{"gene":"EXOSC6","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2000,"finding":"EXOSC6 (hRrp46p), the human homologue of yeast Rrp46p, was identified as a novel component of the human RNA exosome complex. Recombinant hRrp46p co-fractionated by size exclusion chromatography with other exosome subunits (hRrp4p, PM/Scl-100, hRrp40p, hRrp41p), was co-immunoprecipitated by anti-PM/Scl patient sera, and the immunoprecipitated complex demonstrated 3'→5' exoribonuclease activity in vitro. hRrp41p (a closely related subunit) suppressed lethality upon genetic depletion of yeast Rrp41p, confirming functional conservation.","method":"Size exclusion chromatography, co-immunoprecipitation with patient antisera, in vitro exoribonuclease activity assay, complementation of yeast deletion","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (co-IP, biochemical fractionation, enzymatic assay, yeast complementation) in a single study demonstrating complex membership and activity","pmids":["11110791"],"is_preprint":false},{"year":2001,"finding":"The human exosome, purified and characterized by mass spectrometry, contains a composition similar to its yeast counterpart and is required for rapid 3'→5' degradation of ARE-containing mRNAs in a cell-free RNA decay system. ARE-binding proteins (such as TTP and BRF1) were shown to interact with the exosome and recruit it to unstable mRNAs, establishing the exosome's role in ARE-mediated mRNA decay.","method":"Affinity purification coupled to mass spectrometry, cell-free RNA decay assay, immunodepletion, co-immunoprecipitation of ARE-binding proteins with exosome subunits","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — purification and MS identification of complex composition combined with functional reconstitution in cell-free decay system; foundational study with >700 citations","pmids":["11719186"],"is_preprint":false},{"year":2004,"finding":"A two-hybrid protein interaction map of human mRNA decay factors provided evidence for the internal organization of the exosome complex, including interactions among exosome subunits and between the exosome and the poly(A) ribonuclease (PARN) and Lsm complexes, predicting the architecture of the human exosome network.","method":"Yeast two-hybrid interaction mapping among 54 constructs from 38 human mRNA decay proteins","journal":"Genome research","confidence":"Low","confidence_rationale":"Tier 3–4 — two-hybrid only; indirect evidence for EXOSC6's place in the interaction network without direct validation of specific EXOSC6 interactions","pmids":["15231747"],"is_preprint":false},{"year":2006,"finding":"The crystal structure of the nine-subunit human RNA exosome core was determined at 3.35 Å. EXOSC6 (hRrp46p) is one of the six PH-domain-containing subunits forming the ring-like barrel structure. Reconstitution experiments showed the nine-subunit human exosome (including EXOSC6) exhibits processive phosphorolytic 3'→5' exoribonuclease activity contributed by the hRrp41/hRrp45 heterodimer within the ring, and that the human exosome core itself has phosphorolytic activity, distinguishing it from the yeast core.","method":"X-ray crystallography (3.35 Å), reconstitution of recombinant human and yeast exosome subcomplexes, comparative biochemical activity assays with AU-rich, poly(A), generic, and structured RNA substrates","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution crystal structure plus in vitro reconstitution with functional validation; rigorous study defining EXOSC6's structural position in the exosome barrel","pmids":["17174896"],"is_preprint":false},{"year":2010,"finding":"The nine-subunit human exosome core (including EXOSC6/hRrp46p) associates with two distinct processive RNase II/R-type catalytic subunits: hDIS3 (predominantly nuclear, retaining both exo- and endonuclease activities) and hDIS3L (strictly cytoplasmic, exonuclease only), establishing that the same structural core couples to compartment-specific catalytic subunits to mediate nuclear and cytoplasmic RNA degradation.","method":"Co-immunoprecipitation, immunofluorescence/subcellular fractionation, siRNA knockdown with RNA substrate accumulation assays, in vitro exonuclease activity assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, localization experiments with functional consequence, enzymatic assays; replicated in parallel by Staals et al. 2010","pmids":["20531386"],"is_preprint":false},{"year":2010,"finding":"Proteomic analysis of immunoaffinity-purified human exosome complexes (which include EXOSC6) identified hDis3L1 as a novel cytoplasmic exosome-associated exoribonuclease. Co-immunoprecipitation confirmed its physical association with the exosome core. siRNA knockdown of hDis3L1 elevated poly(A)-tailed 28S rRNA degradation intermediates, implicating the EXOSC6-containing cytoplasmic exosome in cytoplasmic RNA decay.","method":"Immunoaffinity purification coupled to mass spectrometry, co-immunoprecipitation, siRNA knockdown with Northern blot analysis of RNA substrates, in vitro exoribonuclease assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — MS-based complex identification confirmed by co-IP and functional knockdown; concordant with Tomecki et al. 2010","pmids":["20531389"],"is_preprint":false},{"year":2011,"finding":"The RNA exosome complex (containing EXOSC6 as a core structural subunit) was found to associate with AID (activation-induced cytidine deaminase) in B lymphocytes activated for class switch recombination, accumulates on immunoglobulin heavy-chain switch regions in an AID-dependent manner, and is required for optimal class switch recombination. A recombinant nine-subunit exosome core reconstituted in vitro conferred AID- and transcription-dependent deamination of both strands of transcribed DNA substrates, revealing a non-RNA-degradation role for the exosome core in targeting AID to template DNA strands.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown with CSR assay, in vitro transcription-coupled deamination assay with recombinant exosome core and AID","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution with recombinant exosome core plus multiple orthogonal in vivo approaches; reveals a novel non-degradative function of the exosome core","pmids":["21255825"],"is_preprint":false},{"year":2015,"finding":"Large-scale affinity-purification mass spectrometry (BioPlex) in HEK293T cells identified EXOSC6 interaction partners within the human exosome complex, placing it within a defined protein community corresponding to the RNA exosome, and confirming its co-complex associations with other exosome subunits at proteome scale.","method":"High-throughput affinity purification coupled to mass spectrometry (AP-MS) across 2,594 human proteins","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — large-scale AP-MS with high coverage; confirms complex membership but does not define specific pairwise interactions for EXOSC6","pmids":["26186194"],"is_preprint":false},{"year":2015,"finding":"Biochemical fractionation coupled with quantitative mass spectrometry across diverse metazoan species demonstrated that the RNA exosome complex (including EXOSC6 orthologues) is among the most ancient and conserved macromolecular assemblies, present across all extant animals, consistent with a core housekeeping role in RNA processing and degradation.","method":"Extensive biochemical fractionation (>1,000 fractions) with quantitative tandem mass spectrometry across multiple metazoan species; co-fractionation profiling","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 — cross-species co-fractionation proteomics; supports evolutionary conservation of EXOSC6-containing exosome complex but does not resolve EXOSC6-specific function","pmids":["26344197"],"is_preprint":false}],"current_model":"EXOSC6 (hRrp46p) is a structural PH-domain subunit of the nine-subunit human RNA exosome core, forming part of the hexameric ring barrel as revealed by X-ray crystallography; it participates in the 3'→5' degradation and processing of diverse RNA substrates (including AU-rich element-containing mRNAs) by coupling the catalytically inert core to processive RNases (hDIS3 in the nucleus, hDIS3L/hDIS3L1 in the cytoplasm), and the exosome core containing EXOSC6 also performs a non-degradative function by recruiting AID to transcribed DNA to enable antibody class switch recombination."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing that EXOSC6 (hRrp46p) is a bona fide subunit of the human exosome resolved whether the yeast exosome architecture is conserved in humans and demonstrated that the immunoprecipitated complex possesses 3'→5' exoribonuclease activity.","evidence":"Size exclusion co-fractionation, co-IP with patient antisera, in vitro exoribonuclease assays, and yeast complementation","pmids":["11110791"],"confidence":"High","gaps":["Specific pairwise contacts of EXOSC6 within the ring not determined","Whether EXOSC6 itself contributes catalytic activity was unresolved"]},{"year":2001,"claim":"Demonstrating that the exosome is recruited by ARE-binding proteins (TTP, BRF1) for rapid 3'→5' degradation of AU-rich mRNAs established a key physiological substrate class and recruitment mechanism for the EXOSC6-containing complex.","evidence":"Affinity purification-MS of exosome composition, cell-free ARE-mRNA decay reconstitution, immunodepletion, co-IP of ARE-binding proteins","pmids":["11719186"],"confidence":"High","gaps":["Whether EXOSC6 contacts RNA directly during ARE-mediated decay was unknown","Relative contributions of individual subunits to substrate threading not addressed"]},{"year":2006,"claim":"Solving the 3.35 Å crystal structure of the nine-subunit human exosome defined EXOSC6 as one of six PH-domain ring subunits and revealed that the human core retains phosphorolytic activity (via the hRrp41/hRrp45 heterodimer), answering the long-standing question of whether the eukaryotic exosome barrel is catalytically inert.","evidence":"X-ray crystallography of the reconstituted nine-subunit human exosome core with comparative biochemical activity assays","pmids":["17174896"],"confidence":"High","gaps":["EXOSC6 itself lacks catalytic residues; its structural role in RNA channeling was inferred but not directly tested by mutagenesis","How substrate selectivity is achieved at the ring level remained unclear"]},{"year":2010,"claim":"Identifying hDIS3 (nuclear) and hDIS3L/hDIS3L1 (cytoplasmic) as compartment-specific catalytic partners of the same structural core resolved how a single ring scaffold mediates RNA degradation in distinct cellular compartments.","evidence":"Reciprocal co-IP, subcellular fractionation/immunofluorescence, siRNA knockdown with RNA accumulation assays, and in vitro exonuclease assays in two concordant studies","pmids":["20531386","20531389"],"confidence":"High","gaps":["Whether EXOSC6 makes direct contacts with the catalytic subunits or only contributes indirectly through ring integrity was not resolved","Regulation of exosome catalytic subunit switching was not addressed"]},{"year":2011,"claim":"Discovering that the exosome core associates with AID and is required for class switch recombination revealed an unexpected non-degradative function: the reconstituted nine-subunit ring enables AID-dependent deamination of template-strand DNA at switch regions.","evidence":"Co-IP of exosome–AID, ChIP at IgH switch regions, siRNA knockdown with CSR functional assay, in vitro transcription-coupled deamination with recombinant exosome core","pmids":["21255825"],"confidence":"High","gaps":["Whether EXOSC6 directly contacts AID or the switch-region RNA:DNA hybrid was not determined","How the exosome is targeted specifically to switch regions rather than other transcribed loci remained open","Whether catalytic subunits (DIS3) are needed for the DNA-targeting function was unclear"]},{"year":null,"claim":"The specific structural contributions of EXOSC6 within the exosome ring—its direct contacts with RNA or DNA substrates, its role in recruiting or positioning catalytic subunits, and any EXOSC6-specific mutations linked to human disease—remain to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No EXOSC6-specific mutagenesis or structure-function dissection reported","No disease-associated mutations in EXOSC6 described, unlike neighboring exosome subunits","Mechanism by which EXOSC6 contributes to substrate channeling through the barrel is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,3,4,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]}],"complexes":["RNA exosome core"],"partners":["EXOSC4","EXOSC7","EXOSC8","EXOSC9","DIS3","DIS3L","AICDA"],"other_free_text":[]},"mechanistic_narrative":"EXOSC6 is a structural PH-domain subunit of the nine-subunit human RNA exosome core, where it contributes to the hexameric ring barrel that channels RNA substrates toward associated catalytic subunits for processive 3'→5' degradation [PMID:17174896]. The EXOSC6-containing exosome core couples to compartment-specific catalytic RNases—hDIS3 in the nucleus and hDIS3L/hDIS3L1 in the cytoplasm—to degrade diverse RNA substrates including AU-rich element-containing mRNAs recruited by ARE-binding proteins such as TTP and BRF1 [PMID:11719186, PMID:20531386, PMID:20531389]. Beyond RNA degradation, the reconstituted nine-subunit exosome core associates with activation-induced cytidine deaminase (AID) in B lymphocytes and enables AID-dependent deamination of both DNA strands at immunoglobulin switch regions, establishing a non-degradative role for the exosome in antibody class switch recombination [PMID:21255825]."},"prefetch_data":{"uniprot":{"accession":"Q5RKV6","full_name":"Exosome complex component MTR3","aliases":["Exosome component 6","mRNA transport regulator 3 homolog","hMtr3","p11"],"length_aa":272,"mass_kda":28.2,"function":"Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes","subcellular_location":"Cytoplasm; Nucleus, nucleolus; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q5RKV6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EXOSC6","classification":"Common Essential","n_dependent_lines":1196,"n_total_lines":1208,"dependency_fraction":0.9900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EXOSC6","total_profiled":1310},"omim":[{"mim_id":"606490","title":"EXOSOME COMPONENT 6; EXOSC6","url":"https://www.omim.org/entry/606490"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EXOSC6"},"hgnc":{"alias_symbol":["MTR3","hMtr3p","Mtr3p","EAP4","p11"],"prev_symbol":[]},"alphafold":{"accession":"Q5RKV6","domains":[{"cath_id":"3.30.230.70","chopping":"36-71_93-271","consensus_level":"medium","plddt":88.2108,"start":36,"end":271}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5RKV6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5RKV6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5RKV6-F1-predicted_aligned_error_v6.png","plddt_mean":80.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EXOSC6","jax_strain_url":"https://www.jax.org/strain/search?query=EXOSC6"},"sequence":{"accession":"Q5RKV6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5RKV6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5RKV6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5RKV6"}},"corpus_meta":[{"pmid":"7951320","id":"PMC_7951320","title":"Identification 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complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21145461","id":"PMC_21145461","title":"Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21145461","citation_count":318,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21255825","id":"PMC_21255825","title":"The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates.","date":"2011","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21255825","citation_count":248,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30033366","id":"PMC_30033366","title":"Mapping the Genetic Landscape of Human Cells.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/30033366","citation_count":225,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20531386","id":"PMC_20531386","title":"The human core exosome interacts with differentially localized processive RNases: hDIS3 and hDIS3L.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/20531386","citation_count":224,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26618866","id":"PMC_26618866","title":"∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26618866","citation_count":209,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32203420","id":"PMC_32203420","title":"Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32203420","citation_count":194,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32807901","id":"PMC_32807901","title":"UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32807901","citation_count":168,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30804502","id":"PMC_30804502","title":"H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30804502","citation_count":162,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19322201","id":"PMC_19322201","title":"Ubiquitin-mediated proteolysis of HuR by heat shock.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19322201","citation_count":142,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27926873","id":"PMC_27926873","title":"FOXA1 Directs H3K4 Monomethylation at Enhancers via Recruitment of the Methyltransferase MLL3.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27926873","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32989298","id":"PMC_32989298","title":"PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase.","date":"2020","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/32989298","citation_count":129,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15231747","id":"PMC_15231747","title":"A protein interaction framework for human mRNA degradation.","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15231747","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20531389","id":"PMC_20531389","title":"Dis3-like 1: a novel exoribonuclease associated with the human exosome.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/20531389","citation_count":119,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28718761","id":"PMC_28718761","title":"The human cytoplasmic dynein interactome reveals novel activators of motility.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28718761","citation_count":118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33658012","id":"PMC_33658012","title":"FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2.","date":"2021","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33658012","citation_count":106,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11110791","id":"PMC_11110791","title":"Three novel components of the human exosome.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11110791","citation_count":101,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43846,"output_tokens":276,"usd":0.067839},"stage2":{"model":"","input_tokens":0,"output_tokens":0,"usd":0.0},"total_usd":0.292868,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":56220,"output_tokens":3339,"usd":0.109372},"round2_rules_fired":"R1","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6231,"output_tokens":1838,"usd":0.115657}},"stage1_raw":"Looking at the corpus, I need to identify papers about EXOSC6 specifically. Scanning through all 100 abstracts, I find that the vast majority are about chromosomal translocations, cytogenetic variants, p11 (S100A10/annexin A2 light chain), GSTP1-1, and various chromosomal syndromes — none of which are EXOSC6 (also known as MTR3, a component of the RNA exosome complex).\n\nEXOSC6 is a non-catalytic structural subunit of the RNA exosome complex. None of the 100 abstracts in this corpus describe EXOSC6 or its function. The \"p11\" discussed extensively in these papers refers to S100A10 (annexin II light chain), not EXOSC6. The chromosomal locus references (e.g., p11.2) are cytogenetic band designations, not the gene EXOSC6.\n\nThere are no mechanistic findings about EXOSC6 in the available literature provided.\n\n```json\n{\n  \"discoveries\": [],\n  \"current_model\": \"No mechanistic findings in the available literature.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nThe retrieved papers (100) are almost entirely about S100A10/p11 (a different protein), chromosomal band nomenclature, or unrelated genes. EXOSC6 is a component of the RNA exosome complex (also known as hRrp46p/Rrp46).\n\nFrom the gene2pubmed-curated papers (30), relevant papers about the RNA exosome include:\n- PMID:11719186 (Chen et al., 2001) — human exosome purification, ARE-mRNA degradation — KEEP\n- PMID:17174896 (Liu et al., 2006) — reconstitution and structure of eukaryotic exosome — KEEP\n- PMID:11110791 (Brouwer et al., 2000) — three novel human exosome components including hRrp46p (EXOSC6) — KEEP\n- PMID:21255825 (Basu et al., 2011) — RNA exosome targets AID — KEEP\n- PMID:20531386 (Tomecki et al., 2010) — human exosome core and catalytic subunits — KEEP\n- PMID:20531389 (Staals et al., 2010) — hDis3L1 associated with human exosome — KEEP\n- PMID:15231747 (Lehner & Sanderson, 2004) — mRNA degradation protein interaction framework — KEEP (mentions exosome internal organization)\n- PMID:12477932 — MGC cDNA sequencing — LOW relevance, no mechanistic finding about EXOSC6 specifically\n- PMID:26186194, 28514442, 33961781 — BioPlex interactome — KEEP for interaction data\n- PMID:26496610 — human interactome — KEEP\n- PMID:22939629 — human protein complexes — KEEP\n- PMID:26344197 — metazoan complexes — KEEP\n- PMID:22681889 — mRNA-bound proteome — marginal, no specific EXOSC6 finding\n- PMID:29395067 — mRNA granules BioID — marginal\n- PMID:34079125 — BioID cell map — marginal\n- Others (UFMylation, AURORA-A, BRCA1, dynein, FOXA1, HuR, CRL, CFTR, FBW7) — EXCLUDE (not about EXOSC6)\n\nAll 100 retrieved papers are about S100A10/p11 or chromosomal loci — EXCLUDE all.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"EXOSC6 (hRrp46p), the human homologue of yeast Rrp46p, was identified as a novel component of the human RNA exosome complex. Recombinant hRrp46p co-fractionated by size exclusion chromatography with other exosome subunits (hRrp4p, PM/Scl-100, hRrp40p, hRrp41p), was co-immunoprecipitated by anti-PM/Scl patient sera, and the immunoprecipitated complex demonstrated 3'→5' exoribonuclease activity in vitro. hRrp41p (a closely related subunit) suppressed lethality upon genetic depletion of yeast Rrp41p, confirming functional conservation.\",\n      \"method\": \"Size exclusion chromatography, co-immunoprecipitation with patient antisera, in vitro exoribonuclease activity assay, complementation of yeast deletion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (co-IP, biochemical fractionation, enzymatic assay, yeast complementation) in a single study demonstrating complex membership and activity\",\n      \"pmids\": [\"11110791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The human exosome, purified and characterized by mass spectrometry, contains a composition similar to its yeast counterpart and is required for rapid 3'→5' degradation of ARE-containing mRNAs in a cell-free RNA decay system. ARE-binding proteins (such as TTP and BRF1) were shown to interact with the exosome and recruit it to unstable mRNAs, establishing the exosome's role in ARE-mediated mRNA decay.\",\n      \"method\": \"Affinity purification coupled to mass spectrometry, cell-free RNA decay assay, immunodepletion, co-immunoprecipitation of ARE-binding proteins with exosome subunits\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — purification and MS identification of complex composition combined with functional reconstitution in cell-free decay system; foundational study with >700 citations\",\n      \"pmids\": [\"11719186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A two-hybrid protein interaction map of human mRNA decay factors provided evidence for the internal organization of the exosome complex, including interactions among exosome subunits and between the exosome and the poly(A) ribonuclease (PARN) and Lsm complexes, predicting the architecture of the human exosome network.\",\n      \"method\": \"Yeast two-hybrid interaction mapping among 54 constructs from 38 human mRNA decay proteins\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3–4 — two-hybrid only; indirect evidence for EXOSC6's place in the interaction network without direct validation of specific EXOSC6 interactions\",\n      \"pmids\": [\"15231747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The crystal structure of the nine-subunit human RNA exosome core was determined at 3.35 Å. EXOSC6 (hRrp46p) is one of the six PH-domain-containing subunits forming the ring-like barrel structure. Reconstitution experiments showed the nine-subunit human exosome (including EXOSC6) exhibits processive phosphorolytic 3'→5' exoribonuclease activity contributed by the hRrp41/hRrp45 heterodimer within the ring, and that the human exosome core itself has phosphorolytic activity, distinguishing it from the yeast core.\",\n      \"method\": \"X-ray crystallography (3.35 Å), reconstitution of recombinant human and yeast exosome subcomplexes, comparative biochemical activity assays with AU-rich, poly(A), generic, and structured RNA substrates\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution crystal structure plus in vitro reconstitution with functional validation; rigorous study defining EXOSC6's structural position in the exosome barrel\",\n      \"pmids\": [\"17174896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The nine-subunit human exosome core (including EXOSC6/hRrp46p) associates with two distinct processive RNase II/R-type catalytic subunits: hDIS3 (predominantly nuclear, retaining both exo- and endonuclease activities) and hDIS3L (strictly cytoplasmic, exonuclease only), establishing that the same structural core couples to compartment-specific catalytic subunits to mediate nuclear and cytoplasmic RNA degradation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence/subcellular fractionation, siRNA knockdown with RNA substrate accumulation assays, in vitro exonuclease activity assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, localization experiments with functional consequence, enzymatic assays; replicated in parallel by Staals et al. 2010\",\n      \"pmids\": [\"20531386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Proteomic analysis of immunoaffinity-purified human exosome complexes (which include EXOSC6) identified hDis3L1 as a novel cytoplasmic exosome-associated exoribonuclease. Co-immunoprecipitation confirmed its physical association with the exosome core. siRNA knockdown of hDis3L1 elevated poly(A)-tailed 28S rRNA degradation intermediates, implicating the EXOSC6-containing cytoplasmic exosome in cytoplasmic RNA decay.\",\n      \"method\": \"Immunoaffinity purification coupled to mass spectrometry, co-immunoprecipitation, siRNA knockdown with Northern blot analysis of RNA substrates, in vitro exoribonuclease assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-based complex identification confirmed by co-IP and functional knockdown; concordant with Tomecki et al. 2010\",\n      \"pmids\": [\"20531389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The RNA exosome complex (containing EXOSC6 as a core structural subunit) was found to associate with AID (activation-induced cytidine deaminase) in B lymphocytes activated for class switch recombination, accumulates on immunoglobulin heavy-chain switch regions in an AID-dependent manner, and is required for optimal class switch recombination. A recombinant nine-subunit exosome core reconstituted in vitro conferred AID- and transcription-dependent deamination of both strands of transcribed DNA substrates, revealing a non-RNA-degradation role for the exosome core in targeting AID to template DNA strands.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown with CSR assay, in vitro transcription-coupled deamination assay with recombinant exosome core and AID\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution with recombinant exosome core plus multiple orthogonal in vivo approaches; reveals a novel non-degradative function of the exosome core\",\n      \"pmids\": [\"21255825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Large-scale affinity-purification mass spectrometry (BioPlex) in HEK293T cells identified EXOSC6 interaction partners within the human exosome complex, placing it within a defined protein community corresponding to the RNA exosome, and confirming its co-complex associations with other exosome subunits at proteome scale.\",\n      \"method\": \"High-throughput affinity purification coupled to mass spectrometry (AP-MS) across 2,594 human proteins\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large-scale AP-MS with high coverage; confirms complex membership but does not define specific pairwise interactions for EXOSC6\",\n      \"pmids\": [\"26186194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Biochemical fractionation coupled with quantitative mass spectrometry across diverse metazoan species demonstrated that the RNA exosome complex (including EXOSC6 orthologues) is among the most ancient and conserved macromolecular assemblies, present across all extant animals, consistent with a core housekeeping role in RNA processing and degradation.\",\n      \"method\": \"Extensive biochemical fractionation (>1,000 fractions) with quantitative tandem mass spectrometry across multiple metazoan species; co-fractionation profiling\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cross-species co-fractionation proteomics; supports evolutionary conservation of EXOSC6-containing exosome complex but does not resolve EXOSC6-specific function\",\n      \"pmids\": [\"26344197\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EXOSC6 (hRrp46p) is a structural PH-domain subunit of the nine-subunit human RNA exosome core, forming part of the hexameric ring barrel as revealed by X-ray crystallography; it participates in the 3'→5' degradation and processing of diverse RNA substrates (including AU-rich element-containing mRNAs) by coupling the catalytically inert core to processive RNases (hDIS3 in the nucleus, hDIS3L/hDIS3L1 in the cytoplasm), and the exosome core containing EXOSC6 also performs a non-degradative function by recruiting AID to transcribed DNA to enable antibody class switch recombination.\"\n}\n```","stage2_raw":"\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"EXOSC6 is a structural PH-domain subunit of the nine-subunit human RNA exosome core, where it contributes to the hexameric ring barrel that channels RNA substrates toward associated catalytic subunits for processive 3'→5' degradation [PMID:17174896]. The EXOSC6-containing exosome core couples to compartment-specific catalytic RNases—hDIS3 in the nucleus and hDIS3L/hDIS3L1 in the cytoplasm—to degrade diverse RNA substrates including AU-rich element-containing mRNAs recruited by ARE-binding proteins such as TTP and BRF1 [PMID:11719186, PMID:20531386, PMID:20531389]. Beyond RNA degradation, the reconstituted nine-subunit exosome core associates with activation-induced cytidine deaminase (AID) in B lymphocytes and enables AID-dependent deamination of both DNA strands at immunoglobulin switch regions, establishing a non-degradative role for the exosome in antibody class switch recombination [PMID:21255825].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that EXOSC6 (hRrp46p) is a bona fide subunit of the human exosome resolved whether the yeast exosome architecture is conserved in humans and demonstrated that the immunoprecipitated complex possesses 3'→5' exoribonuclease activity.\",\n      \"evidence\": \"Size exclusion co-fractionation, co-IP with patient antisera, in vitro exoribonuclease assays, and yeast complementation\",\n      \"pmids\": [\"11110791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific pairwise contacts of EXOSC6 within the ring not determined\", \"Whether EXOSC6 itself contributes catalytic activity was unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating that the exosome is recruited by ARE-binding proteins (TTP, BRF1) for rapid 3'→5' degradation of AU-rich mRNAs established a key physiological substrate class and recruitment mechanism for the EXOSC6-containing complex.\",\n      \"evidence\": \"Affinity purification-MS of exosome composition, cell-free ARE-mRNA decay reconstitution, immunodepletion, co-IP of ARE-binding proteins\",\n      \"pmids\": [\"11719186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EXOSC6 contacts RNA directly during ARE-mediated decay was unknown\", \"Relative contributions of individual subunits to substrate threading not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Solving the 3.35 Å crystal structure of the nine-subunit human exosome defined EXOSC6 as one of six PH-domain ring subunits and revealed that the human core retains phosphorolytic activity (via the hRrp41/hRrp45 heterodimer), answering the long-standing question of whether the eukaryotic exosome barrel is catalytically inert.\",\n      \"evidence\": \"X-ray crystallography of the reconstituted nine-subunit human exosome core with comparative biochemical activity assays\",\n      \"pmids\": [\"17174896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EXOSC6 itself lacks catalytic residues; its structural role in RNA channeling was inferred but not directly tested by mutagenesis\", \"How substrate selectivity is achieved at the ring level remained unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying hDIS3 (nuclear) and hDIS3L/hDIS3L1 (cytoplasmic) as compartment-specific catalytic partners of the same structural core resolved how a single ring scaffold mediates RNA degradation in distinct cellular compartments.\",\n      \"evidence\": \"Reciprocal co-IP, subcellular fractionation/immunofluorescence, siRNA knockdown with RNA accumulation assays, and in vitro exonuclease assays in two concordant studies\",\n      \"pmids\": [\"20531386\", \"20531389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EXOSC6 makes direct contacts with the catalytic subunits or only contributes indirectly through ring integrity was not resolved\", \"Regulation of exosome catalytic subunit switching was not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovering that the exosome core associates with AID and is required for class switch recombination revealed an unexpected non-degradative function: the reconstituted nine-subunit ring enables AID-dependent deamination of template-strand DNA at switch regions.\",\n      \"evidence\": \"Co-IP of exosome–AID, ChIP at IgH switch regions, siRNA knockdown with CSR functional assay, in vitro transcription-coupled deamination with recombinant exosome core\",\n      \"pmids\": [\"21255825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EXOSC6 directly contacts AID or the switch-region RNA:DNA hybrid was not determined\", \"How the exosome is targeted specifically to switch regions rather than other transcribed loci remained open\", \"Whether catalytic subunits (DIS3) are needed for the DNA-targeting function was unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific structural contributions of EXOSC6 within the exosome ring—its direct contacts with RNA or DNA substrates, its role in recruiting or positioning catalytic subunits, and any EXOSC6-specific mutations linked to human disease—remain to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No EXOSC6-specific mutagenesis or structure-function dissection reported\", \"No disease-associated mutations in EXOSC6 described, unlike neighboring exosome subunits\", \"Mechanism by which EXOSC6 contributes to substrate channeling through the barrel is unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"RNA exosome core\"\n    ],\n    \"partners\": [\n      \"EXOSC4\",\n      \"EXOSC7\",\n      \"EXOSC8\",\n      \"EXOSC9\",\n      \"DIS3\",\n      \"DIS3L\",\n      \"AICDA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}