{"gene":"PRPF6","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1990,"finding":"Yeast PRP6 (ortholog of human PRPF6) encodes a U4/U6 snRNP-associated protein required for pre-mRNA splicing; immunoprecipitation showed that PRP6 protein co-precipitates U4/U6 snRNAs, and in vitro splicing of extracts from temperature-sensitive prp6 mutants was defective.","method":"Immunoprecipitation of snRNAs with PRP6 antibodies; in vitro splicing assays in prp6 mutant extracts","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct biochemical immunoprecipitation identifying snRNA association, replicated by two independent labs in the same year with complementary methods","pmids":["2147224"],"is_preprint":false},{"year":1990,"finding":"Yeast PRP6 (ortholog of human PRPF6) encodes a 899 amino acid protein with repeated helix-loop-helix motifs and cysteine/histidine zinc finger-like motifs; directed mutagenesis of specific cysteine/histidine residues critically impairs PRP6 function, and the protein contains leucine repeat motifs potentially mediating protein–protein interactions.","method":"DNA sequencing, directed mutagenesis of conserved cysteine/histidine residues, functional complementation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site/domain mutagenesis with functional readout, single lab but multiple orthogonal approaches (sequencing + mutagenesis + phenotypic complementation)","pmids":["2118103"],"is_preprint":false},{"year":1993,"finding":"Yeast PRP6 protein (ortholog of human PRPF6) is required for the accumulation of the [U4/U6.U5] tri-snRNP but is not present in the U4/U6 di-snRNP particle; heat-inactivation of prp6-1 mutant extracts severely reduces tri-snRNP levels while U4/U6 snRNPs remain normally represented.","method":"Glycerol gradient sedimentation analysis of snRNP particles from prp6 temperature-sensitive mutant extracts; antibody co-immunoprecipitation of U4, U5, and U6 snRNAs","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods (glycerol gradients + co-IP), clearly places PRP6 in tri-snRNP assembly pathway, replicated conceptually by later human studies","pmids":["8479905"],"is_preprint":false},{"year":2005,"finding":"Human PRPF6 (U5-102K) is a component of the 20S U5 snRNP and plays an essential role in tri-snRNP formation; it directly interacts with the U4/U6-61K protein to bridge U5 and U4/U6 snRNPs. PRPF6 also physically interacts with U5-52K (CD2BP2) via the N-terminal two-thirds of U5-52K, but U5-52K dissociates upon tri-snRNP formation, suggesting PRPF6 functions in tri-snRNP assembly.","method":"Protein sequencing; yeast two-hybrid screening; GST pulldown assays; mass spectrometry-based identification of snRNP complexes; immunoprecipitation","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal pulldown and yeast two-hybrid identifying direct binding partners, combined with snRNP complex fractionation; multiple orthogonal methods in a single study","pmids":["15840814"],"is_preprint":false},{"year":2011,"finding":"A missense mutation in PRPF6 (p.Arg729Trp) causes autosomal-dominant retinitis pigmentosa; patient lymphoblasts show abnormal nuclear localization of PRPF6, with accumulation in Cajal bodies rather than normal nuclear distribution, indicating impairment of tri-snRNP assembly or recycling. Expression of GFP-tagged mutant PRPF6 in HeLa cells reproduced this Cajal body accumulation. Patient cells also exhibited intron retention in pre-mRNAs with specific splicing signals.","method":"Mutation screening; confocal immunofluorescence microscopy of endogenous and GFP-tagged PRPF6 in patient lymphoblasts and HeLa cells; RT-PCR analysis of endogenous transcripts for intron retention","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional consequence (Cajal body mislocalization tied to splicing defects), multiple orthogonal methods (immunofluorescence + GFP tagging + transcript analysis), validated in patient and heterologous cells","pmids":["21549338"],"is_preprint":false},{"year":2014,"finding":"PRPF6 drives cancer cell proliferation as a member of the tri-snRNP spliceosome complex; inhibition of PRPF6 (but not other snRNP complex proteins) selectively abrogates growth in cancer cells with high tri-snRNP levels. Reduced PRPF6 alters constitutive and alternative splicing of a discrete number of genes including an oncogenic isoform of ZAK kinase, establishing PRPF6's role in cancer via preferential splicing of growth-related gene products.","method":"RNAi-mediated knockdown of PRPF6 and other spliceosomal proteins; high-resolution transcriptome (RNA-seq) analysis; cell proliferation assays; in vivo tumor growth assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with specific phenotypic readout (growth arrest) plus genome-wide transcriptome analysis identifying splicing targets, multiple orthogonal methods in a single rigorous study","pmids":["24788092"],"is_preprint":false},{"year":2022,"finding":"PRPF6 promotes metastasis and paclitaxel resistance in ovarian cancer by inducing alternative splicing of SNHG16, causing downregulation of SNHG16-L isoform, which in turn releases inhibition of GATA3 transcription mediated by CEBPB, leading to upregulation of GATA3 expression.","method":"Immunohistochemistry; RT-PCR for transcript isoforms; in vitro and in vivo functional assays (proliferation, migration, drug resistance); mechanistic pathway analysis","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — alternative splicing mechanism identified with functional readout, but mechanistic chain relies partly on correlative transcript measurements and single-lab study without reconstitution","pmids":["37303939"],"is_preprint":false}],"current_model":"PRPF6 (hPrp6/U5-102K) is an essential component of the U5 snRNP that bridges the U5 and U4/U6 snRNPs through direct protein–protein interactions (notably with U4/U6-61K) to promote assembly and stabilization of the [U4/U6.U5] tri-snRNP; loss or mutation of PRPF6 leads to tri-snRNP depletion, intron retention, and—when mislocalized to Cajal bodies by a dominant RP-associated missense mutation—impaired tri-snRNP recycling causing retinal degeneration, while overexpression in cancer cells drives preferential splicing of growth-regulatory transcripts including an oncogenic ZAK isoform."},"narrative":{"mechanistic_narrative":"PRPF6 (hPrp6/U5-102K) is an essential pre-mRNA splicing factor that bridges the U5 and U4/U6 snRNPs to drive assembly of the [U4/U6.U5] tri-snRNP, a function conserved from the yeast ortholog PRP6 [PMID:2147224, PMID:15840814]. As a component of the 20S U5 snRNP, PRPF6 directly contacts the U4/U6-61K protein to physically link the two particles and is specifically required for tri-snRNP accumulation rather than for the upstream U4/U6 di-snRNP, since loss of its function depletes tri-snRNP while leaving U4/U6 intact [PMID:8479905, PMID:15840814]. PRPF6 also interacts with U5-52K (CD2BP2), which dissociates upon tri-snRNP formation, consistent with a role in the assembly transition [PMID:15840814]. A dominant p.Arg729Trp missense mutation causes autosomal-dominant retinitis pigmentosa, mislocalizing PRPF6 to Cajal bodies and producing intron retention in transcripts with specific splicing signals, implicating defective tri-snRNP assembly/recycling in retinal degeneration [PMID:21549338]. In cancer, PRPF6 acts through this splicing activity to favor production of growth-promoting transcript isoforms, including an oncogenic ZAK kinase isoform, such that its depletion selectively arrests proliferation of tumor cells with high tri-snRNP levels [PMID:24788092].","teleology":[{"year":1990,"claim":"Established that the gene product is a bona fide splicing factor physically associated with snRNAs, defining its place in the spliceosome rather than a generic nuclear role.","evidence":"Anti-PRP6 immunoprecipitation of U4/U6 snRNAs and defective in vitro splicing in temperature-sensitive prp6 yeast extracts; parallel sequencing/mutagenesis identifying conserved cysteine/histidine and helix-loop-helix motifs","pmids":["2147224","2118103"],"confidence":"High","gaps":["Did not resolve which snRNP particle PRP6 is a stable subunit of versus transiently associated with","Functional role of the zinc-finger-like and leucine repeat motifs in partner binding not directly demonstrated"]},{"year":1993,"claim":"Pinpointed the step in spliceosome assembly that requires PRP6, distinguishing tri-snRNP formation from di-snRNP maintenance.","evidence":"Glycerol gradient sedimentation and snRNA co-IP from heat-inactivated prp6-1 yeast extracts showing selective loss of [U4/U6.U5] tri-snRNP","pmids":["8479905"],"confidence":"High","gaps":["Did not identify the direct protein-protein contacts mediating the bridging","Performed in yeast; human counterpart not yet shown"]},{"year":2005,"claim":"Defined the molecular bridging mechanism in humans by identifying the direct binding partners that link U5 to U4/U6.","evidence":"Protein sequencing, yeast two-hybrid, GST pulldowns, mass spectrometry of snRNP complexes, and immunoprecipitation showing PRPF6 (U5-102K) binds U4/U6-61K and U5-52K","pmids":["15840814"],"confidence":"High","gaps":["Structural basis of the U4/U6-61K interaction not resolved","Timing/regulation of U5-52K dissociation during assembly not mechanistically dissected"]},{"year":2011,"claim":"Connected PRPF6 dysfunction to human disease, showing that a single missense mutation disrupts spliceosome recycling and causes inherited retinal degeneration.","evidence":"Mutation screening, confocal immunofluorescence of endogenous and GFP-tagged PRPF6 in patient lymphoblasts and HeLa cells, and RT-PCR for intron retention identifying p.Arg729Trp with Cajal body accumulation","pmids":["21549338"],"confidence":"High","gaps":["Why retinal cells are selectively vulnerable to a ubiquitous splicing defect is unexplained","Whether mislocalization reflects impaired assembly versus recycling not distinguished"]},{"year":2014,"claim":"Showed that PRPF6's splicing function is co-opted in cancer, biasing isoform choice of growth-regulatory genes and creating a selective dependency.","evidence":"RNAi knockdown of PRPF6 versus other snRNP proteins, RNA-seq, proliferation assays, and in vivo tumor growth showing selective growth arrest and an oncogenic ZAK isoform shift","pmids":["24788092"],"confidence":"High","gaps":["How PRPF6 levels achieve preferential splicing of a discrete gene subset rather than global change is unclear","Direct contribution of the ZAK isoform to the proliferation phenotype not isolated"]},{"year":2022,"claim":"Extended the splicing-driven oncogenic role to a specific downstream regulatory cascade in ovarian cancer.","evidence":"IHC, RT-PCR for isoforms, and in vitro/in vivo functional assays linking PRPF6 to SNHG16-L downregulation, CEBPB-mediated GATA3 derepression","pmids":["37303939"],"confidence":"Medium","gaps":["Mechanistic chain relies partly on correlative transcript measurements without reconstitution","Single-lab study; direct PRPF6 control of SNHG16 splicing not shown biochemically"]},{"year":null,"claim":"The structural basis by which PRPF6 simultaneously engages U4/U6-61K and the U5 snRNP, and the rules governing its substrate isoform selectivity, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of PRPF6 within the human tri-snRNP in the timeline","Determinants of which transcripts are preferentially spliced upon PRPF6 changes are uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,2,4,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3,5]}],"complexes":["U5 snRNP","[U4/U6.U5] tri-snRNP"],"partners":["PRPF31","CD2BP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94906","full_name":"Pre-mRNA-processing factor 6","aliases":["Androgen receptor N-terminal domain-transactivating protein 1","ANT-1","PRP6 homolog","U5 snRNP-associated 102 kDa protein","U5-102 kDa protein"],"length_aa":941,"mass_kda":106.9,"function":"Involved in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex, one of the building blocks of the spliceosome (PubMed:20118938, PubMed:21549338, PubMed:28781166). Enhances dihydrotestosterone-induced transactivation activity of AR, as well as dexamethasone-induced transactivation activity of NR3C1, but does not affect estrogen-induced transactivation","subcellular_location":"Nucleus, nucleoplasm; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/O94906/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PRPF6","classification":"Common Essential","n_dependent_lines":1205,"n_total_lines":1208,"dependency_fraction":0.9975165562913907},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EFTUD2","stoichiometry":10.0},{"gene":"PRPF4B","stoichiometry":10.0},{"gene":"PRPF8","stoichiometry":10.0},{"gene":"RBM42","stoichiometry":10.0},{"gene":"CD2BP2","stoichiometry":4.0},{"gene":"SNRNP40","stoichiometry":4.0},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"PGK1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRPF6","total_profiled":1310},"omim":[{"mim_id":"617722","title":"THIOREDOXIN-LIKE 4B; TXNL4B","url":"https://www.omim.org/entry/617722"},{"mim_id":"617470","title":"UBIQUITIN-SPECIFIC PEPTIDASE-LIKE 1; USPL1","url":"https://www.omim.org/entry/617470"},{"mim_id":"613983","title":"RETINITIS PIGMENTOSA 60; RP60","url":"https://www.omim.org/entry/613983"},{"mim_id":"613979","title":"PRE-mRNA-PROCESSING FACTOR 6; PRPF6","url":"https://www.omim.org/entry/613979"},{"mim_id":"611203","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 5; DNAJC5","url":"https://www.omim.org/entry/611203"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRPF6"},"hgnc":{"alias_symbol":["TOM","bB152O15.1","ANT-1","U5-102K","Prp6","hPrp6","SNRNP102","RP60"],"prev_symbol":["C20orf14"]},"alphafold":{"accession":"O94906","domains":[{"cath_id":"1.25.40.10","chopping":"287-410","consensus_level":"medium","plddt":90.1565,"start":287,"end":410},{"cath_id":"1.25.40","chopping":"837-935","consensus_level":"high","plddt":89.576,"start":837,"end":935}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94906","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94906-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94906-F1-predicted_aligned_error_v6.png","plddt_mean":79.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRPF6","jax_strain_url":"https://www.jax.org/strain/search?query=PRPF6"},"sequence":{"accession":"O94906","fasta_url":"https://rest.uniprot.org/uniprotkb/O94906.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94906/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94906"}},"corpus_meta":[{"pmid":"22280891","id":"PMC_22280891","title":"Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin.","date":"2012","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/22280891","citation_count":542,"is_preprint":false},{"pmid":"30446870","id":"PMC_30446870","title":"Hi-TOM: a platform for high-throughput tracking of mutations induced by CRISPR/Cas systems.","date":"2018","source":"Science China. 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interacts with U5-102K (hPrp6), a U4/U6.U5 tri-snRNP bridging protein, but dissociates upon tri-snRNP formation.","date":"2005","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15840814","citation_count":50,"is_preprint":false},{"pmid":"25083920","id":"PMC_25083920","title":"Cooperation of TOM and TIM23 complexes during translocation of proteins into mitochondria.","date":"2014","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25083920","citation_count":50,"is_preprint":false},{"pmid":"8035817","id":"PMC_8035817","title":"The Drosophila tom retrotransposon encodes an envelope protein.","date":"1994","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8035817","citation_count":50,"is_preprint":false},{"pmid":"12719229","id":"PMC_12719229","title":"Comparison of the TIM and TOM channel activities of the mitochondrial protein import complexes.","date":"2003","source":"Biophysical 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Requirement of presequence elements and tom components for precursor binding to the TOM complex.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15337763","citation_count":48,"is_preprint":false},{"pmid":"8612740","id":"PMC_8612740","title":"Identification of a third yeast mitochondrial Tom protein with tetratrico peptide repeats.","date":"1996","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8612740","citation_count":46,"is_preprint":false},{"pmid":"2851093","id":"PMC_2851093","title":"Retrovirus-like features and site specific insertions of a transposable element, tom, in Drosophila ananassae.","date":"1988","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/2851093","citation_count":46,"is_preprint":false},{"pmid":"40080546","id":"PMC_40080546","title":"Structure of human PINK1 at a mitochondrial TOM-VDAC array.","date":"2025","source":"Science (New York, 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physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26719120","citation_count":35,"is_preprint":false},{"pmid":"19165229","id":"PMC_19165229","title":"TOM-independent complex formation of Bax and Bak in mammalian mitochondria during TNFalpha-induced apoptosis.","date":"2009","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/19165229","citation_count":35,"is_preprint":false},{"pmid":"18279676","id":"PMC_18279676","title":"The outer membrane form of the mitochondrial protein Mcr1 follows a TOM-independent membrane insertion pathway.","date":"2008","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/18279676","citation_count":35,"is_preprint":false},{"pmid":"22915742","id":"PMC_22915742","title":"The tomato (Solanum lycopersicum cv. Micro-Tom) natural genetic variation Rg1 and the DELLA mutant procera control the competence necessary to form adventitious roots and shoots.","date":"2012","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/22915742","citation_count":34,"is_preprint":false},{"pmid":"38848361","id":"PMC_38848361","title":"Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/38848361","citation_count":33,"is_preprint":false},{"pmid":"23877244","id":"PMC_23877244","title":"The PRP6-like splicing factor STA1 is involved in RNA-directed DNA methylation by facilitating the production of Pol V-dependent scaffold RNAs.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23877244","citation_count":32,"is_preprint":false},{"pmid":"34347503","id":"PMC_34347503","title":"The receptor subunit Tom20 is dynamically associated with the TOM complex in mitochondria of human cells.","date":"2021","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/34347503","citation_count":32,"is_preprint":false},{"pmid":"12628251","id":"PMC_12628251","title":"Biogenesis of yeast mitochondrial cytochrome c: a unique relationship to the TOM machinery.","date":"2003","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12628251","citation_count":32,"is_preprint":false},{"pmid":"21194841","id":"PMC_21194841","title":"Molecular detection of Babesia bovis and Babesia bigemina in white-tailed deer (Odocoileus virginianus) from Tom Green County in central Texas.","date":"2010","source":"Veterinary parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/21194841","citation_count":31,"is_preprint":false},{"pmid":"23350036","id":"PMC_23350036","title":"Novel TPR-containing subunit of TOM complex functions as cytosolic receptor for Entamoeba mitosomal transport.","date":"2013","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/23350036","citation_count":30,"is_preprint":false},{"pmid":"14985332","id":"PMC_14985332","title":"Targeting and assembly of rat mitochondrial translocase of outer membrane 22 (TOM22) into the TOM complex.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14985332","citation_count":30,"is_preprint":false},{"pmid":"29723826","id":"PMC_29723826","title":"Genome-wide transcriptomic analysis of BR-deficient Micro-Tom reveals correlations between drought stress tolerance and brassinosteroid signaling in tomato.","date":"2018","source":"Plant physiology and biochemistry : PPB","url":"https://pubmed.ncbi.nlm.nih.gov/29723826","citation_count":30,"is_preprint":false},{"pmid":"34064787","id":"PMC_34064787","title":"A Biochemical and Structural Understanding of TOM Complex Interactions and Implications for Human Health and Disease.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34064787","citation_count":29,"is_preprint":false},{"pmid":"35674314","id":"PMC_35674314","title":"Towards a molecular mechanism underlying mitochondrial protein import through the TOM and TIM23 complexes.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/35674314","citation_count":29,"is_preprint":false},{"pmid":"15975739","id":"PMC_15975739","title":"Expressed sequence tags from the laboratory-grown miniature tomato (Lycopersicon esculentum) cultivar Micro-Tom and mining for single nucleotide polymorphisms and insertions/deletions in tomato cultivars.","date":"2005","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15975739","citation_count":29,"is_preprint":false},{"pmid":"30608924","id":"PMC_30608924","title":"Triplet-pore structure of a highly divergent TOM complex of hydrogenosomes in Trichomonas vaginalis.","date":"2019","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/30608924","citation_count":27,"is_preprint":false},{"pmid":"31180117","id":"PMC_31180117","title":"Growth performance and gastrointestinal responses in heavy Tom turkeys fed antibiotic free corn-soybean meal diets supplemented with multiple doses of a single strain Bacillus subtilis probiotic (DSM29784)1.","date":"2019","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/31180117","citation_count":27,"is_preprint":false},{"pmid":"22608078","id":"PMC_22608078","title":"Enhancement of phytosterols, taraxasterol and induction of extracellular pathogenesis-related proteins in cell cultures of Solanum lycopersicum cv Micro-Tom elicited with cyclodextrins and methyl jasmonate.","date":"2012","source":"Journal of plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22608078","citation_count":26,"is_preprint":false},{"pmid":"25875815","id":"PMC_25875815","title":"The pro-apoptotic BH3-only protein Bim interacts with components of the translocase of the outer mitochondrial membrane (TOM).","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25875815","citation_count":26,"is_preprint":false},{"pmid":"19690949","id":"PMC_19690949","title":"The TOM complex is involved in the release of superoxide anion from mitochondria.","date":"2009","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/19690949","citation_count":25,"is_preprint":false},{"pmid":"35391620","id":"PMC_35391620","title":"The role of the individual TOM subunits in the association of PINK1 with depolarized mitochondria.","date":"2022","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/35391620","citation_count":24,"is_preprint":false},{"pmid":"37579144","id":"PMC_37579144","title":"Two conformations of the Tom20 preprotein receptor in the TOM holo complex.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37579144","citation_count":23,"is_preprint":false},{"pmid":"21256529","id":"PMC_21256529","title":"Ectopic expression of apple fruit homogentisate phytyltransferase gene (MdHPT1) increases tocopherol in transgenic tomato (Solanum lycopersicum cv. Micro-Tom) leaves and fruits.","date":"2011","source":"Phytochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21256529","citation_count":21,"is_preprint":false},{"pmid":"32142473","id":"PMC_32142473","title":"The structure of the TOM core complex in the mitochondrial outer membrane.","date":"2020","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32142473","citation_count":17,"is_preprint":false},{"pmid":"24263924","id":"PMC_24263924","title":"The Tom Thumb dwarfing gene Rht3 in wheat : 2. Effects on height, yield and grain quality.","date":"1983","source":"TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/24263924","citation_count":16,"is_preprint":false},{"pmid":"37303939","id":"PMC_37303939","title":"PRPF6 promotes metastasis and paclitaxel resistance of ovarian cancer via SNHG16/CEBPB/GATA3 axis.","date":"2022","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/37303939","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42467,"output_tokens":2633,"usd":0.083448,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9111,"output_tokens":2541,"usd":0.05454,"stage2_stop_reason":"end_turn"},"total_usd":0.137988,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the corpus, I need to identify papers about PRPF6 (also known as hPrp6, U5-102K, SNRNP102, TOM, Prp6, etc.) and extract mechanistic findings. The key challenge is that \"TOM\" is also an alias for PRPF6, but most papers in this corpus about \"TOM\" refer to the mitochondrial translocase complex (TOM complex), which is completely unrelated to PRPF6. I need to carefully distinguish these.\n\nPapers clearly about PRPF6 (spliceosome/pre-mRNA splicing protein):\n- PMID 21549338 (Tanackovic 2011) - missense mutation, RP, tri-snRNP, Cajal body localization\n- PMID 24788092 (Adler 2014) - colon cancer, tri-snRNP, splicing\n- PMID 15840814 (Laggerbauer 2005) - U5-102K/hPrp6, interaction with U5-52K/CD2BP2\n- PMID 2147224 (Abovich 1990) - yeast PRP6, U4/U6 snRNP protein\n- PMID 2118103 (Legrain 1990) - yeast PRP6 molecular characterization\n- PMID 8479905 (Galisson 1993) - PRP6 required for [U4/U6.U5] tri-snRNP accumulation\n- PMID 37303939 (Wang 2022) - PRPF6 in ovarian cancer, alternative splicing of SNHG16\n\nPapers about Arabidopsis STA1 (PRP6-like) - PMID 23877244 - this is about a plant ortholog involved in RNA-directed DNA methylation, not directly the human PRPF6 protein, so I'll skip.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"Yeast PRP6 (ortholog of human PRPF6) encodes a U4/U6 snRNP-associated protein required for pre-mRNA splicing; immunoprecipitation showed that PRP6 protein co-precipitates U4/U6 snRNAs, and in vitro splicing of extracts from temperature-sensitive prp6 mutants was defective.\",\n      \"method\": \"Immunoprecipitation of snRNAs with PRP6 antibodies; in vitro splicing assays in prp6 mutant extracts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct biochemical immunoprecipitation identifying snRNA association, replicated by two independent labs in the same year with complementary methods\",\n      \"pmids\": [\"2147224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Yeast PRP6 (ortholog of human PRPF6) encodes a 899 amino acid protein with repeated helix-loop-helix motifs and cysteine/histidine zinc finger-like motifs; directed mutagenesis of specific cysteine/histidine residues critically impairs PRP6 function, and the protein contains leucine repeat motifs potentially mediating protein–protein interactions.\",\n      \"method\": \"DNA sequencing, directed mutagenesis of conserved cysteine/histidine residues, functional complementation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site/domain mutagenesis with functional readout, single lab but multiple orthogonal approaches (sequencing + mutagenesis + phenotypic complementation)\",\n      \"pmids\": [\"2118103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Yeast PRP6 protein (ortholog of human PRPF6) is required for the accumulation of the [U4/U6.U5] tri-snRNP but is not present in the U4/U6 di-snRNP particle; heat-inactivation of prp6-1 mutant extracts severely reduces tri-snRNP levels while U4/U6 snRNPs remain normally represented.\",\n      \"method\": \"Glycerol gradient sedimentation analysis of snRNP particles from prp6 temperature-sensitive mutant extracts; antibody co-immunoprecipitation of U4, U5, and U6 snRNAs\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods (glycerol gradients + co-IP), clearly places PRP6 in tri-snRNP assembly pathway, replicated conceptually by later human studies\",\n      \"pmids\": [\"8479905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human PRPF6 (U5-102K) is a component of the 20S U5 snRNP and plays an essential role in tri-snRNP formation; it directly interacts with the U4/U6-61K protein to bridge U5 and U4/U6 snRNPs. PRPF6 also physically interacts with U5-52K (CD2BP2) via the N-terminal two-thirds of U5-52K, but U5-52K dissociates upon tri-snRNP formation, suggesting PRPF6 functions in tri-snRNP assembly.\",\n      \"method\": \"Protein sequencing; yeast two-hybrid screening; GST pulldown assays; mass spectrometry-based identification of snRNP complexes; immunoprecipitation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal pulldown and yeast two-hybrid identifying direct binding partners, combined with snRNP complex fractionation; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"15840814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A missense mutation in PRPF6 (p.Arg729Trp) causes autosomal-dominant retinitis pigmentosa; patient lymphoblasts show abnormal nuclear localization of PRPF6, with accumulation in Cajal bodies rather than normal nuclear distribution, indicating impairment of tri-snRNP assembly or recycling. Expression of GFP-tagged mutant PRPF6 in HeLa cells reproduced this Cajal body accumulation. Patient cells also exhibited intron retention in pre-mRNAs with specific splicing signals.\",\n      \"method\": \"Mutation screening; confocal immunofluorescence microscopy of endogenous and GFP-tagged PRPF6 in patient lymphoblasts and HeLa cells; RT-PCR analysis of endogenous transcripts for intron retention\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional consequence (Cajal body mislocalization tied to splicing defects), multiple orthogonal methods (immunofluorescence + GFP tagging + transcript analysis), validated in patient and heterologous cells\",\n      \"pmids\": [\"21549338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PRPF6 drives cancer cell proliferation as a member of the tri-snRNP spliceosome complex; inhibition of PRPF6 (but not other snRNP complex proteins) selectively abrogates growth in cancer cells with high tri-snRNP levels. Reduced PRPF6 alters constitutive and alternative splicing of a discrete number of genes including an oncogenic isoform of ZAK kinase, establishing PRPF6's role in cancer via preferential splicing of growth-related gene products.\",\n      \"method\": \"RNAi-mediated knockdown of PRPF6 and other spliceosomal proteins; high-resolution transcriptome (RNA-seq) analysis; cell proliferation assays; in vivo tumor growth assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with specific phenotypic readout (growth arrest) plus genome-wide transcriptome analysis identifying splicing targets, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"24788092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRPF6 promotes metastasis and paclitaxel resistance in ovarian cancer by inducing alternative splicing of SNHG16, causing downregulation of SNHG16-L isoform, which in turn releases inhibition of GATA3 transcription mediated by CEBPB, leading to upregulation of GATA3 expression.\",\n      \"method\": \"Immunohistochemistry; RT-PCR for transcript isoforms; in vitro and in vivo functional assays (proliferation, migration, drug resistance); mechanistic pathway analysis\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — alternative splicing mechanism identified with functional readout, but mechanistic chain relies partly on correlative transcript measurements and single-lab study without reconstitution\",\n      \"pmids\": [\"37303939\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRPF6 (hPrp6/U5-102K) is an essential component of the U5 snRNP that bridges the U5 and U4/U6 snRNPs through direct protein–protein interactions (notably with U4/U6-61K) to promote assembly and stabilization of the [U4/U6.U5] tri-snRNP; loss or mutation of PRPF6 leads to tri-snRNP depletion, intron retention, and—when mislocalized to Cajal bodies by a dominant RP-associated missense mutation—impaired tri-snRNP recycling causing retinal degeneration, while overexpression in cancer cells drives preferential splicing of growth-regulatory transcripts including an oncogenic ZAK isoform.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRPF6 (hPrp6/U5-102K) is an essential pre-mRNA splicing factor that bridges the U5 and U4/U6 snRNPs to drive assembly of the [U4/U6.U5] tri-snRNP, a function conserved from the yeast ortholog PRP6 [#0, #3]. As a component of the 20S U5 snRNP, PRPF6 directly contacts the U4/U6-61K protein to physically link the two particles and is specifically required for tri-snRNP accumulation rather than for the upstream U4/U6 di-snRNP, since loss of its function depletes tri-snRNP while leaving U4/U6 intact [#2, #3]. PRPF6 also interacts with U5-52K (CD2BP2), which dissociates upon tri-snRNP formation, consistent with a role in the assembly transition [#3]. A dominant p.Arg729Trp missense mutation causes autosomal-dominant retinitis pigmentosa, mislocalizing PRPF6 to Cajal bodies and producing intron retention in transcripts with specific splicing signals, implicating defective tri-snRNP assembly/recycling in retinal degeneration [#4]. In cancer, PRPF6 acts through this splicing activity to favor production of growth-promoting transcript isoforms, including an oncogenic ZAK kinase isoform, such that its depletion selectively arrests proliferation of tumor cells with high tri-snRNP levels [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that the gene product is a bona fide splicing factor physically associated with snRNAs, defining its place in the spliceosome rather than a generic nuclear role.\",\n      \"evidence\": \"Anti-PRP6 immunoprecipitation of U4/U6 snRNAs and defective in vitro splicing in temperature-sensitive prp6 yeast extracts; parallel sequencing/mutagenesis identifying conserved cysteine/histidine and helix-loop-helix motifs\",\n      \"pmids\": [\"2147224\", \"2118103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which snRNP particle PRP6 is a stable subunit of versus transiently associated with\", \"Functional role of the zinc-finger-like and leucine repeat motifs in partner binding not directly demonstrated\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Pinpointed the step in spliceosome assembly that requires PRP6, distinguishing tri-snRNP formation from di-snRNP maintenance.\",\n      \"evidence\": \"Glycerol gradient sedimentation and snRNA co-IP from heat-inactivated prp6-1 yeast extracts showing selective loss of [U4/U6.U5] tri-snRNP\",\n      \"pmids\": [\"8479905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the direct protein-protein contacts mediating the bridging\", \"Performed in yeast; human counterpart not yet shown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the molecular bridging mechanism in humans by identifying the direct binding partners that link U5 to U4/U6.\",\n      \"evidence\": \"Protein sequencing, yeast two-hybrid, GST pulldowns, mass spectrometry of snRNP complexes, and immunoprecipitation showing PRPF6 (U5-102K) binds U4/U6-61K and U5-52K\",\n      \"pmids\": [\"15840814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the U4/U6-61K interaction not resolved\", \"Timing/regulation of U5-52K dissociation during assembly not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected PRPF6 dysfunction to human disease, showing that a single missense mutation disrupts spliceosome recycling and causes inherited retinal degeneration.\",\n      \"evidence\": \"Mutation screening, confocal immunofluorescence of endogenous and GFP-tagged PRPF6 in patient lymphoblasts and HeLa cells, and RT-PCR for intron retention identifying p.Arg729Trp with Cajal body accumulation\",\n      \"pmids\": [\"21549338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why retinal cells are selectively vulnerable to a ubiquitous splicing defect is unexplained\", \"Whether mislocalization reflects impaired assembly versus recycling not distinguished\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed that PRPF6's splicing function is co-opted in cancer, biasing isoform choice of growth-regulatory genes and creating a selective dependency.\",\n      \"evidence\": \"RNAi knockdown of PRPF6 versus other snRNP proteins, RNA-seq, proliferation assays, and in vivo tumor growth showing selective growth arrest and an oncogenic ZAK isoform shift\",\n      \"pmids\": [\"24788092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PRPF6 levels achieve preferential splicing of a discrete gene subset rather than global change is unclear\", \"Direct contribution of the ZAK isoform to the proliferation phenotype not isolated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the splicing-driven oncogenic role to a specific downstream regulatory cascade in ovarian cancer.\",\n      \"evidence\": \"IHC, RT-PCR for isoforms, and in vitro/in vivo functional assays linking PRPF6 to SNHG16-L downregulation, CEBPB-mediated GATA3 derepression\",\n      \"pmids\": [\"37303939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic chain relies partly on correlative transcript measurements without reconstitution\", \"Single-lab study; direct PRPF6 control of SNHG16 splicing not shown biochemically\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis by which PRPF6 simultaneously engages U4/U6-61K and the U5 snRNP, and the rules governing its substrate isoform selectivity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of PRPF6 within the human tri-snRNP in the timeline\", \"Determinants of which transcripts are preferentially spliced upon PRPF6 changes are uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 2, 4, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3, 5]}\n    ],\n    \"complexes\": [\n      \"U5 snRNP\",\n      \"[U4/U6.U5] tri-snRNP\"\n    ],\n    \"partners\": [\n      \"PRPF31\",\n      \"CD2BP2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}