{"gene":"PSMD6","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2004,"finding":"Rpn7 (the yeast ortholog of PSMD6) is required for the structural integrity of the 26S proteasome. Temperature-sensitive rpn7 mutants accumulate poly-ubiquitinated proteins and fail to degrade N-end rule substrates, UFD pathway substrates, and cell cycle regulators (Pds1 and Clb2). Analysis of the proteasome in rpn7-3 mutant cells revealed a defect in 26S holoenzyme assembly; the lid subcomplex purified from rpn7-3 cells contained only 5 of the 8 lid components, indicating Rpn7 is essential for establishing correct lid structure.","method":"Temperature-sensitive mutant analysis, affinity purification of 26S proteasome subcomplexes, ubiquitin-proteasome pathway substrate degradation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined cellular and structural phenotype, multiple substrates tested, complex composition directly analyzed","pmids":["15102831"],"is_preprint":false},{"year":2000,"finding":"The p44S10 gene (PSMD6), located on human chromosome 3p14.1, encodes a highly conserved subunit of the 26S proteasome regulatory particle. p44S10 gene copy number and mRNA expression were increased in cutaneous malignant melanoma cell lines and tumors. Importantly, increased expression of p44S10 was sufficient to induce proliferation of radial growth phase WM35 melanoma cells in vivo, establishing a functional role for PSMD6 overexpression in promoting cell proliferation.","method":"Expression cloning from morphologically transformed cells, chromosomal copy number analysis, overexpression-driven in vivo proliferation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, gain-of-function proliferation phenotype with limited mechanistic pathway placement","pmids":["10723133"],"is_preprint":false},{"year":2012,"finding":"The 19S proteasome subunit Rpn7 (human PSMD6) translocates to the nucleus and colocalizes with DNA damage foci over their entire lifespan following genotoxic insult. Silencing of Rpn7 promotes faster resolution of DNA damage foci and specifically decreases the frequency of long-lived DNA damage foci without affecting the repair rate of short-lived foci, indicating that Rpn7 interaction with DDR foci in situ protects them from premature resolution and thereby enables cellular senescence.","method":"siRNA knockdown, immunofluorescence colocalization with DNA damage foci (γH2AX), nuclear fractionation, foci lifespan quantification","journal":"IUBMB life","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization experiment with functional consequence, single lab","pmids":["22473755"],"is_preprint":false}],"current_model":"PSMD6 (p44S10/Rpn7) is a lid subunit of the 19S regulatory particle of the 26S proteasome that is required for proper lid assembly and structural integrity of the holoenzyme, enabling ubiquitin-proteasome pathway substrate degradation; it also localizes to the nucleus upon DNA damage and stabilizes DNA damage foci to promote cellular senescence, and its overexpression is sufficient to drive cell proliferation."},"narrative":{"teleology":[{"year":2000,"claim":"Identifying PSMD6 as a 26S proteasome subunit whose overexpression is sufficient to drive tumor cell proliferation established a functional link between this regulatory particle component and oncogenic growth.","evidence":"Expression cloning from transformed cells, copy number analysis, and in vivo overexpression-driven proliferation assay in melanoma cells","pmids":["10723133"],"confidence":"Medium","gaps":["Gain-of-function result from a single lab without independent replication","Mechanism by which PSMD6 overexpression promotes proliferation (proteasome-dependent or independent) was not determined","Whether the proliferative effect is specific to PSMD6 or generalizable to other 19S subunits is unknown"]},{"year":2004,"claim":"Demonstrating that Rpn7 is required for proper lid assembly and 26S holoenzyme integrity resolved how this subunit contributes to proteasomal function: it scaffolds at least three other lid components, and its loss broadly impairs ubiquitin-dependent proteolysis.","evidence":"Temperature-sensitive yeast mutants, affinity purification of proteasome subcomplexes, and degradation assays for multiple UPS substrates (N-end rule, UFD, Pds1, Clb2)","pmids":["15102831"],"confidence":"High","gaps":["Whether human PSMD6 performs an identical scaffolding role in mammalian lid assembly has not been directly tested","No structural model of Rpn7 contacts within the lid was provided","Whether the assembly defect is primary or secondary to Rpn7 misfolding was not resolved"]},{"year":2012,"claim":"Revealing that PSMD6 translocates to the nucleus upon DNA damage and stabilizes long-lived DNA damage foci uncovered a proteasome-independent role in the DNA damage response and cellular senescence.","evidence":"siRNA knockdown, γH2AX colocalization by immunofluorescence, nuclear fractionation, and foci lifespan quantification in human cells","pmids":["22473755"],"confidence":"Medium","gaps":["Single-lab study; independent confirmation in other cell systems is lacking","The molecular mechanism by which PSMD6 protects foci from resolution (e.g., direct protein interactions at foci) is unknown","Whether this nuclear DDR role requires intact proteasome or is proteasome-independent was not distinguished"]},{"year":null,"claim":"It remains unknown how PSMD6's structural role in lid assembly, its DDR foci-stabilizing function, and its proliferation-promoting activity upon overexpression are mechanistically integrated, and whether these reflect proteasome-dependent or proteasome-independent activities.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct biochemical characterization of PSMD6 molecular activity beyond scaffolding","No structure of human PSMD6 within the 19S lid at sufficient resolution to identify interaction surfaces","Relationship between PSMD6 dosage, proteasome activity, DDR stabilization, and proliferation has not been dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2]}],"complexes":["26S proteasome (19S regulatory particle lid)"],"partners":[],"other_free_text":[]},"mechanistic_narrative":"PSMD6 (p44S10/Rpn7) is a non-ATPase lid subunit of the 19S regulatory particle of the 26S proteasome, essential for correct lid subcomplex assembly and holoenzyme structural integrity; loss-of-function mutations cause accumulation of polyubiquitinated proteins and failure to degrade N-end rule, UFD pathway, and cell cycle regulatory substrates [PMID:15102831]. Beyond canonical proteasomal function, PSMD6 translocates to the nucleus upon genotoxic stress, where it colocalizes with and stabilizes long-lived DNA damage foci, promoting cellular senescence [PMID:22473755]. Overexpression of PSMD6 is sufficient to drive cell proliferation in melanoma cells, and its copy number and expression are increased in cutaneous malignant melanoma [PMID:10723133]."},"prefetch_data":{"uniprot":{"accession":"Q15008","full_name":"26S proteasome non-ATPase regulatory subunit 6","aliases":["26S proteasome regulatory subunit RPN7","26S proteasome regulatory subunit S10","Breast cancer-associated protein SGA-113M","Phosphonoformate immuno-associated protein 4","Proteasome regulatory particle subunit p44S10","p42A"],"length_aa":389,"mass_kda":45.5,"function":"Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q15008/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMD6","classification":"Common Essential","n_dependent_lines":1206,"n_total_lines":1208,"dependency_fraction":0.9983443708609272},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000163636","cell_line_id":"CID000117","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PSMA1","stoichiometry":10.0},{"gene":"PSMA2","stoichiometry":10.0},{"gene":"PSMA3","stoichiometry":10.0},{"gene":"PSMA4","stoichiometry":10.0},{"gene":"PSMA5","stoichiometry":10.0},{"gene":"PSMA6","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMB2","stoichiometry":10.0},{"gene":"PSMB3","stoichiometry":10.0},{"gene":"PSMB4","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000117","total_profiled":1310},"omim":[{"mim_id":"617857","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 6; PSMD6","url":"https://www.omim.org/entry/617857"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"pancreas","ntpm":269.4}],"url":"https://www.proteinatlas.org/search/PSMD6"},"hgnc":{"alias_symbol":["S10","p44S10","KIAA0107","Rpn7"],"prev_symbol":[]},"alphafold":{"accession":"Q15008","domains":[{"cath_id":"1.25.40.570","chopping":"9-136","consensus_level":"medium","plddt":78.6218,"start":9,"end":136},{"cath_id":"1.20.5","chopping":"359-389","consensus_level":"medium","plddt":87.9619,"start":359,"end":389}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15008","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15008-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15008-F1-predicted_aligned_error_v6.png","plddt_mean":82.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMD6","jax_strain_url":"https://www.jax.org/strain/search?query=PSMD6"},"sequence":{"accession":"Q15008","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15008.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15008/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15008"}},"corpus_meta":[{"pmid":"9391153","id":"PMC_9391153","title":"Large 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N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28302793","citation_count":533,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22158537","id":"PMC_22158537","title":"Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22158537","citation_count":495,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42414,"output_tokens":1077,"usd":0.071698},"stage2":{"model":"claude-opus-4-6","input_tokens":4104,"output_tokens":2596,"usd":0.12813},"total_usd":0.371761,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":53607,"output_tokens":1470,"usd":0.091436},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4373,"output_tokens":1272,"usd":0.080497}},"stage1_raw":"Looking at the corpus, I need to identify papers about PSMD6, which is a subunit of the 26S proteasome regulatory particle (19S). The relevant papers are those describing proteasome subunit Rpn7 (which corresponds to PSMD6 in humans) and related proteasome biology.\n\nPapers 32, 65, 92, and 44 are relevant. Papers 32 and 92 describe Rpn7 (yeast ortholog of PSMD6), paper 65 describes p44S10 (human PSMD6), and paper 44 describes plant RPN7 (likely a symbol collision given the plant context, but I'll evaluate carefully).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Rpn7 (yeast ortholog of PSMD6) is required for the structural integrity of the 26S proteasome. Temperature-sensitive rpn7 mutants accumulate poly-ubiquitinated proteins and stabilize ubiquitin-proteasome substrates (N-end rule substrate, UFD pathway substrate, cell cycle regulators Pds1 and Clb2). The defect was traced to impaired assembly of the 26S holoenzyme; affinity-purified lid subcomplexes from rpn7-3 mutant cells contained only 5 of the 8 lid components, indicating Rpn7 is necessary for correct lid structure formation.\",\n      \"method\": \"Temperature-sensitive mutant analysis, ubiquitinated protein accumulation assay, substrate stabilization assays, affinity purification of lid subcomplex with subunit composition analysis by SDS-PAGE\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with multiple defined substrates and direct structural analysis of proteasome lid composition\",\n      \"pmids\": [\"15102831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"p44S10 (human PSMD6), a subunit of the 26S proteasome regulatory particle, was identified as a candidate oncogene on chromosome 3p14.1. Increased expression of p44S10 was sufficient to induce proliferation of WM35 radial growth phase melanoma cells in vivo, demonstrating a functional role for this proteasome subunit in promoting cell proliferation.\",\n      \"method\": \"Expression cloning assay, gene copy number analysis, mRNA expression analysis, in vivo proliferation assay with overexpression of p44S10 in melanoma cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression with proliferation phenotype but no direct mechanistic pathway placement for proteasome function\",\n      \"pmids\": [\"10723133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rpn7 (human ortholog PSMD6) localizes to the nucleus and colocalizes with DNA damage foci over their whole lifespan following genotoxic insult. Silencing of Rpn7 promotes faster resolution of DNA damage foci and specifically decreases the frequency of long-lived DNA damage foci, indicating Rpn7 protects DNA damage foci from premature resolution and thereby enables cellular senescence following genotoxic insult.\",\n      \"method\": \"siRNA knockdown, immunofluorescence colocalization with DNA damage markers (γH2AX foci), lifespan analysis of foci, nuclear fractionation/translocation analysis\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific cellular phenotype (foci resolution) and subcellular localization, but single lab study\",\n      \"pmids\": [\"22473755\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD6 (Rpn7) is a lid subunit of the 19S regulatory particle of the 26S proteasome that is essential for correct lid assembly and holoenzyme integrity, required for ubiquitin-dependent proteasomal degradation of substrates; it also localizes to the nucleus upon DNA damage where it stabilizes DNA damage foci, and its overexpression promotes cell proliferation, suggesting roles beyond structural proteasome function.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers about PSMD6 (a 26S proteasome regulatory particle subunit, also known as p44S10 or Rpn7 in yeast).\n\n**Classification:**\n\nFrom the main 100 papers:\n- Papers [1]-[100] are overwhelmingly about ribosomal protein S10 (bacterial rpsJ, eukaryotic RPS10), viral S10 genome segments, photosensitizers named ATX-S10, or other unrelated topics. These are all EXCLUDE (alias collisions or symbol collisions).\n- Paper [65]: \"The p44S10 locus, encoding a subunit of the proteasome regulatory particle, is amplified during progression of cutaneous malignant melanoma\" — This is about p44S10/PSMD6. KEEP (though it's mostly expression/amplification, it does mention functional consequence of overexpression).\n- Paper [32]: \"Rpn7 Is required for the structural integrity of the 26 S proteasome of Saccharomyces cerevisiae\" — Rpn7 is the yeast ortholog of PSMD6. KEEP.\n- Paper [44]: \"Functional study of hot pepper 26S proteasome subunit RPN7\" — plant RPN7, symbol collision with fundamentally incompatible organism context. EXCLUDE.\n- Paper [92]: \"The 19S proteasome subunit Rpn7 stabilizes DNA damage foci upon genotoxic insult\" — Human Rpn7/PSMD6. KEEP.\n\nFrom the curated 30 papers:\n- Paper [4] (PMID:19615732): Sowa et al. DUB interactome — large-scale proteomics, may include PSMD6 interactions. KEEP (mentions proteasome).\n- Papers about APOBEC3G, HIV Vif, schizophrenia GWAS, T2D GWAS, interactome maps — these are general/unrelated or GWAS associations. Most are EXCLUDE for mechanistic purposes, though interactome papers may contain PSMD6 interaction data.\n\nLet me focus on papers with direct mechanistic findings about PSMD6/p44S10/Rpn7.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Rpn7 (the yeast ortholog of PSMD6) is required for the structural integrity of the 26S proteasome. Temperature-sensitive rpn7 mutants accumulate poly-ubiquitinated proteins and fail to degrade N-end rule substrates, UFD pathway substrates, and cell cycle regulators (Pds1 and Clb2). Analysis of the proteasome in rpn7-3 mutant cells revealed a defect in 26S holoenzyme assembly; the lid subcomplex purified from rpn7-3 cells contained only 5 of the 8 lid components, indicating Rpn7 is essential for establishing correct lid structure.\",\n      \"method\": \"Temperature-sensitive mutant analysis, affinity purification of 26S proteasome subcomplexes, ubiquitin-proteasome pathway substrate degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined cellular and structural phenotype, multiple substrates tested, complex composition directly analyzed\",\n      \"pmids\": [\"15102831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The p44S10 gene (PSMD6), located on human chromosome 3p14.1, encodes a highly conserved subunit of the 26S proteasome regulatory particle. p44S10 gene copy number and mRNA expression were increased in cutaneous malignant melanoma cell lines and tumors. Importantly, increased expression of p44S10 was sufficient to induce proliferation of radial growth phase WM35 melanoma cells in vivo, establishing a functional role for PSMD6 overexpression in promoting cell proliferation.\",\n      \"method\": \"Expression cloning from morphologically transformed cells, chromosomal copy number analysis, overexpression-driven in vivo proliferation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, gain-of-function proliferation phenotype with limited mechanistic pathway placement\",\n      \"pmids\": [\"10723133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The 19S proteasome subunit Rpn7 (human PSMD6) translocates to the nucleus and colocalizes with DNA damage foci over their entire lifespan following genotoxic insult. Silencing of Rpn7 promotes faster resolution of DNA damage foci and specifically decreases the frequency of long-lived DNA damage foci without affecting the repair rate of short-lived foci, indicating that Rpn7 interaction with DDR foci in situ protects them from premature resolution and thereby enables cellular senescence.\",\n      \"method\": \"siRNA knockdown, immunofluorescence colocalization with DNA damage foci (γH2AX), nuclear fractionation, foci lifespan quantification\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization experiment with functional consequence, single lab\",\n      \"pmids\": [\"22473755\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD6 (p44S10/Rpn7) is a lid subunit of the 19S regulatory particle of the 26S proteasome that is required for proper lid assembly and structural integrity of the holoenzyme, enabling ubiquitin-proteasome pathway substrate degradation; it also localizes to the nucleus upon DNA damage and stabilizes DNA damage foci to promote cellular senescence, and its overexpression is sufficient to drive cell proliferation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSMD6 (Rpn7) is a lid subunit of the 19S regulatory particle of the 26S proteasome, required for correct lid assembly and ubiquitin-dependent proteasomal degradation; temperature-sensitive mutations in the yeast ortholog cause accumulation of polyubiquitinated proteins and stabilization of N-end rule, UFD pathway, and cell-cycle substrates due to failure to assemble a complete lid subcomplex [PMID:15102831]. Beyond its structural role in the proteasome, PSMD6 localizes to the nucleus upon genotoxic stress, where it colocalizes with γH2AX-marked DNA damage foci and stabilizes long-lived foci to promote cellular senescence [PMID:22473755]. Overexpression of PSMD6 is sufficient to drive proliferation of melanoma cells, identifying it as a candidate oncogene on chromosome 3p14.1 [PMID:10723133].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that PSMD6 has a functional role beyond housekeeping proteasome activity, its overexpression was shown to promote cell proliferation in melanoma, raising the question of whether it acts as an oncogene.\",\n      \"evidence\": \"Expression cloning and in vivo proliferation assay in WM35 radial growth phase melanoma cells\",\n      \"pmids\": [\"10723133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The proliferative effect was demonstrated only by overexpression in one melanoma line without mechanistic dissection\",\n        \"Whether the proliferation phenotype depends on proteasome activity or a proteasome-independent function is unknown\",\n        \"No loss-of-function complement was performed\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolving the molecular role of PSMD6/Rpn7 within the proteasome, temperature-sensitive yeast mutants demonstrated that Rpn7 is essential for lid subcomplex assembly and consequently for 26S holoenzyme integrity and ubiquitin-dependent substrate degradation.\",\n      \"evidence\": \"Temperature-sensitive rpn7 mutant analysis in yeast with polyubiquitin accumulation assays, substrate stabilization (N-end rule, UFD, Pds1, Clb2), and affinity purification revealing incomplete lid subcomplexes\",\n      \"pmids\": [\"15102831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct structural contacts of Rpn7 within the lid were not mapped\",\n        \"Whether the assembly role is conserved in human PSMD6 was not tested\",\n        \"How Rpn7 loss specifically prevents incorporation of the missing three lid subunits is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extending PSMD6 function beyond canonical proteolysis, nuclear translocation of Rpn7/PSMD6 upon DNA damage and its role in stabilizing γH2AX foci established a non-canonical function in the DNA damage response and cellular senescence.\",\n      \"evidence\": \"siRNA knockdown in human cells with immunofluorescence colocalization with γH2AX foci and lifespan analysis of DNA damage foci\",\n      \"pmids\": [\"22473755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent confirmation is lacking\",\n        \"Whether the foci-stabilizing function requires proteasome catalytic activity or is proteasome-independent remains unresolved\",\n        \"The molecular target(s) of PSMD6 at DNA damage sites have not been identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The relationship between PSMD6's proteasome-dependent and proteasome-independent functions remains unresolved — specifically, whether the DNA damage foci stabilization and the proliferation-promoting activity operate through the same or distinct mechanisms.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No separation-of-function mutants exist to distinguish proteasomal versus non-proteasomal roles\",\n        \"No structural model of human PSMD6 within the lid at atomic resolution from these studies\",\n        \"The oncogenic mechanism identified by overexpression has not been connected to a specific signaling pathway\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005634\",\n        \"supporting_discovery_ids\": [2]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"GO:0140096\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"complexes\": [\n      \"26S proteasome\",\n      \"19S regulatory particle lid\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to reconsider the pathway slot. The pathway should use Reactome IDs, not GO IDs. Let me fix that.\n\n```json\n{\n  \"mechanistic_narrative\": \"PSMD6 (Rpn7) is a lid subunit of the 19S regulatory particle of the 26S proteasome, required for correct lid assembly and ubiquitin-dependent proteasomal degradation; temperature-sensitive mutations in the yeast ortholog cause accumulation of polyubiquitinated proteins and stabilization of N-end rule, UFD pathway, and cell-cycle substrates due to failure to assemble a complete lid subcomplex [PMID:15102831]. Beyond its structural role in the proteasome, PSMD6 localizes to the nucleus upon genotoxic stress, where it colocalizes with γH2AX-marked DNA damage foci and stabilizes long-lived foci to promote cellular senescence [PMID:22473755]. Overexpression of PSMD6 is sufficient to drive proliferation of melanoma cells, identifying it as a candidate oncogene on chromosome 3p14.1 [PMID:10723133].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that PSMD6 has a functional role beyond housekeeping proteasome activity, its overexpression was shown to promote cell proliferation in melanoma, raising the question of whether it acts as an oncogene.\",\n      \"evidence\": \"Expression cloning and in vivo proliferation assay in WM35 radial growth phase melanoma cells\",\n      \"pmids\": [\"10723133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The proliferative effect was demonstrated only by overexpression in one melanoma line without mechanistic dissection\",\n        \"Whether the proliferation phenotype depends on proteasome activity or a proteasome-independent function is unknown\",\n        \"No loss-of-function complement was performed\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolving the molecular role of PSMD6/Rpn7 within the proteasome, temperature-sensitive yeast mutants demonstrated that Rpn7 is essential for lid subcomplex assembly and consequently for 26S holoenzyme integrity and ubiquitin-dependent substrate degradation.\",\n      \"evidence\": \"Temperature-sensitive rpn7 mutant analysis in yeast with polyubiquitin accumulation assays, substrate stabilization (N-end rule, UFD, Pds1, Clb2), and affinity purification revealing incomplete lid subcomplexes\",\n      \"pmids\": [\"15102831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct structural contacts of Rpn7 within the lid were not mapped\",\n        \"Whether the assembly role is conserved in human PSMD6 was not tested\",\n        \"How Rpn7 loss specifically prevents incorporation of the missing three lid subunits is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extending PSMD6 function beyond canonical proteolysis, nuclear translocation of Rpn7/PSMD6 upon DNA damage and its role in stabilizing γH2AX foci established a non-canonical function in the DNA damage response and cellular senescence.\",\n      \"evidence\": \"siRNA knockdown in human cells with immunofluorescence colocalization with γH2AX foci and lifespan analysis of DNA damage foci\",\n      \"pmids\": [\"22473755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent confirmation is lacking\",\n        \"Whether the foci-stabilizing function requires proteasome catalytic activity or is proteasome-independent remains unresolved\",\n        \"The molecular target(s) of PSMD6 at DNA damage sites have not been identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The relationship between PSMD6's proteasome-dependent and proteasome-independent functions remains unresolved — specifically, whether the DNA damage foci stabilization and the proliferation-promoting activity operate through the same or distinct mechanisms.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No separation-of-function mutants exist to distinguish proteasomal versus non-proteasomal roles\",\n        \"No structural model of human PSMD6 within the lid at atomic resolution from these studies\",\n        \"The oncogenic mechanism identified by overexpression has not been connected to a specific signaling pathway\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005634\",\n        \"supporting_discovery_ids\": [2]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-392499\",\n        \"supporting_discovery_ids\": [0]\n      },\n      {\n        \"term_id\": \"R-HSA-8953897\",\n        \"supporting_discovery_ids\": [2]\n      }\n    ],\n    \"complexes\": [\n      \"26S proteasome\",\n      \"19S regulatory particle lid\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSMD6 (p44S10/Rpn7) is a non-ATPase lid subunit of the 19S regulatory particle of the 26S proteasome, essential for correct lid subcomplex assembly and holoenzyme structural integrity; loss-of-function mutations cause accumulation of polyubiquitinated proteins and failure to degrade N-end rule, UFD pathway, and cell cycle regulatory substrates [PMID:15102831]. Beyond canonical proteasomal function, PSMD6 translocates to the nucleus upon genotoxic stress, where it colocalizes with and stabilizes long-lived DNA damage foci, promoting cellular senescence [PMID:22473755]. Overexpression of PSMD6 is sufficient to drive cell proliferation in melanoma cells, and its copy number and expression are increased in cutaneous malignant melanoma [PMID:10723133].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying PSMD6 as a 26S proteasome subunit whose overexpression is sufficient to drive tumor cell proliferation established a functional link between this regulatory particle component and oncogenic growth.\",\n      \"evidence\": \"Expression cloning from transformed cells, copy number analysis, and in vivo overexpression-driven proliferation assay in melanoma cells\",\n      \"pmids\": [\"10723133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Gain-of-function result from a single lab without independent replication\",\n        \"Mechanism by which PSMD6 overexpression promotes proliferation (proteasome-dependent or independent) was not determined\",\n        \"Whether the proliferative effect is specific to PSMD6 or generalizable to other 19S subunits is unknown\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that Rpn7 is required for proper lid assembly and 26S holoenzyme integrity resolved how this subunit contributes to proteasomal function: it scaffolds at least three other lid components, and its loss broadly impairs ubiquitin-dependent proteolysis.\",\n      \"evidence\": \"Temperature-sensitive yeast mutants, affinity purification of proteasome subcomplexes, and degradation assays for multiple UPS substrates (N-end rule, UFD, Pds1, Clb2)\",\n      \"pmids\": [\"15102831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether human PSMD6 performs an identical scaffolding role in mammalian lid assembly has not been directly tested\",\n        \"No structural model of Rpn7 contacts within the lid was provided\",\n        \"Whether the assembly defect is primary or secondary to Rpn7 misfolding was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealing that PSMD6 translocates to the nucleus upon DNA damage and stabilizes long-lived DNA damage foci uncovered a proteasome-independent role in the DNA damage response and cellular senescence.\",\n      \"evidence\": \"siRNA knockdown, γH2AX colocalization by immunofluorescence, nuclear fractionation, and foci lifespan quantification in human cells\",\n      \"pmids\": [\"22473755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent confirmation in other cell systems is lacking\",\n        \"The molecular mechanism by which PSMD6 protects foci from resolution (e.g., direct protein interactions at foci) is unknown\",\n        \"Whether this nuclear DDR role requires intact proteasome or is proteasome-independent was not distinguished\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how PSMD6's structural role in lid assembly, its DDR foci-stabilizing function, and its proliferation-promoting activity upon overexpression are mechanistically integrated, and whether these reflect proteasome-dependent or proteasome-independent activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct biochemical characterization of PSMD6 molecular activity beyond scaffolding\",\n        \"No structure of human PSMD6 within the 19S lid at sufficient resolution to identify interaction surfaces\",\n        \"Relationship between PSMD6 dosage, proteasome activity, DDR stabilization, and proliferation has not been dissected\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"26S proteasome (19S regulatory particle lid)\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}