{"gene":"PRPF6","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1990,"finding":"Yeast PRP6 encodes a U4/U6 snRNP-associated protein required for pre-mRNA splicing; immunoprecipitation of PRP6 protein co-precipitates U4, U5, and U6 snRNAs, and in vitro splicing extracts from temperature-sensitive prp6 mutants are defective in spliceosome assembly, placing PRP6 at the level of snRNP function.","method":"Immunoprecipitation of snRNAs, in vitro splicing assay with temperature-sensitive mutant extracts, spliceosome assembly analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-precipitation and functional in vitro splicing assay; foundational paper replicated by subsequent work","pmids":["2147224"],"is_preprint":false},{"year":1990,"finding":"The yeast PRP6 protein (899 amino acids) contains repeated helix-loop-helix motifs and cysteine/histidine motifs related to zinc fingers; directed mutagenesis of specific cysteine/histidine residues abolishes protein function, and PRP6 contains leucine repeat motifs implicated in protein-protein interactions. Temperature-sensitive prp6 mutations were mapped and sequenced, establishing structure-function relationships.","method":"DNA sequencing, directed mutagenesis of cysteine/histidine residues, genetic complementation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with defined functional readout; single rigorous paper with multiple orthogonal approaches","pmids":["2118103"],"is_preprint":false},{"year":1993,"finding":"Antibodies against yeast PRP6 co-precipitate U4, U5, and U6 snRNAs. In heat-inactivated prp6-1 mutant extracts, the [U4/U6.U5] tri-snRNP is present in very low amounts while U4/U6 di-snRNP particles remain normally represented, establishing that PRP6 is specifically required for accumulation of the tri-snRNP but is not a component of the U4/U6 di-snRNP.","method":"Antibody co-immunoprecipitation of snRNAs, glycerol gradient sedimentation analysis of snRNP complexes from temperature-sensitive mutant extracts","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus sedimentation analysis in defined mutant background; replicated the earlier genetic findings with biochemical resolution","pmids":["8479905"],"is_preprint":false},{"year":2005,"finding":"Human PRPF6 (U5-102K/hPrp6) is a component of the 20S U5 snRNP and functions as a bridging protein essential for U4/U6.U5 tri-snRNP formation by binding the U4/U6-associated 61K protein; it also interacts with the U5-specific 52K protein (CD2BP2) through its N-terminal region, but this interaction is lost upon tri-snRNP assembly, suggesting a role for 52K in tri-snRNP assembly rather than as a stable tri-snRNP component.","method":"Yeast two-hybrid screening, GST pulldown assays, mass spectrometry protein identification, immunofluorescence localization","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 — reciprocal pulldown and Y2H with functional context; defines hPrp6 as tri-snRNP bridging protein","pmids":["15840814"],"is_preprint":false},{"year":2011,"finding":"A missense mutation c.2185C>T (p.Arg729Trp) in PRPF6, affecting a residue conserved from humans to yeast, causes autosomal-dominant retinitis pigmentosa. Patient lymphoblasts show abnormal nuclear localization of endogenous PRPF6 with accumulation in Cajal bodies, indicating impaired tri-snRNP assembly or recycling. GFP-tagged mutant PRPF6 expressed in HeLa cells recapitulates the Cajal body accumulation phenotype. Patient cells display intron retention for pre-mRNAs bearing specific splicing signals, consistent with a splicing defect.","method":"Mutation screening by sequencing, immunofluorescence localization of endogenous and GFP-tagged PRPF6 in patient lymphoblasts and HeLa cells, endogenous transcript analysis for intron retention","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence (Cajal body accumulation + intron retention), patient-derived cells plus heterologous expression validation","pmids":["21549338"],"is_preprint":false},{"year":2014,"finding":"PRPF6 drives cancer cell proliferation through preferential splicing of growth-regulatory genes. Inhibition of PRPF6 and other tri-snRNP complex proteins, but not other snRNP complexes, selectively abrogates growth in cancer cells with high tri-snRNP levels. Reduced PRPF6 alters constitutive and alternative splicing of a discrete set of genes, including production of an oncogenic isoform of the ZAK kinase, establishing PRPF6 as a tri-snRNP-specific splicing factor with oncogenic roles.","method":"RNAi knockdown, high-resolution transcriptome analysis (RNA-seq), cancer cell proliferation assays, isoform-specific splicing analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype and transcriptome-wide mechanistic follow-up; multiple orthogonal methods in single rigorous study","pmids":["24788092"],"is_preprint":false},{"year":2012,"finding":"PRPF6 was identified as a component of the human spliceosome through comprehensive proteomic analysis; it is present in purified functional spliceosomes along with other U5 snRNP proteins.","method":"Affinity chromatography purification of spliceosomes, nanoscale LC-MS/MS mass spectrometry","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 3 — single proteomics identification without mechanistic follow-up specific to PRPF6","pmids":["12226669"],"is_preprint":false},{"year":2012,"finding":"Systematic yeast two-hybrid and co-immunoprecipitation analyses of the human spliceosomal protein interaction network identified specific protein-protein interactions involving hPrp6 (PRPF6) within the tri-snRNP complex, contributing to the dynamic wiring map of the spliceosome across its assembly states.","method":"Comprehensive Y2H interaction matrix, co-immunoprecipitation validation, integration with spliceosomal complex purification data","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 3 — Y2H with CoIP validation but PRPF6-specific interactions not individually characterized in detail","pmids":["22365833"],"is_preprint":false}],"current_model":"PRPF6 (human) / PRP6 (yeast) is a U5 snRNP protein that functions as an essential bridging factor for U4/U6.U5 tri-snRNP assembly and stability: it associates with U4, U5, and U6 snRNAs, binds the U4/U6-associated 61K protein to bridge di-snRNP and U5 snRNP into the tri-snRNP, and loss-of-function causes selective depletion of tri-snRNP with consequent pre-mRNA splicing defects; in humans, a pathogenic missense mutation (p.Arg729Trp) impairs tri-snRNP assembly/recycling, causing aberrant Cajal body accumulation of PRPF6 and intron retention leading to autosomal-dominant retinitis pigmentosa, while PRPF6 overactivity in cancer promotes growth through preferential splicing of oncogenic gene isoforms including ZAK kinase."},"narrative":{"teleology":[{"year":1990,"claim":"Establishing that PRP6 is a snRNP-associated protein required for splicing resolved whether this gene product acts at the level of snRNP function rather than at other steps of mRNA metabolism.","evidence":"Immunoprecipitation of U4/U5/U6 snRNAs with PRP6 antibodies and in vitro splicing defects in temperature-sensitive yeast mutant extracts","pmids":["2147224","2118103"],"confidence":"High","gaps":["Whether PRP6 is a component of the U4/U6 di-snRNP or specifically of the tri-snRNP was not resolved","The direct protein-protein contacts mediating PRP6 function were unknown","No human ortholog had been characterized"]},{"year":1993,"claim":"Demonstrating that PRP6 loss selectively depletes the tri-snRNP while sparing the U4/U6 di-snRNP established PRP6 as a tri-snRNP-specific assembly factor rather than a general snRNP component.","evidence":"Glycerol gradient sedimentation of snRNP complexes from heat-inactivated prp6-1 yeast extracts combined with antibody co-immunoprecipitation","pmids":["8479905"],"confidence":"High","gaps":["The molecular mechanism by which PRP6 bridges di-snRNP to U5 snRNP was unknown","Whether this role is conserved in human PRPF6 had not been tested"]},{"year":2005,"claim":"Identifying human PRPF6 as the bridging protein that connects U4/U6 di-snRNP (via the 61K protein) to U5 snRNP defined the molecular mechanism of tri-snRNP assembly in human cells.","evidence":"Yeast two-hybrid screening, GST pulldown, and mass spectrometry with human spliceosomal proteins","pmids":["15840814"],"confidence":"High","gaps":["Structural basis of the PRPF6–61K interaction was not determined","Whether PRPF6 has functions beyond tri-snRNP bridging was unclear"]},{"year":2011,"claim":"Linking a conserved PRPF6 missense mutation (p.Arg729Trp) to autosomal-dominant retinitis pigmentosa established that impaired tri-snRNP assembly causes tissue-specific human disease, with Cajal body accumulation serving as a cytological marker of the defect.","evidence":"Mutation screening in RP families, immunofluorescence of endogenous and GFP-tagged PRPF6 in patient lymphoblasts and HeLa cells, intron retention analysis","pmids":["21549338"],"confidence":"High","gaps":["Why retinal photoreceptors are selectively vulnerable to a general splicing defect was not explained","The specific pre-mRNA targets whose mis-splicing leads to retinal degeneration were not identified"]},{"year":2012,"claim":"Proteomic and systematic interaction mapping placed PRPF6 within the broader spliceosomal protein network and confirmed its presence in functional human spliceosomes.","evidence":"Spliceosome affinity purification with LC-MS/MS and comprehensive Y2H/co-IP interaction matrix","pmids":["12226669","22365833"],"confidence":"Medium","gaps":["PRPF6-specific interactions were not individually characterized in mechanistic detail","Dynamic rearrangement of PRPF6 contacts across spliceosome catalytic states was not resolved"]},{"year":2014,"claim":"Demonstrating that PRPF6 knockdown selectively impairs cancer cell growth and alters splicing of oncogenic gene isoforms (including ZAK kinase) revealed a tri-snRNP-specific vulnerability in tumors with high tri-snRNP expression.","evidence":"RNAi knockdown, RNA-seq transcriptome analysis, and cancer cell proliferation assays","pmids":["24788092"],"confidence":"High","gaps":["Whether PRPF6 overexpression is a driver or passenger event in cancer initiation was not established","The mechanism by which PRPF6 levels dictate splicing outcome for specific transcripts was not resolved"]},{"year":null,"claim":"A high-resolution structural model of PRPF6 within the tri-snRNP and the basis for its substrate-specific splicing effects remain to be determined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of PRPF6 in the context of the tri-snRNP has been reported in this timeline","The mechanism by which PRPF6 levels preferentially influence alternative splicing of specific pre-mRNAs is unresolved","Why mutations in a ubiquitous splicing factor cause retina-specific disease is unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[4,6]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5]}],"complexes":["U5 snRNP","U4/U6.U5 tri-snRNP"],"partners":["PRPF31","CD2BP2"],"other_free_text":[]},"mechanistic_narrative":"PRPF6 is a U5 snRNP-associated protein that serves as the principal bridging factor for assembly of the U4/U6.U5 tri-snRNP, a key intermediate required for spliceosome formation and pre-mRNA splicing. It associates with U4, U5, and U6 snRNAs and connects the U4/U6 di-snRNP to U5 snRNP by binding the U4/U6-associated 61K protein; loss of PRPF6 function selectively depletes tri-snRNP while leaving the U4/U6 di-snRNP intact [PMID:8479905, PMID:15840814]. A conserved missense mutation (p.Arg729Trp) causes autosomal-dominant retinitis pigmentosa by impairing tri-snRNP assembly or recycling, leading to aberrant Cajal body accumulation and intron retention in patient cells [PMID:21549338]. PRPF6 also supports cancer cell proliferation through tri-snRNP-dependent preferential splicing of growth-regulatory genes including an oncogenic ZAK kinase isoform [PMID:24788092]."},"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":534,"is_preprint":false,"source_track":"pubmed_title"},{"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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temperature-sensitive mutants are deficient in spliceosome assembly.\",\n      \"method\": \"Immunoprecipitation of snRNAs with PRP6 protein; in vitro splicing assays in prp6 mutant extracts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and functional in vitro assay, foundational study replicated by subsequent work\",\n      \"pmids\": [\"2147224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Molecular characterization of yeast PRP6 reveals the protein contains repeated helix-loop-helix motifs and cysteine/histidine zinc finger-like motifs; directed mutagenesis of specific cysteine/histidine residues abolishes protein function, and the protein contains leucine repeat motifs implicated in protein-protein interactions.\",\n      \"method\": \"DNA sequencing, directed mutagenesis, phenotypic complementation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site/domain mutagenesis with functional readout in a defined genetic system\",\n      \"pmids\": [\"2118103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"PRP6 protein is required for accumulation of the [U4/U6.U5] tri-snRNP; in heat-inactivated prp6-1 mutant extracts, tri-snRNPs are present at very low levels while U4/U6 di-snRNP particles are normally represented, indicating PRP6 acts specifically at the step of tri-snRNP assembly rather than di-snRNP formation. PRP6 antibodies co-precipitate U4, U5, and U6 snRNAs.\",\n      \"method\": \"Glycerol gradient sedimentation of splicing extracts from heat-inactivated prp6-1 mutants; immunoprecipitation with anti-PRP6 antibodies\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (gradient sedimentation + immunoprecipitation + genetic inactivation) in a single study\",\n      \"pmids\": [\"8479905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human PRPF6 (U5-102K/hPrp6) is a U4/U6.U5 tri-snRNP bridging protein that interacts with the U4/U6 di-snRNP-associated 61K protein; the U5 snRNP-specific 52K protein (CD2BP2) directly binds PRPF6 via its N-terminal two-thirds in pulldown assays, but dissociates upon tri-snRNP formation, consistent with a role for PRPF6 in tri-snRNP assembly.\",\n      \"method\": \"Yeast two-hybrid screening; pulldown assays; immunoprecipitation of snRNP fractions; immunofluorescence\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldown/Co-IP and two-hybrid with defined domain mapping, replicated mechanistic context\",\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 accumulation of endogenous PRPF6 in Cajal bodies (rather than nuclear speckles), indicating impairment of tri-snRNP assembly or recycling. GFP-tagged mutant PRPF6 expressed in HeLa cells recapitulates the Cajal body accumulation phenotype. Patient cells show intron retention for pre-mRNAs bearing specific splicing signals.\",\n      \"method\": \"Immunofluorescence localization in patient lymphoblasts; GFP-tagged expression in HeLa cells; endogenous transcript analysis (intron retention assay)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (localization, splicing assay, patient-derived cells, cell line overexpression) in a single study\",\n      \"pmids\": [\"21549338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PRPF6, as a member of the tri-snRNP spliceosome complex, drives cancer cell proliferation by preferential splicing of growth-regulatory genes; inhibition of PRPF6 (but not other snRNP complexes) selectively abrogates growth in cancer cells with high tri-snRNP levels. Reduced PRPF6 alters constitutive and alternative splicing of discrete genes including an oncogenic isoform of ZAK kinase.\",\n      \"method\": \"RNAi knockdown; high-resolution transcriptome analysis (RNA-seq); cell proliferation assays; comparative snRNP inhibition\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined molecular (splicing) and cellular (proliferation) phenotypes, orthogonal transcriptome analysis\",\n      \"pmids\": [\"24788092\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRPF6 (human ortholog of yeast PRP6) is an essential component of the U4/U6.U5 tri-snRNP spliceosome complex that associates with U4, U5, and U6 snRNAs and is required specifically for tri-snRNP assembly and stability; it bridges U4/U6 and U5 snRNPs through protein-protein interactions (including with the 61K and 52K/CD2BP2 proteins), and loss-of-function mutations cause defective tri-snRNP recycling—evidenced by Cajal body accumulation and intron retention—leading to autosomal-dominant retinitis pigmentosa, while in cancer cells PRPF6 drives proliferation through preferential splicing of growth-regulatory genes including oncogenic ZAK kinase isoforms.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe target gene is PRPF6 (human pre-mRNA processing factor 6), a U4/U6.U5 tri-snRNP component involved in pre-mRNA splicing.\n\n**KEEP papers** (about PRPF6 or its clear ortholog PRP6/yeast):\n- PMID:21549338 — PRPF6 missense mutation, RP, tri-snRNP\n- PMID:24788092 — PRPF6 in colon cancer, tri-snRNP splicing\n- PMID:15840814 — hPrp6 (U5-102K), U4/U6.U5 tri-snRNP bridging protein\n- PMID:2147224 — Yeast PRP6, U4/U6 snRNP protein (ortholog)\n- PMID:2118103 — Yeast PRP6 molecular characterization (ortholog)\n- PMID:8479905 — Yeast prp6-1, tri-snRNP accumulation (ortholog)\n\nFrom the gene2pubmed additional papers:\n- PMID:12226669 — Comprehensive spliceosome proteomics (PRPF6 identified as component)\n- PMID:22365833 — Dynamic spliceosomal protein-protein interactions (includes hPrp6 interactions)\n- PMID:11991638 — Native spliceosome purification\n\n**EXCLUDE papers:**\n- All TOM complex/mitochondria papers (alias collision — \"TOM\" = Translocase of Outer Membrane)\n- Tomato/Micro-Tom papers (plant cultivar, symbol collision)\n- Drosophila tom retrotransposon papers (symbol collision)\n- Arabidopsis TOM2 papers (plant, symbol collision)\n- PINK1/Parkin papers (mitochondria TOM complex)\n- ToM (Theory of Mind) genetics paper\n- Tom turkey/poultry paper\n- Babesia in Tom Green County paper\n- MALAT1, RBP atlas, cDNA collection papers (no specific PRPF6 mechanism)\n- Hi-TOM CRISPR tool paper\n- Most large interactome/proteome papers unless they specifically characterize PRPF6 mechanism\n- STA1 Arabidopsis paper (plant ortholog — fundamentally incompatible cellular context, RdDM pathway)\n- PMID:23877244 — STA1 is a plant PRP6-like protein involved in RdDM, not canonical mammalian PRPF6 mechanism — EXCLUDE (symbol collision/plant)\n\nFor the large interactome papers (BioPlex, etc.) — these detect PRPF6 as a co-purifying protein but don't establish mechanism; EXCLUDE as they don't meet \"direct experiment establishing HOW the protein works.\"\n\nPMID:11991638 — identifies spliceosomal components but PRPF6 not specifically mechanistically characterized here — borderline, but no specific PRPF6 mechanism extracted.\n\nPMID:22365833 — includes specific Y2H/CoIP interactions for hPrp6 within spliceosomal network — KEEP for interaction data.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"Yeast PRP6 encodes a U4/U6 snRNP-associated protein required for pre-mRNA splicing; immunoprecipitation of PRP6 protein co-precipitates U4, U5, and U6 snRNAs, and in vitro splicing extracts from temperature-sensitive prp6 mutants are defective in spliceosome assembly, placing PRP6 at the level of snRNP function.\",\n      \"method\": \"Immunoprecipitation of snRNAs, in vitro splicing assay with temperature-sensitive mutant extracts, spliceosome assembly analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-precipitation and functional in vitro splicing assay; foundational paper replicated by subsequent work\",\n      \"pmids\": [\"2147224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The yeast PRP6 protein (899 amino acids) contains repeated helix-loop-helix motifs and cysteine/histidine motifs related to zinc fingers; directed mutagenesis of specific cysteine/histidine residues abolishes protein function, and PRP6 contains leucine repeat motifs implicated in protein-protein interactions. Temperature-sensitive prp6 mutations were mapped and sequenced, establishing structure-function relationships.\",\n      \"method\": \"DNA sequencing, directed mutagenesis of cysteine/histidine residues, genetic complementation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with defined functional readout; single rigorous paper with multiple orthogonal approaches\",\n      \"pmids\": [\"2118103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Antibodies against yeast PRP6 co-precipitate U4, U5, and U6 snRNAs. In heat-inactivated prp6-1 mutant extracts, the [U4/U6.U5] tri-snRNP is present in very low amounts while U4/U6 di-snRNP particles remain normally represented, establishing that PRP6 is specifically required for accumulation of the tri-snRNP but is not a component of the U4/U6 di-snRNP.\",\n      \"method\": \"Antibody co-immunoprecipitation of snRNAs, glycerol gradient sedimentation analysis of snRNP complexes from temperature-sensitive mutant extracts\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus sedimentation analysis in defined mutant background; replicated the earlier genetic findings with biochemical resolution\",\n      \"pmids\": [\"8479905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human PRPF6 (U5-102K/hPrp6) is a component of the 20S U5 snRNP and functions as a bridging protein essential for U4/U6.U5 tri-snRNP formation by binding the U4/U6-associated 61K protein; it also interacts with the U5-specific 52K protein (CD2BP2) through its N-terminal region, but this interaction is lost upon tri-snRNP assembly, suggesting a role for 52K in tri-snRNP assembly rather than as a stable tri-snRNP component.\",\n      \"method\": \"Yeast two-hybrid screening, GST pulldown assays, mass spectrometry protein identification, immunofluorescence localization\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldown and Y2H with functional context; defines hPrp6 as tri-snRNP bridging protein\",\n      \"pmids\": [\"15840814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A missense mutation c.2185C>T (p.Arg729Trp) in PRPF6, affecting a residue conserved from humans to yeast, causes autosomal-dominant retinitis pigmentosa. Patient lymphoblasts show abnormal nuclear localization of endogenous PRPF6 with accumulation in Cajal bodies, indicating impaired tri-snRNP assembly or recycling. GFP-tagged mutant PRPF6 expressed in HeLa cells recapitulates the Cajal body accumulation phenotype. Patient cells display intron retention for pre-mRNAs bearing specific splicing signals, consistent with a splicing defect.\",\n      \"method\": \"Mutation screening by sequencing, immunofluorescence localization of endogenous and GFP-tagged PRPF6 in patient lymphoblasts and HeLa cells, endogenous transcript analysis for intron retention\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence (Cajal body accumulation + intron retention), patient-derived cells plus heterologous expression validation\",\n      \"pmids\": [\"21549338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PRPF6 drives cancer cell proliferation through preferential splicing of growth-regulatory genes. Inhibition of PRPF6 and other tri-snRNP complex proteins, but not other snRNP complexes, selectively abrogates growth in cancer cells with high tri-snRNP levels. Reduced PRPF6 alters constitutive and alternative splicing of a discrete set of genes, including production of an oncogenic isoform of the ZAK kinase, establishing PRPF6 as a tri-snRNP-specific splicing factor with oncogenic roles.\",\n      \"method\": \"RNAi knockdown, high-resolution transcriptome analysis (RNA-seq), cancer cell proliferation assays, isoform-specific splicing analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype and transcriptome-wide mechanistic follow-up; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"24788092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PRPF6 was identified as a component of the human spliceosome through comprehensive proteomic analysis; it is present in purified functional spliceosomes along with other U5 snRNP proteins.\",\n      \"method\": \"Affinity chromatography purification of spliceosomes, nanoscale LC-MS/MS mass spectrometry\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single proteomics identification without mechanistic follow-up specific to PRPF6\",\n      \"pmids\": [\"12226669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Systematic yeast two-hybrid and co-immunoprecipitation analyses of the human spliceosomal protein interaction network identified specific protein-protein interactions involving hPrp6 (PRPF6) within the tri-snRNP complex, contributing to the dynamic wiring map of the spliceosome across its assembly states.\",\n      \"method\": \"Comprehensive Y2H interaction matrix, co-immunoprecipitation validation, integration with spliceosomal complex purification data\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Y2H with CoIP validation but PRPF6-specific interactions not individually characterized in detail\",\n      \"pmids\": [\"22365833\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRPF6 (human) / PRP6 (yeast) is a U5 snRNP protein that functions as an essential bridging factor for U4/U6.U5 tri-snRNP assembly and stability: it associates with U4, U5, and U6 snRNAs, binds the U4/U6-associated 61K protein to bridge di-snRNP and U5 snRNP into the tri-snRNP, and loss-of-function causes selective depletion of tri-snRNP with consequent pre-mRNA splicing defects; in humans, a pathogenic missense mutation (p.Arg729Trp) impairs tri-snRNP assembly/recycling, causing aberrant Cajal body accumulation of PRPF6 and intron retention leading to autosomal-dominant retinitis pigmentosa, while PRPF6 overactivity in cancer promotes growth through preferential splicing of oncogenic gene isoforms including ZAK kinase.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PRPF6 is an essential splicing factor that functions specifically in the assembly of the U4/U6.U5 tri-snRNP, bridging the U4/U6 di-snRNP and U5 snRNP subcomplexes through direct protein–protein interactions with the 61K (U4/U6-associated) and 52K/CD2BP2 (U5-associated) proteins [PMID:8479905, PMID:15840814]. The protein contains functionally required cysteine/histidine motifs and leucine repeats that mediate these interactions, and loss of PRPF6 function leads to depletion of tri-snRNPs while leaving U4/U6 di-snRNPs intact [PMID:2118103, PMID:8479905]. A missense mutation (p.Arg729Trp) in PRPF6 causes autosomal-dominant retinitis pigmentosa, with patient cells exhibiting aberrant Cajal body accumulation of PRPF6 and intron retention indicative of defective tri-snRNP recycling [PMID:21549338]. In cancer cells, PRPF6 drives proliferation by directing preferential splicing of growth-regulatory transcripts, including oncogenic ZAK kinase isoforms [PMID:24788092].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Establishing that PRP6 is a spliceosome component associated with U4/U6 snRNPs resolved what protein factors are required for pre-mRNA splicing and showed PRP6 co-precipitates U4, U5, and U6 snRNAs.\",\n      \"evidence\": \"Immunoprecipitation of snRNAs and in vitro splicing assays in yeast prp6 temperature-sensitive mutant extracts\",\n      \"pmids\": [\"2147224\", \"2118103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The step at which PRP6 acts in snRNP biogenesis was not yet defined\",\n        \"Structural basis for the functional requirement of cysteine/histidine motifs was unknown\",\n        \"Human ortholog had not been characterized\"\n      ]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Pinpointing PRP6 function to the tri-snRNP assembly step — rather than U4/U6 di-snRNP formation — established its specific mechanistic role as the factor that joins U5 snRNP to the U4/U6 particle.\",\n      \"evidence\": \"Glycerol gradient sedimentation of heat-inactivated prp6-1 mutant splicing extracts showing normal di-snRNP but depleted tri-snRNP levels\",\n      \"pmids\": [\"8479905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding partners within the tri-snRNP were not identified\",\n        \"Whether the mechanism is conserved in humans was untested\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of PRPF6 as a bridging protein that contacts both U4/U6-associated 61K and U5-associated 52K/CD2BP2 proteins defined the molecular architecture of human tri-snRNP assembly.\",\n      \"evidence\": \"Yeast two-hybrid, pulldown assays, and co-immunoprecipitation of human snRNP fractions with domain mapping\",\n      \"pmids\": [\"15840814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural details of the PRPF6–61K and PRPF6–52K interfaces were not resolved\",\n        \"Functional consequence of disrupting these interactions in human cells was not tested\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linking the PRPF6 p.Arg729Trp mutation to autosomal-dominant retinitis pigmentosa demonstrated that defective tri-snRNP recycling — manifested as Cajal body accumulation and intron retention — causes retinal degeneration in humans.\",\n      \"evidence\": \"Immunofluorescence in patient lymphoblasts and GFP-tagged expression in HeLa cells; intron retention analysis of endogenous transcripts\",\n      \"pmids\": [\"21549338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Why retinal photoreceptors are selectively vulnerable to a general splicing defect remained unexplained\",\n        \"Whether additional PRPF6 mutations cause RP was not established\",\n        \"The specific splicing targets responsible for retinal degeneration were not identified\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that PRPF6 depletion selectively kills cancer cells by altering splicing of growth-regulatory genes (including ZAK kinase isoforms) revealed a non-housekeeping, gene-selective role for the tri-snRNP in oncogenesis.\",\n      \"evidence\": \"RNAi knockdown, RNA-seq transcriptome analysis, and proliferation assays comparing PRPF6 with other snRNP subunits in cancer versus normal cells\",\n      \"pmids\": [\"24788092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How PRPF6 levels or tri-snRNP abundance selectively affect splicing of specific growth-regulatory transcripts is mechanistically undefined\",\n        \"Whether PRPF6 itself has direct RNA-recognition specificity or acts solely through tri-snRNP stoichiometry is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PRPF6 dysfunction leads to tissue-selective pathology (retina vs. other tissues), what structural features of PRPF6 determine its bridging specificity within the tri-snRNP, and whether its cancer-selective splicing effects are exploitable therapeutically.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of PRPF6 within the tri-snRNP showing its bridging contacts\",\n        \"Tissue-specific splicing targets responsible for retinal degeneration not identified\",\n        \"Mechanism by which tri-snRNP levels confer gene-selective splicing effects is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3, 5]}\n    ],\n    \"complexes\": [\n      \"U4/U6.U5 tri-snRNP\"\n    ],\n    \"partners\": [\n      \"SART1\",\n      \"CD2BP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PRPF6 is a U5 snRNP-associated protein that serves as the principal bridging factor for assembly of the U4/U6.U5 tri-snRNP, a key intermediate required for spliceosome formation and pre-mRNA splicing. It associates with U4, U5, and U6 snRNAs and connects the U4/U6 di-snRNP to U5 snRNP by binding the U4/U6-associated 61K protein; loss of PRPF6 function selectively depletes tri-snRNP while leaving the U4/U6 di-snRNP intact [PMID:8479905, PMID:15840814]. A conserved missense mutation (p.Arg729Trp) causes autosomal-dominant retinitis pigmentosa by impairing tri-snRNP assembly or recycling, leading to aberrant Cajal body accumulation and intron retention in patient cells [PMID:21549338]. PRPF6 also supports cancer cell proliferation through tri-snRNP-dependent preferential splicing of growth-regulatory genes including an oncogenic ZAK kinase isoform [PMID:24788092].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Establishing that PRP6 is a snRNP-associated protein required for splicing resolved whether this gene product acts at the level of snRNP function rather than at other steps of mRNA metabolism.\",\n      \"evidence\": \"Immunoprecipitation of U4/U5/U6 snRNAs with PRP6 antibodies and in vitro splicing defects in temperature-sensitive yeast mutant extracts\",\n      \"pmids\": [\"2147224\", \"2118103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PRP6 is a component of the U4/U6 di-snRNP or specifically of the tri-snRNP was not resolved\",\n        \"The direct protein-protein contacts mediating PRP6 function were unknown\",\n        \"No human ortholog had been characterized\"\n      ]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstrating that PRP6 loss selectively depletes the tri-snRNP while sparing the U4/U6 di-snRNP established PRP6 as a tri-snRNP-specific assembly factor rather than a general snRNP component.\",\n      \"evidence\": \"Glycerol gradient sedimentation of snRNP complexes from heat-inactivated prp6-1 yeast extracts combined with antibody co-immunoprecipitation\",\n      \"pmids\": [\"8479905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular mechanism by which PRP6 bridges di-snRNP to U5 snRNP was unknown\",\n        \"Whether this role is conserved in human PRPF6 had not been tested\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying human PRPF6 as the bridging protein that connects U4/U6 di-snRNP (via the 61K protein) to U5 snRNP defined the molecular mechanism of tri-snRNP assembly in human cells.\",\n      \"evidence\": \"Yeast two-hybrid screening, GST pulldown, and mass spectrometry with human spliceosomal proteins\",\n      \"pmids\": [\"15840814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the PRPF6–61K interaction was not determined\",\n        \"Whether PRPF6 has functions beyond tri-snRNP bridging was unclear\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linking a conserved PRPF6 missense mutation (p.Arg729Trp) to autosomal-dominant retinitis pigmentosa established that impaired tri-snRNP assembly causes tissue-specific human disease, with Cajal body accumulation serving as a cytological marker of the defect.\",\n      \"evidence\": \"Mutation screening in RP families, immunofluorescence of endogenous and GFP-tagged PRPF6 in patient lymphoblasts and HeLa cells, intron retention analysis\",\n      \"pmids\": [\"21549338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Why retinal photoreceptors are selectively vulnerable to a general splicing defect was not explained\",\n        \"The specific pre-mRNA targets whose mis-splicing leads to retinal degeneration were not identified\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Proteomic and systematic interaction mapping placed PRPF6 within the broader spliceosomal protein network and confirmed its presence in functional human spliceosomes.\",\n      \"evidence\": \"Spliceosome affinity purification with LC-MS/MS and comprehensive Y2H/co-IP interaction matrix\",\n      \"pmids\": [\"12226669\", \"22365833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"PRPF6-specific interactions were not individually characterized in mechanistic detail\",\n        \"Dynamic rearrangement of PRPF6 contacts across spliceosome catalytic states was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that PRPF6 knockdown selectively impairs cancer cell growth and alters splicing of oncogenic gene isoforms (including ZAK kinase) revealed a tri-snRNP-specific vulnerability in tumors with high tri-snRNP expression.\",\n      \"evidence\": \"RNAi knockdown, RNA-seq transcriptome analysis, and cancer cell proliferation assays\",\n      \"pmids\": [\"24788092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PRPF6 overexpression is a driver or passenger event in cancer initiation was not established\",\n        \"The mechanism by which PRPF6 levels dictate splicing outcome for specific transcripts was not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structural model of PRPF6 within the tri-snRNP and the basis for its substrate-specific splicing effects remain to be determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No atomic-resolution structure of PRPF6 in the context of the tri-snRNP has been reported in this timeline\",\n        \"The mechanism by which PRPF6 levels preferentially influence alternative splicing of specific pre-mRNAs is unresolved\",\n        \"Why mutations in a ubiquitous splicing factor cause retina-specific disease is unexplained\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 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}\n```"}