{"gene":"POLR3C","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2015,"finding":"Crystal structure of the human RPC62 (POLR3C)–RPC32β complex revealed that RPC32β binds to the extended winged-helix 1 and 2 (eWH1/eWH2) domains and the coiled-coil domain of RPC62, acting as a molecular bridge between these RPC62 domains. Fitting of the complex into existing EM density of Pol III suggests that RPC32 has a bi-functional role: contacts with the largest Pol III subunit on one face, and solvent-exposed residues available for external interactions on the other.","method":"X-ray crystallography of the RPC62–RPC32β core domain complex, combined with fitting into Pol III EM density","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with domain-level functional mapping, single lab but orthogonal structural (X-ray + EM fitting) methods","pmids":["26394183"],"is_preprint":false},{"year":2015,"finding":"A minimal core-interacting domain of RPC32 sufficient for interaction with RPC62 was identified; RPC32β (but not the stem-cell-restricted RPC32α isoform context) was used to define this interface, and the two RPC32 isoforms share this core binding mode with RPC62.","method":"Co-crystallization and deletion mapping of the RPC32β core domain with RPC62","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct structural determination with deletion mapping, single lab, orthogonal X-ray and EM methods","pmids":["26394183"],"is_preprint":false},{"year":2024,"finding":"In trypanosomatid orthologs (T. brucei and L. major), C82 (POLR3C ortholog) localizes to the nucleus, associates with RNAP III-dependent gene loci (tRNA and 5S rRNA genes), and interacts with C34 as a binding partner; knock-down of C82 by RNAi significantly reduced tRNA and 5S rRNA levels and caused death of procyclic T. brucei. The C31 subunit (RPC32 ortholog) was not detected as an interacting partner in trypanosomatids, unlike in yeast/vertebrates.","method":"RNAi knockdown with RNA quantification, chromatin immunoprecipitation (ChIP), tandem affinity purification (TAP) mass spectrometry, nuclear localization by microscopy","journal":"Parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal TAP-MS, ChIP, and RNAi phenotype in non-mammalian parasite orthologs; multiple orthogonal methods but single lab and divergent organism","pmids":["39523652"],"is_preprint":false}],"current_model":"POLR3C (RPC62) is a structural subunit of RNA Polymerase III that directly binds RPC32 (via its eWH1/eWH2 and coiled-coil domains) to form the RPC62/RPC39/RPC32 subcomplex required for promoter-specific Pol III transcription initiation; RPC32 acts as a molecular bridge within this subcomplex, and the complex occupies a functionally critical position at the surface of the Pol III holoenzyme."},"narrative":{"mechanistic_narrative":"POLR3C (RPC62) is a structural subunit of RNA Polymerase III that contributes to promoter-specific transcription initiation by directly assembling with RPC32 [PMID:26394183]. The crystal structure of the human RPC62–RPC32β complex shows that RPC32β engages the extended winged-helix domains (eWH1/eWH2) and the coiled-coil domain of RPC62 and bridges these RPC62 domains, while fitting into Pol III EM density places the subcomplex at the polymerase surface where RPC32 simultaneously contacts the largest Pol III subunit and exposes residues for external interactions [PMID:26394183]. A minimal RPC32 core domain is sufficient for this interface, a binding mode shared by both RPC32 isoforms [PMID:26394183]. Functional conservation of the subunit's role in Pol III transcription is supported by trypanosomatid orthologs, where the C82 ortholog localizes to the nucleus, associates with tRNA and 5S rRNA gene loci, and is required for their expression and for cell viability [PMID:39523652]. Beyond the structural definition of the RPC62–RPC32 interface and ortholog-based functional evidence, no further mechanistic detail of POLR3C has been characterized in the available corpus.","teleology":[{"year":2015,"claim":"Established the structural basis of how POLR3C/RPC62 is incorporated into Pol III, showing RPC32 bridges the eWH1/eWH2 and coiled-coil domains of RPC62 and positions the subcomplex at the polymerase surface.","evidence":"X-ray crystallography of the human RPC62–RPC32β core domain complex fitted into Pol III EM density","pmids":["26394183"],"confidence":"High","gaps":["Does not resolve how this subcomplex contributes mechanistically to promoter recognition or open-complex formation","Functional consequences of the proposed solvent-exposed external interactions not tested","Isoform-specific (RPC32α vs RPC32β) functional differences not addressed structurally"]},{"year":2015,"claim":"Defined the minimal RPC32 core domain sufficient for RPC62 interaction and showed both RPC32 isoforms use the same binding mode, delimiting the assembly interface.","evidence":"Co-crystallization and deletion mapping of the RPC32β core domain with RPC62","pmids":["26394183"],"confidence":"High","gaps":["Stem-cell-restricted RPC32α context not directly co-crystallized","Affinity/kinetics of the interface and its contribution to holoenzyme stability not quantified"]},{"year":2024,"claim":"Demonstrated functional conservation of the subunit's role in Pol III–dependent gene expression using trypanosomatid orthologs, while revealing a divergence in subcomplex partners.","evidence":"RNAi knockdown with RNA quantification, ChIP, TAP-MS, and nuclear localization microscopy in T. brucei and L. major","pmids":["39523652"],"confidence":"Medium","gaps":["Divergent organism — RPC32 ortholog (C31) was not detected as a partner, so the human RPC62–RPC32 interface may not be conserved","Does not establish the human POLR3C loss-of-function phenotype","Partner C34 interaction not structurally mapped"]},{"year":null,"claim":"How POLR3C contributes mechanistically to Pol III initiation, recruitment, and isoform-specific transcription programs in human cells remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct human loss-of-function or transcriptional profiling in the corpus","Role of solvent-exposed external interaction surface untested functionally","No disease association established in the available corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2]}],"complexes":["RNA Polymerase III","RPC62/RPC39/RPC32 subcomplex"],"partners":["RPC32","C34"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BUI4","full_name":"DNA-directed RNA polymerase III subunit RPC3","aliases":["DNA-directed RNA polymerase III subunit C","RNA polymerase III 62 kDa subunit","RPC62"],"length_aa":534,"mass_kda":60.6,"function":"DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates (PubMed:20413673, PubMed:33558764, PubMed:33558766, PubMed:34675218, PubMed:35637192). Specific peripheric component of RNA polymerase III (Pol III) which synthesizes small non-coding RNAs including 5S rRNA, snRNAs, tRNAs and miRNAs from at least 500 distinct genomic loci (PubMed:20413673, PubMed:33558764, PubMed:33558766, PubMed:35637192). Part of POLR3C/RPC3-POLR3F/RPC6-POLR3G/RPC7 heterotrimer, coordinates the dynamics of Pol III stalk and clamp modules during the transition from apo to elongation state (PubMed:33558764, PubMed:33558766). Pol III plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as a nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF-kappa-B through the RIG-I pathway (PubMed:19609254, PubMed:19631370). Preferentially binds single-stranded DNA (ssDNA) in a sequence-independent manner (PubMed:21358628)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BUI4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/POLR3C","classification":"Common Essential","n_dependent_lines":1155,"n_total_lines":1208,"dependency_fraction":0.9561258278145696},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000186141","cell_line_id":"CID000711","localizations":[{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"POLR1C","stoichiometry":10.0},{"gene":"POLR1D","stoichiometry":10.0},{"gene":"POLR2F","stoichiometry":10.0},{"gene":"POLR2H","stoichiometry":10.0},{"gene":"POLR2K","stoichiometry":10.0},{"gene":"POLR3A","stoichiometry":10.0},{"gene":"POLR3B","stoichiometry":10.0},{"gene":"POLR3H","stoichiometry":10.0},{"gene":"POLR3F","stoichiometry":10.0},{"gene":"POLR3G","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000711","total_profiled":1310},"omim":[{"mim_id":"617456","title":"POLYMERASE III, RNA, SUBUNIT G; POLR3G","url":"https://www.omim.org/entry/617456"},{"mim_id":"617454","title":"POLYMERASE III, RNA, SUBUNIT C; POLR3C","url":"https://www.omim.org/entry/617454"},{"mim_id":"614258","title":"POLYMERASE III, RNA, SUBUNIT A; POLR3A","url":"https://www.omim.org/entry/614258"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/POLR3C"},"hgnc":{"alias_symbol":["RPC62","RPC3","C82"],"prev_symbol":[]},"alphafold":{"accession":"Q9BUI4","domains":[{"cath_id":"1.10.10.10","chopping":"2-78","consensus_level":"high","plddt":94.6065,"start":2,"end":78},{"cath_id":"1.10.10.10","chopping":"86-164_183-201_232-237","consensus_level":"medium","plddt":92.1298,"start":86,"end":237},{"cath_id":"1.10.10.10","chopping":"241-336","consensus_level":"high","plddt":92.8897,"start":241,"end":336},{"cath_id":"1.10.10.10","chopping":"340-426","consensus_level":"medium","plddt":93.5274,"start":340,"end":426},{"cath_id":"1.10.287","chopping":"436-474_487-531","consensus_level":"high","plddt":92.7145,"start":436,"end":531}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BUI4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BUI4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BUI4-F1-predicted_aligned_error_v6.png","plddt_mean":89.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=POLR3C","jax_strain_url":"https://www.jax.org/strain/search?query=POLR3C"},"sequence":{"accession":"Q9BUI4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BUI4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BUI4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BUI4"}},"corpus_meta":[{"pmid":"19403166","id":"PMC_19403166","title":"The effect of Gd@C82(OH)22 nanoparticles on the release of Th1/Th2 cytokines and induction of TNF-alpha mediated cellular immunity.","date":"2009","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/19403166","citation_count":151,"is_preprint":false},{"pmid":"22949663","id":"PMC_22949663","title":"Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C82(OH)22 and its implication for de novo design of nanomedicine.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22949663","citation_count":144,"is_preprint":false},{"pmid":"16436273","id":"PMC_16436273","title":"Antioxidative function and biodistribution of [Gd@C82(OH)22]n nanoparticles in tumor-bearing mice.","date":"2006","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16436273","citation_count":113,"is_preprint":false},{"pmid":"17586634","id":"PMC_17586634","title":"Bacteriochlorophyllide c C-8(2) and C-12(1) methyltransferases are essential for adaptation to low light in Chlorobaculum tepidum.","date":"2007","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/17586634","citation_count":79,"is_preprint":false},{"pmid":"28807667","id":"PMC_28807667","title":"Inhibition of β-Catenin Signaling in the Skin Rescues Cutaneous Adipogenesis in Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial of C-82.","date":"2017","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/28807667","citation_count":46,"is_preprint":false},{"pmid":"21541378","id":"PMC_21541378","title":"Biosafety assessment of Gd@C82(OH)22 nanoparticles on Caenorhabditis elegans.","date":"2011","source":"Nanoscale","url":"https://pubmed.ncbi.nlm.nih.gov/21541378","citation_count":32,"is_preprint":false},{"pmid":"25701412","id":"PMC_25701412","title":"Quantitative analysis of Gd@C82(OH)22 and cisplatin uptake in single cells by inductively coupled plasma mass spectrometry.","date":"2015","source":"Analytical and bioanalytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25701412","citation_count":31,"is_preprint":false},{"pmid":"31882904","id":"PMC_31882904","title":"β-catenin signaling inhibitors ICG-001 and C-82 improve fibrosis in preclinical models of endometriosis.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31882904","citation_count":26,"is_preprint":false},{"pmid":"38840269","id":"PMC_38840269","title":"Rational Design of Dual-Functionalized Gd@C82 Nanoparticles to Relieve Neuronal Cytotoxicity in Alzheimer's Disease via Inhibition of Aβ Aggregation.","date":"2024","source":"ACS nano","url":"https://pubmed.ncbi.nlm.nih.gov/38840269","citation_count":19,"is_preprint":false},{"pmid":"24738346","id":"PMC_24738346","title":"Gd@C82(OH)22 nanoparticles constrain macrophages migration into tumor tissue to prevent metastasis.","date":"2014","source":"Journal of 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research","url":"https://pubmed.ncbi.nlm.nih.gov/26220181","citation_count":13,"is_preprint":false},{"pmid":"26394183","id":"PMC_26394183","title":"Structural analysis of human RPC32β-RPC62 complex.","date":"2015","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/26394183","citation_count":11,"is_preprint":false},{"pmid":"11348111","id":"PMC_11348111","title":"The C(8)-(2'-deoxy-beta-D-ribofuranoside) of 7-deazaguanine: synthesis and base pairing of oligonucleotides with unusually linked nucleobases.","date":"2001","source":"The Journal of organic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11348111","citation_count":10,"is_preprint":false},{"pmid":"20377178","id":"PMC_20377178","title":"The C8-2'-deoxyguanosine adduct of 2-amino-3-methylimidazo[1,2-d]naphthalene, a carbocyclic analogue of the potent mutagen 2-amino-3-methylimidazo[4,5-f]quinoline, is a block to replication in vitro.","date":"2010","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/20377178","citation_count":8,"is_preprint":false},{"pmid":"34200169","id":"PMC_34200169","title":"Effects of Aqueous Dispersions of C60, C70 and Gd@C82 Fullerenes on Genes Involved in Oxidative Stress and Anti-Inflammatory Pathways.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34200169","citation_count":8,"is_preprint":false},{"pmid":"29860839","id":"PMC_29860839","title":"Distance Measurement of a Noncovalently Bound Y@C82 Pair with Double Electron Electron Resonance Spectroscopy.","date":"2018","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/29860839","citation_count":7,"is_preprint":false},{"pmid":"21121366","id":"PMC_21121366","title":"Transmembrane delivery of aggregated [Gd@C82(OH)22]n nanoparticles.","date":"2010","source":"Journal of nanoscience and nanotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/21121366","citation_count":6,"is_preprint":false},{"pmid":"21449388","id":"PMC_21449388","title":"An anti-tumor nanoparticle, [Gd@C82(OH)22]n, induces macrophage activation.","date":"2011","source":"Journal of nanoscience and nanotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/21449388","citation_count":6,"is_preprint":false},{"pmid":"25469552","id":"PMC_25469552","title":"Unprecedented chemical reactivity of a paramagnetic endohedral metallofullerene La@C(s)-C82 that leads hydrogen addition in the 1,3-dipolar cycloaddition reaction.","date":"2014","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/25469552","citation_count":3,"is_preprint":false},{"pmid":"40442688","id":"PMC_40442688","title":"Venetoclax synergizes with Wnt/β-catenin inhibitor C-82 in acute myeloid leukemia by increasing the degradation of Mcl-1 protein.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/40442688","citation_count":2,"is_preprint":false},{"pmid":"36821424","id":"PMC_36821424","title":"Effects of Aqueous Dispersions of C60, C70, and Gd@C82 Fullerenes on DNA Oxidative Damage/Repair and Apoptosis in Human Embryonic Lung Fibroblasts.","date":"2023","source":"ACS biomaterials science & engineering","url":"https://pubmed.ncbi.nlm.nih.gov/36821424","citation_count":2,"is_preprint":false},{"pmid":"31903755","id":"PMC_31903755","title":"6-Nitrochrysene-Derived C8-2'-Deoxyadenosine Adduct: Synthesis of Site-Specific Oligodeoxynucleotides and Mutagenicity in Escherichia coli.","date":"2020","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/31903755","citation_count":2,"is_preprint":false},{"pmid":"17588181","id":"PMC_17588181","title":"Calculations of the C2 fragmentation energies of higher fullerenes C80 and C82.","date":"2007","source":"Journal of molecular modeling","url":"https://pubmed.ncbi.nlm.nih.gov/17588181","citation_count":2,"is_preprint":false},{"pmid":"39377172","id":"PMC_39377172","title":"Computational insights into Diels-Alder reactions of paramagnetic endohedral metallofullerenes: M@C82 (M = Sc, Y, La) and La@C72.","date":"2024","source":"Physical chemistry chemical physics : PCCP","url":"https://pubmed.ncbi.nlm.nih.gov/39377172","citation_count":1,"is_preprint":false},{"pmid":"28628210","id":"PMC_28628210","title":"Synthesis of Oligodeoxynucleotides Containing a C8-2'-Deoxyguanosine Adduct Formed by the Carcinogen 3-Nitrobenzanthrone.","date":"2017","source":"Current protocols in nucleic acid chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28628210","citation_count":1,"is_preprint":false},{"pmid":"39523652","id":"PMC_39523652","title":"Analyses of the essential C82 subunit uncovered some differences in RNA polymerase III transcription between Trypanosoma brucei and Leishmania major.","date":"2024","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/39523652","citation_count":0,"is_preprint":false},{"pmid":"41961832","id":"PMC_41961832","title":"Water-soluble gadolinium fullerenes Gd@C82-TEGs as a potential magnetic resonance imaging contrast agent.","date":"2026","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/41961832","citation_count":0,"is_preprint":false},{"pmid":"40035581","id":"PMC_40035581","title":"Noncovalent interactions and properties of host-guest systems based on C82/C82Gd bucky-balls and symmetry broken nanohoop TP-[11]CPP.","date":"2025","source":"The Journal of chemical physics","url":"https://pubmed.ncbi.nlm.nih.gov/40035581","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17200,"output_tokens":1349,"usd":0.035917,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7420,"output_tokens":1751,"usd":0.040438,"stage2_stop_reason":"end_turn"},"total_usd":0.076355,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the papers, I need to identify which ones are about the canonical protein POLR3C (also known as RPC62, RPC3, C82) — a subunit of RNA Polymerase III.\n\nGoing through the papers:\n- Papers [1]-[3], [6]-[12], [17]-[23], [25]-[27], [29]-[30]: These are about Gd@C82 nanoparticles (fullerene chemistry) — NOT the POLR3C protein. Symbol collision.\n- Paper [4]: About BchQ/BchR in Chlorobaculum tepidum — unrelated.\n- Paper [5]: About C-82 as a Wnt/β-catenin inhibitor drug — NOT POLR3C protein.\n- Paper [8]: C-82 Wnt inhibitor — NOT POLR3C.\n- Paper [13]: DNA polymerases κ and ζ — NOT POLR3C.\n- Paper [14]: **RPC32β-RPC62 complex structural analysis** — this IS about POLR3C (RPC62).\n- Paper [15]: Nucleoside chemistry — NOT POLR3C.\n- Paper [16]: DNA adduct/polymerase — NOT POLR3C.\n- Paper [22]: C-82 Wnt inhibitor in AML — NOT POLR3C.\n- Paper [24]: DNA adduct — NOT POLR3C.\n- Paper [28]: C82 subunit of RNAP III in Trypanosoma brucei/Leishmania major — this IS about the ortholog of POLR3C/RPC62/C82 in trypanosomatids.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of the human RPC62 (POLR3C)–RPC32β complex revealed that RPC32β binds to the extended winged-helix 1 and 2 (eWH1/eWH2) domains and the coiled-coil domain of RPC62, acting as a molecular bridge between these RPC62 domains. Fitting of the complex into existing EM density of Pol III suggests that RPC32 has a bi-functional role: contacts with the largest Pol III subunit on one face, and solvent-exposed residues available for external interactions on the other.\",\n      \"method\": \"X-ray crystallography of the RPC62–RPC32β core domain complex, combined with fitting into Pol III EM density\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with domain-level functional mapping, single lab but orthogonal structural (X-ray + EM fitting) methods\",\n      \"pmids\": [\"26394183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A minimal core-interacting domain of RPC32 sufficient for interaction with RPC62 was identified; RPC32β (but not the stem-cell-restricted RPC32α isoform context) was used to define this interface, and the two RPC32 isoforms share this core binding mode with RPC62.\",\n      \"method\": \"Co-crystallization and deletion mapping of the RPC32β core domain with RPC62\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct structural determination with deletion mapping, single lab, orthogonal X-ray and EM methods\",\n      \"pmids\": [\"26394183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In trypanosomatid orthologs (T. brucei and L. major), C82 (POLR3C ortholog) localizes to the nucleus, associates with RNAP III-dependent gene loci (tRNA and 5S rRNA genes), and interacts with C34 as a binding partner; knock-down of C82 by RNAi significantly reduced tRNA and 5S rRNA levels and caused death of procyclic T. brucei. The C31 subunit (RPC32 ortholog) was not detected as an interacting partner in trypanosomatids, unlike in yeast/vertebrates.\",\n      \"method\": \"RNAi knockdown with RNA quantification, chromatin immunoprecipitation (ChIP), tandem affinity purification (TAP) mass spectrometry, nuclear localization by microscopy\",\n      \"journal\": \"Parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal TAP-MS, ChIP, and RNAi phenotype in non-mammalian parasite orthologs; multiple orthogonal methods but single lab and divergent organism\",\n      \"pmids\": [\"39523652\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"POLR3C (RPC62) is a structural subunit of RNA Polymerase III that directly binds RPC32 (via its eWH1/eWH2 and coiled-coil domains) to form the RPC62/RPC39/RPC32 subcomplex required for promoter-specific Pol III transcription initiation; RPC32 acts as a molecular bridge within this subcomplex, and the complex occupies a functionally critical position at the surface of the Pol III holoenzyme.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"POLR3C (RPC62) is a structural subunit of RNA Polymerase III that contributes to promoter-specific transcription initiation by directly assembling with RPC32 [#0]. The crystal structure of the human RPC62–RPC32β complex shows that RPC32β engages the extended winged-helix domains (eWH1/eWH2) and the coiled-coil domain of RPC62 and bridges these RPC62 domains, while fitting into Pol III EM density places the subcomplex at the polymerase surface where RPC32 simultaneously contacts the largest Pol III subunit and exposes residues for external interactions [#0]. A minimal RPC32 core domain is sufficient for this interface, a binding mode shared by both RPC32 isoforms [#1]. Functional conservation of the subunit's role in Pol III transcription is supported by trypanosomatid orthologs, where the C82 ortholog localizes to the nucleus, associates with tRNA and 5S rRNA gene loci, and is required for their expression and for cell viability [#2]. Beyond the structural definition of the RPC62–RPC32 interface and ortholog-based functional evidence, no further mechanistic detail of POLR3C has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established the structural basis of how POLR3C/RPC62 is incorporated into Pol III, showing RPC32 bridges the eWH1/eWH2 and coiled-coil domains of RPC62 and positions the subcomplex at the polymerase surface.\",\n      \"evidence\": \"X-ray crystallography of the human RPC62–RPC32β core domain complex fitted into Pol III EM density\",\n      \"pmids\": [\n        \"26394183\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not resolve how this subcomplex contributes mechanistically to promoter recognition or open-complex formation\",\n        \"Functional consequences of the proposed solvent-exposed external interactions not tested\",\n        \"Isoform-specific (RPC32α vs RPC32β) functional differences not addressed structurally\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the minimal RPC32 core domain sufficient for RPC62 interaction and showed both RPC32 isoforms use the same binding mode, delimiting the assembly interface.\",\n      \"evidence\": \"Co-crystallization and deletion mapping of the RPC32β core domain with RPC62\",\n      \"pmids\": [\n        \"26394183\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stem-cell-restricted RPC32α context not directly co-crystallized\",\n        \"Affinity/kinetics of the interface and its contribution to holoenzyme stability not quantified\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated functional conservation of the subunit's role in Pol III–dependent gene expression using trypanosomatid orthologs, while revealing a divergence in subcomplex partners.\",\n      \"evidence\": \"RNAi knockdown with RNA quantification, ChIP, TAP-MS, and nuclear localization microscopy in T. brucei and L. major\",\n      \"pmids\": [\n        \"39523652\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Divergent organism — RPC32 ortholog (C31) was not detected as a partner, so the human RPC62–RPC32 interface may not be conserved\",\n        \"Does not establish the human POLR3C loss-of-function phenotype\",\n        \"Partner C34 interaction not structurally mapped\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How POLR3C contributes mechanistically to Pol III initiation, recruitment, and isoform-specific transcription programs in human cells remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct human loss-of-function or transcriptional profiling in the corpus\",\n        \"Role of solvent-exposed external interaction surface untested functionally\",\n        \"No disease association established in the available corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [\n          0,\n          1\n        ]\n      },\n      {\n        \"term_id\": \"GO:0003677\",\n        \"supporting_discovery_ids\": [\n          2\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005634\",\n        \"supporting_discovery_ids\": [\n          2\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-74160\",\n        \"supporting_discovery_ids\": [\n          2\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"RNA Polymerase III\",\n      \"RPC62/RPC39/RPC32 subcomplex\"\n    ],\n    \"partners\": [\n      \"RPC32\",\n      \"C34\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":2,"faith_total":4,"faith_pct":50.0}}