction confirmed by in vitro functional bypass, replicated and extended in the 2002 study\",\n      \"pmids\": [\"9153314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Slu7 contains two functionally important domains: a zinc knuckle (residues 122–135) and a Prp18-interaction domain (residues 215–224). Zinc knuckle mutations (C122A, H130A, C135A) make Slu7 spliceosome binding dependent on Prp18. Alanine mutations in the Prp18-interaction domain abrogate binding to Prp18 in two-hybrid and in vitro assays but do not impair splicing alone; compound mutations in both domains are lethal and abolish splicing. Second-step factors are recruited in the order Slu7 → Prp18 → Prp22, and all three are released after step 2 concomitant with mRNA release.\",\n      \"method\": \"Alanine cluster mutagenesis; two-hybrid assay; in vitro splicing reconstitution; depletion/reconstitution immunoprecipitations\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (mutagenesis, two-hybrid, in vitro reconstitution, immunoprecipitation) in a single rigorous study\",\n      \"pmids\": [\"12212850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fission yeast SpSlu7 has widespread intron-specific splicing functions; a missense mutant reveals global splicing derangements. Features including branchpoint-to-3'SS distance, intron length, and A/U content at the intron 5' end determine SpSlu7 dependence. Unexpectedly, an early splicing arrest in the spslu7-2 mutant reveals a role before catalysis. SpSlu7 shows a salt-stable association with U5 snRNP and genetic interactions with spprp1+ (homolog of human U5-102k), suggesting a role in facilitating spliceosome transitions that promote catalysis.\",\n      \"method\": \"Missense mutant analysis; global splicing assays; co-fractionation/salt-stability assay with U5 snRNP; genetic interaction analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal methods (mutant analysis, co-fractionation, genetics) but no in vitro reconstitution\",\n      \"pmids\": [\"23754748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human SLU7 knockdown in liver cells and mouse liver causes profound changes in pre-mRNA splicing and gene expression, impairs glucose and lipid metabolism, increases proliferation, and reverts hepatocytes to a fetal-like gene expression pattern. SLU7 governs splicing and/or expression of SRSF3 and HNF4α, key hepatocellular differentiation genes, and is critical for cAMP-regulated gene transcription.\",\n      \"method\": \"siRNA knockdown in human liver cells and mouse liver; RNA-seq; gene expression analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD in cells and in vivo mouse model with defined splicing and functional phenotypes; single lab\",\n      \"pmids\": [\"24865429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SLU7 binds the C13orf25 primary transcript that encodes the miR-17-92 cluster and is required for its processing and expression. SLU7 knockdown alters splicing of C13orf25, reducing miR-17, miR-20, and miR-92a levels, leading to upregulation of CDKN1A (p21) and BCL2L11 (BIM). Rescue with miR-17 mimic reversed oxidative stress, autophagy and apoptosis upon SLU7 KD in HCC cells.\",\n      \"method\": \"RNA binding/co-immunoprecipitation of SLU7 with C13orf25 transcript; splicing analysis; miRNA expression; miR-17 mimic rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct binding shown by pulldown, functional consequences confirmed by rescue experiment; single lab\",\n      \"pmids\": [\"26804174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLU7 knockdown results in R-loop formation, DNA damage, cell-cycle arrest, and severe mitotic derangements including loss of sister chromatid cohesion (SCC). SLU7 controls generation of truncated SRSF3 (SRSF3-TR); SRSF3-TR acts as a dominant negative/gain-of-function to impair splicing of SRSF1 and the SCC protein sororin, linking SLU7 to genome integrity through a SLU7→SRSF3 splicing→SRSF1/sororin pathway.\",\n      \"method\": \"siRNA knockdown; R-loop detection; DNA damage assays; mitotic analysis; splicing analysis; epistasis/pathway placement\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placed by multiple orthogonal readouts (R-loops, mitotic phenotypes, splicing) in cells and mouse liver; single lab\",\n      \"pmids\": [\"30657957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLU7 is required to maintain DNMT1 protein stability and correct DNA methylation. SLU7 is part of the chromatome complex with DNMT1, its adaptor UHRF1, and histone methyltransferase G9a. Mechanistically, SLU7 prevents DNMT1 acetylation and degradation by facilitating DNMT1 interaction with HDAC1 and the deubiquitinase USP7.\",\n      \"method\": \"Mass spectrometry (chromatome); co-immunoprecipitation; SLU7 knockdown/KO in multiple cell lines and in vivo liver proliferation models; DNA methylation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and MS identifying complex, functional validation in multiple cell lines and in vivo; single lab\",\n      \"pmids\": [\"34331453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLU7 protects HNF4α1 protein stability against oxidative stress-induced degradation, thereby preserving hepatic differentiation. SLU7 is identified as a key component of the stress granule proteome (by mass spectrometry of the SLU7 interactome), placing it in the cell's antioxidant machinery. SLU7 haploinsufficiency in mice increases sensitivity to chronic (CCl4) and acute (acetaminophen) liver injury, with enhanced oxidative stress and impaired hepatic function; AAV-SLU7 delivery prevents injury and dedifferentiation.\",\n      \"method\": \"Mass spectrometry of SLU7 interactome; Slu7+/- mouse model; AAV-SLU7 rescue; western blotting for HNF4α protein stability\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interactome MS, in vivo haploinsufficient mouse model, and AAV rescue; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"34170569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLU7 interacts with G3BP1 to form a complex with PABPC1 and eIF4G1 that stabilizes the closed-loop structure of class IA PI3K mRNAs, facilitating their translation and stabilization, thereby activating PI3K/Akt signaling to downregulate MHC-I expression in bladder cancer cells.\",\n      \"method\": \"Co-immunoprecipitation; pulldown assays; SLU7 knockdown in bladder cancer cells; PI3K/Akt pathway activity assays; MHC-I expression analysis\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP identifying complex components plus functional KD experiments; single lab\",\n      \"pmids\": [\"38084438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLU7 interacts with the NMD effector UPF1 and preserves UPF1 protein levels, and SLU7 is required for correct nonsense-mediated mRNA decay (NMD). Caspases activated during liver damage cleave and degrade SLU7, mechanistically linking apoptotic signaling to SLU7 downregulation and NMD inhibition.\",\n      \"method\": \"Co-immunoprecipitation of SLU7 with UPF1; SLU7 knockdown NMD assays; animal models of liver injury; western blotting for caspase-mediated cleavage\",\n      \"journal\": \"JHEP reports : innovation in hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP, functional NMD assay, and in vivo liver injury models; single lab\",\n      \"pmids\": [\"39105183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"THRAP3 recruits SLU7 to facilitate GIT2 Exon14 skipping, promoting ferroptosis resistance in AML cells. Inhibition of GIT2 Exon14 skipping reverses THRAP3-induced ferroptosis resistance.\",\n      \"method\": \"Co-immunoprecipitation of THRAP3 with SLU7; SLU7 knockdown/overexpression; GIT2 splicing analysis; ferroptosis assays in vitro and in vivo\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP, functional splicing analysis, and in vivo tumor models; single lab\",\n      \"pmids\": [\"41326370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NAA50 catalyzes N-terminal acetylation of SLU7, preventing its ubiquitin-proteasomal degradation and sustaining SLU7 stability. SLU7 directly binds MAP3K3 mRNA and promotes its nuclear export (a non-canonical, splicing-independent function), activating p38 MAPK signaling and driving cisplatin resistance in bladder cancer.\",\n      \"method\": \"Mass spectrometry; co-immunoprecipitation; RIP-qPCR (SLU7-MAP3K3 mRNA binding); RNA-FISH and nucleocytoplasmic fractionation; NAA50 pharmacological inhibition; xenograft models\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MS, co-IP, RIP-qPCR, fractionation, in vivo); single lab\",\n      \"pmids\": [\"42151695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In the context of alcoholic liver disease, SLU7 knockdown increased SIRT1 full-length expression while repressing splicing of SIRT1 into the SIRT1-ΔExon8 isoform. SLU7 knockdown also ameliorated splicing of lipin-1 and SRSF3, inhibited NF-κB activity, and reduced oxidative stress.\",\n      \"method\": \"Adenovirus-mediated SLU7 shRNA knockdown in mice; isoform-specific RT-PCR; NF-κB activity assays; oxidative stress markers\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse KD model with specific splicing isoform readouts; single lab\",\n      \"pmids\": [\"29870742\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLU7 is an essential splicing factor that promotes 3' splice site choice during the second catalytic step of pre-mRNA splicing by acting after PRP16, requiring its zinc knuckle domain for spliceosome association and a distinct domain for physical interaction with Prp18; beyond splicing, mammalian SLU7 also regulates genome integrity (suppressing R-loops and maintaining sister chromatid cohesion via SRSF3 splicing), preserves DNMT1 stability and DNA methylation by facilitating DNMT1 interaction with HDAC1 and USP7, protects HNF4α from oxidative degradation as part of the stress granule proteome, supports NMD by stabilizing UPF1, and can promote mRNA nuclear export in a non-canonical splicing-independent manner; its expression is downregulated by caspase-mediated cleavage during liver injury, and it is stabilized by NAA50-mediated N-terminal acetylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLU7 is an essential pre-mRNA splicing factor that governs 3' splice site selection during the second catalytic step of spliceosome action [#0]. It functions downstream of the ATPase PRP16: SLU7 recruitment to the spliceosome is enhanced by prior PRP16 action, and it remains bound to the excised intron and spliced mRNA until ATP-dependent spliceosome disassembly [#1, #2]. Its requirement is dictated by the geometry of the intron, being dispensable when the branchpoint-to-3' splice site distance is short [#2]. SLU7 uses two functionally distinct modules: a zinc knuckle motif that supports efficient spliceosome association and 3' splice site selection, and a separate domain (residues ~200–224) that physically binds Prp18; second-step factors are recruited in the order Slu7 \\u2192 Prp18 \\u2192 Prp22 [#3, #4]. Beyond core splicing, mammalian SLU7 has acquired roles in genome integrity, where its control of SRSF3 splicing suppresses R-loop formation and preserves sister chromatid cohesion via sororin [#8], and in epigenetic maintenance, where it stabilizes DNMT1 and correct DNA methylation by promoting DNMT1 association with HDAC1 and the deubiquitinase USP7 within a chromatome complex with UHRF1 and G9a [#9]. As a component of the stress granule proteome, SLU7 protects HNF4\\u03b1 from oxidative degradation to maintain hepatocyte differentiation [#10], supports nonsense-mediated decay by interacting with and stabilizing UPF1 [#12], and can drive mRNA nuclear export in a splicing-independent manner [#14]. SLU7 levels are controlled by caspase-mediated cleavage during liver injury [#12] and by NAA50-catalyzed N-terminal acetylation that blocks its proteasomal degradation [#14].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established SLU7 as an essential factor that enforces correct 3' splice site choice, defining its place in the second catalytic step rather than in initial spliceosome assembly.\",\n      \"evidence\": \"Genetic and competing 3' splice site assays with zinc knuckle mutagenesis in yeast\",\n      \"pmids\": [\"1427075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not order SLU7 relative to other second-step factors\", \"Mechanism of zinc knuckle contribution to spliceosome binding not resolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Placed SLU7 biochemically downstream of PRP16, showing it acts after the PRP16-dependent transition to complete the second step.\",\n      \"evidence\": \"Glycerol gradient sedimentation and in vitro reconstitution with purified factors\",\n      \"pmids\": [\"7664739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical basis of PRP16-dependent recruitment not defined\", \"Role of co-factor SSF1 relative to SLU7 unclear\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined SLU7 as a substrate-geometry-dependent spliceosome component, required only when branchpoint-to-3'SS distance exceeds ~7 nt, and showed it persists on products until disassembly.\",\n      \"evidence\": \"In vitro splicing with model substrates and anti-SLU7 immunoprecipitation of spliceosomal complexes\",\n      \"pmids\": [\"8756413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for distance dependence not determined\", \"How SLU7 dissociation is coupled to disassembly unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identified Prp18 as a direct SLU7 partner and mapped the interaction domain, showing the two factors act in concert at the second step.\",\n      \"evidence\": \"Two-hybrid mapping and in vitro splicing bypass with deletion mutants\",\n      \"pmids\": [\"9153314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the SLU7\\u2013Prp18 interface not solved\", \"Why excess Slu7 bypasses Prp18 mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Dissected SLU7 into separable zinc knuckle and Prp18-binding domains and ordered the second-step factor assembly Slu7\\u2192Prp18\\u2192Prp22, clarifying functional division of labor.\",\n      \"evidence\": \"Alanine cluster mutagenesis, two-hybrid, in vitro reconstitution, and depletion/reconstitution IPs in yeast\",\n      \"pmids\": [\"12212850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of these domains in the spliceosome lacking\", \"How the two domains cooperate during catalysis not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended SLU7 function to genome-wide intron-specific splicing and revealed an unexpected pre-catalytic role and U5 snRNP association in fission yeast.\",\n      \"evidence\": \"Missense mutant analysis, global splicing assays, salt-stable co-fractionation with U5 snRNP, and genetic interactions\",\n      \"pmids\": [\"23754748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pre-catalytic role not reconstituted in vitro\", \"Direct contacts with U5 snRNP not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established mammalian SLU7 as a regulator of hepatocyte differentiation and metabolism through control of SRSF3 and HNF4\\u03b1, expanding its biology beyond core splicing.\",\n      \"evidence\": \"siRNA knockdown in human liver cells and mouse liver with RNA-seq\",\n      \"pmids\": [\"24865429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect targets not fully separated\", \"Single lab; mechanism of SRSF3/HNF4\\u03b1 selectivity unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed SLU7 directly binds and processes the miR-17-92 host transcript, linking it to oncogenic miRNA biogenesis and stress survival.\",\n      \"evidence\": \"RNA pulldown/co-IP of SLU7 with C13orf25, miRNA quantification, and miR-17 mimic rescue in HCC cells\",\n      \"pmids\": [\"26804174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Splicing vs processing mechanism not distinguished\", \"Single lab; binding site on the transcript not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected SLU7 to alcoholic liver disease pathways through isoform-specific control of SIRT1, lipin-1, and SRSF3 affecting NF-\\u03baB and oxidative stress.\",\n      \"evidence\": \"Adenoviral shRNA knockdown in mice with isoform-specific RT-PCR and stress/NF-\\u03baB readouts\",\n      \"pmids\": [\"29870742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SLU7 targets among these transcripts not confirmed by binding\", \"Single lab; disease relevance correlative\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a SLU7\\u2192SRSF3\\u2192SRSF1/sororin axis that suppresses R-loops and maintains sister chromatid cohesion, tying SLU7 to genome integrity.\",\n      \"evidence\": \"siRNA knockdown with R-loop detection, DNA damage and mitotic assays, and splicing epistasis\",\n      \"pmids\": [\"30657957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct evidence of SLU7 binding the implicated transcripts limited\", \"Single lab; SRSF3-TR dominant-negative mechanism not structurally defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a non-splicing chromatin role: SLU7 stabilizes DNMT1 and preserves DNA methylation by promoting DNMT1 association with HDAC1 and USP7 within a chromatome complex.\",\n      \"evidence\": \"Chromatome mass spectrometry, co-IP, and knockdown/KO with methylation assays in cells and liver models\",\n      \"pmids\": [\"34331453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffolded interactions within the complex not separated\", \"Single lab; stoichiometry and dynamics unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed SLU7 in the stress granule proteome where it protects HNF4\\u03b1 from oxidative degradation, establishing a cytoprotective antioxidant function in liver.\",\n      \"evidence\": \"Interactome mass spectrometry, Slu7+/- mouse model, and AAV-SLU7 rescue of liver injury\",\n      \"pmids\": [\"34170569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SLU7 stabilizes HNF4\\u03b1 not molecularly defined\", \"Single lab; stress granule role overlap with splicing unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a translational role in which SLU7 with G3BP1, PABPC1 and eIF4G1 stabilizes PI3K mRNA closed-loop structure, activating PI3K/Akt and modulating MHC-I in bladder cancer.\",\n      \"evidence\": \"Co-IP, pulldown, knockdown, and pathway/MHC-I assays in bladder cancer cells\",\n      \"pmids\": [\"38084438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA contacts vs complex-mediated effects not separated\", \"Single lab; generality beyond bladder cancer untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed SLU7 supports nonsense-mediated decay by binding and stabilizing UPF1, and that caspase cleavage links apoptotic liver injury to SLU7 loss and NMD inhibition.\",\n      \"evidence\": \"Co-IP with UPF1, NMD assays, liver injury models, and western blotting of caspase cleavage\",\n      \"pmids\": [\"39105183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Caspase cleavage sites and resulting fragments not mapped\", \"Single lab; direct vs indirect UPF1 stabilization unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated THRAP3-directed recruitment of SLU7 to drive GIT2 exon14 skipping, conferring ferroptosis resistance in AML.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, GIT2 splicing analysis, and ferroptosis assays in vitro and in vivo\",\n      \"pmids\": [\"41326370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of THRAP3-mediated recruitment not detailed\", \"Single lab; breadth of THRAP3-SLU7 splicing targets unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a splicing-independent mRNA export function for SLU7 (MAP3K3 mRNA, p38 MAPK activation) and identified NAA50 N-terminal acetylation as a stabilizing post-translational control.\",\n      \"evidence\": \"Mass spectrometry, co-IP, RIP-qPCR, RNA-FISH/fractionation, NAA50 inhibition, and xenografts\",\n      \"pmids\": [\"42151695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Export machinery engaged by SLU7 not identified\", \"Single lab; relationship between acetylation and splicing function untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLU7's conserved core second-step splicing activity is mechanistically partitioned from its many mammalian moonlighting roles (DNA methylation, NMD, mRNA export, translation, genome integrity) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of mammalian SLU7 in or out of the spliceosome\", \"Domain requirements for non-splicing functions undefined\", \"Whether moonlighting functions are independent or splicing-dependent unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7, 11, 14]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\n      \"spliceosome (second-step complex)\",\n      \"stress granule\",\n      \"chromatome complex (with DNMT1/UHRF1/G9a)\"\n    ],\n    \"partners\": [\n      \"PRP18\",\n      \"DNMT1\",\n      \"HDAC1\",\n      \"USP7\",\n      \"UPF1\",\n      \"G3BP1\",\n      \"THRAP3\",\n      \"NAA50\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}