{"gene":"POLR3H","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1994,"finding":"The yeast gene YKL1 encodes the RNA Polymerase III subunit C25 (ortholog of human POLR3H/RPC8). C25 is present in submolar ratios in Pol III, easily dissociates from the enzyme, is essential for cell growth and viability, but is not required for transcription in certain in vitro assays. It is related in sequence to the RNA Polymerase II subunit RPB7. A C25 conditional mutant grown at the nonpermissive temperature synthesizes tRNA at reduced rates relative to 5.8S rRNA, a hallmark of all characterized RNA Polymerase III mutants.","method":"Gene identification by sequence homology to RPB7; SDS-PAGE mobility matching; conditional mutant analysis (temperature-sensitive growth) with tRNA and 5.8S rRNA synthesis assay; dissociation studies from purified Pol III","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (sequence analysis, biochemical dissociation, in vivo conditional mutant with specific RNA synthesis readouts) in a focused study; foundational characterization paper","pmids":["8065349"],"is_preprint":false},{"year":2019,"finding":"A homozygous missense mutation (p.Asp50Gly) in POLR3H causes primary ovarian insufficiency in humans. Complete loss-of-function (knockout) of Polr3h in mice caused early embryonic lethality, establishing that POLR3H is essential for embryonic development. Mice carrying the homozygous point mutation (Polr3hD50G) were viable but showed delayed pubertal development, decreased fertility, small litter sizes, and decreased expression of ovarian Foxo3a with lower numbers of primary follicles.","method":"Whole-exome sequencing in human families; CRISPR/Cas9-generated mouse knockout (lethal) and knock-in point mutation lines; phenotypic analysis of pubertal timing, fertility, litter size; ovarian follicle counting; Foxo3a expression assay","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal human genetics plus two independent CRISPR mouse models (null and point mutation) with multiple defined phenotypic readouts (lethality, puberty, fertility, follicle counts, gene expression)","pmids":["30830215"],"is_preprint":false}],"current_model":"POLR3H (RPC8/C25) is an essential subunit of RNA Polymerase III that is present in submolar ratios and dissociates easily from the enzyme; it is required for normal tRNA synthesis in vivo (but not in certain cell-free transcription assays), is indispensable for embryonic development, and its partial loss of function impairs reproductive development and ovarian folliculogenesis, at least in part through reduced Foxo3a expression."},"narrative":{"mechanistic_narrative":"POLR3H (RPC8/C25) is an essential subunit of RNA Polymerase III, the enzyme responsible for synthesizing tRNAs and other small RNAs, and is required for normal tRNA synthesis in vivo [PMID:8065349]. Within Pol III it is present in submolar ratios and dissociates readily from the purified enzyme, and although a conditional mutant of the yeast ortholog C25 specifically reduces tRNA synthesis relative to 5.8S rRNA, the subunit is dispensable for transcription in certain in vitro assays [PMID:8065349]. POLR3H is indispensable for development: complete loss of function causes early embryonic lethality in mice, whereas a homozygous missense mutation (p.Asp50Gly) is compatible with viability but impairs reproductive development, producing delayed puberty, reduced fertility, and fewer primary ovarian follicles in association with decreased ovarian Foxo3a expression [PMID:30830215]. In humans, this same POLR3H mutation causes primary ovarian insufficiency [PMID:30830215].","teleology":[{"year":1994,"claim":"Established that POLR3H corresponds to a conserved, dissociable subunit of RNA Polymerase III essential for viability and for normal tRNA synthesis, defining its core enzymatic context.","evidence":"Yeast gene identification by sequence homology to RPB7, biochemical dissociation from purified Pol III, and temperature-sensitive conditional mutant analysis scoring tRNA versus 5.8S rRNA synthesis","pmids":["8065349"],"confidence":"High","gaps":["Why the subunit is dispensable in certain in vitro transcription assays yet required in vivo is unresolved","The structural basis for its submolar stoichiometry and easy dissociation is not defined","Its sequence relationship to RPB7 implies but does not demonstrate a specific molecular role within Pol III"]},{"year":2019,"claim":"Connected POLR3H function to mammalian development and human disease, showing the subunit is essential for embryogenesis and that hypomorphic missense alleles selectively disrupt reproductive development.","evidence":"Whole-exome sequencing in human families plus CRISPR/Cas9 mouse null (lethal) and knock-in point-mutation lines, with phenotyping of puberty, fertility, follicle counts, and Foxo3a expression","pmids":["30830215"],"confidence":"High","gaps":["The mechanism linking POLR3H/Pol III activity to reduced Foxo3a expression in the ovary is not established","Whether the p.Asp50Gly allele alters Pol III assembly, stability, or transcriptional output is undefined","Tissue-specific basis for the ovarian/reproductive vulnerability is unknown"]},{"year":null,"claim":"How POLR3H contributes mechanistically to Pol III transcription and how its partial loss translates into the Foxo3a-associated folliculogenesis defect remain open.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of POLR3H within the human Pol III complex in the corpus","No direct link between specific Pol III transcript changes and the reproductive phenotype","No biochemical characterization of how the p.Asp50Gly substitution perturbs subunit function"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]}],"complexes":["RNA Polymerase III"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y535","full_name":"DNA-directed RNA polymerase III subunit RPC8","aliases":["DNA-directed RNA polymerase III subunit H","RNA polymerase III subunit 22.9 kDa subunit","RPC22.9"],"length_aa":204,"mass_kda":22.9,"function":"DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates (PubMed:20413673, PubMed:33558764, PubMed:34675218). 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. With CRCP/RPC9 forms a mobile stalk that protrudes from Pol III core and functions primarily in transcription initiation (By similarity) (PubMed:33558764, PubMed:34675218). Pol III plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as 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)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y535/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/POLR3H","classification":"Common Essential","n_dependent_lines":1205,"n_total_lines":1208,"dependency_fraction":0.9975165562913907},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100413","cell_line_id":"CID000717","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"POLR2E","stoichiometry":10.0},{"gene":"POLR2H","stoichiometry":10.0},{"gene":"POLR2K","stoichiometry":10.0},{"gene":"POLR3A","stoichiometry":10.0},{"gene":"POLR3B","stoichiometry":10.0},{"gene":"POLR3C","stoichiometry":10.0},{"gene":"POLR3D","stoichiometry":10.0},{"gene":"POLR3E","stoichiometry":10.0},{"gene":"POLR3F","stoichiometry":10.0},{"gene":"POLR3G","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000717","total_profiled":1310},"omim":[{"mim_id":"619801","title":"RNA POLYMERASE III, SUBUNIT H; POLR3H","url":"https://www.omim.org/entry/619801"},{"mim_id":"606121","title":"CGRP RECEPTOR COMPONENT; CRCP","url":"https://www.omim.org/entry/606121"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/POLR3H"},"hgnc":{"alias_symbol":["RPC8","KIAA1665","C25"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y535","domains":[{"cath_id":"3.30.1490.120","chopping":"3-78","consensus_level":"high","plddt":94.345,"start":3,"end":78},{"cath_id":"2.40.50.140","chopping":"84-201","consensus_level":"high","plddt":83.9336,"start":84,"end":201}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y535","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y535-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y535-F1-predicted_aligned_error_v6.png","plddt_mean":88.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=POLR3H","jax_strain_url":"https://www.jax.org/strain/search?query=POLR3H"},"sequence":{"accession":"Q9Y535","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y535.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y535/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y535"}},"corpus_meta":[{"pmid":"16309464","id":"PMC_16309464","title":"Novel effects of the prototype translocating Escherichia coli, strain C25 on intestinal epithelial structure and barrier function.","date":"2005","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16309464","citation_count":54,"is_preprint":false},{"pmid":"26941091","id":"PMC_26941091","title":"A Geranylfarnesyl Diphosphate Synthase Provides the Precursor for Sesterterpenoid (C25) Formation in the Glandular Trichomes of the Mint Species Leucosceptrum canum.","date":"2016","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/26941091","citation_count":50,"is_preprint":false},{"pmid":"4031069","id":"PMC_4031069","title":"Biosynthesis of bile acids in cerebrotendinous xanthomatosis. 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C25-Hydroxylation by Substrate-Binding Pocket Engineering.","date":"2026","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41811220","citation_count":0,"is_preprint":false},{"pmid":"39945522","id":"PMC_39945522","title":"Draft genome sequence of Lactobacillus rhamnosus C25, isolated from an Indian dairy cheese.","date":"2025","source":"Microbiology resource announcements","url":"https://pubmed.ncbi.nlm.nih.gov/39945522","citation_count":0,"is_preprint":false},{"pmid":"41558029","id":"PMC_41558029","title":"Pyridine-Fused C25 abeo-Steroid Alkaloids from a Fungus: Biomimetic Semisynthesis and Anti-HIV Mechanistic Study.","date":"2026","source":"Organic letters","url":"https://pubmed.ncbi.nlm.nih.gov/41558029","citation_count":0,"is_preprint":false},{"pmid":"1304855","id":"PMC_1304855","title":"[The effect of isomeric alkyl (C19--C25) methoxybenzoquinones on mitochondrial respiration].","date":"1992","source":"Izvestiia Akademii nauk. Seriia biologicheskaia","url":"https://pubmed.ncbi.nlm.nih.gov/1304855","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.31.673363","title":"Designing Functional Dairy Food Products: Peptide-Fortification Approaches to Improve Safety, Quality, and Consumer Acceptance","date":"2025-09-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.31.673363","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.28.685152","title":"ALGAL HOMOLOGS OF THE PLANT CER1 AND CER3 PROTEINS ARE FUNCTIONAL HYDROCARBON–FORMING ENZYMES","date":"2025-10-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.28.685152","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.10.642414","title":"Characterization of the gut mycobiome in patients with non-alcoholic fatty liver disease and correlations with serum metabolome","date":"2025-03-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.10.642414","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.10.25320355","title":"Impact of SGLT2 Inhibitors on Survival in Gastrointestinal Cancer Patients Undergoing Chemotherapy and/or Radiotherapy: A Real-World Data Retrospective Cohort Study","date":"2025-01-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.10.25320355","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.27.625585","title":"Combining  <sup>13</sup>  C,  <sup>15</sup>  N, and  <sup>2</sup>  H to measure feeding and metabolic activity in marine, shal-low-water sponges – A pilot study","date":"2024-12-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.27.625585","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":34013,"output_tokens":1098,"usd":0.059255,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7228,"output_tokens":1424,"usd":0.03587,"stage2_stop_reason":"end_turn"},"total_usd":0.095125,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about POLR3H (also known as RPC8, KIAA1665, C25 — specifically the RNA Polymerase III subunit H).\n\nThe vast majority of papers are about:\n- \"C25\" as a chemical notation (carbon-25 position in steroids/vitamins)\n- \"C25\" as bacterial strains (E. coli C25, Eubacterium sp. c-25, Lactobacillus rhamnosus C25)\n- \"C25\" as small molecule compounds\n- Sterol/terpene biosynthesis\n- Various unrelated topics\n\nOnly **paper [5]** (PMID: 8065349) is clearly about POLR3H/RPC8/C25 as the RNA Polymerase III subunit in yeast (Saccharomyces cerevisiae ortholog).\n\nPaper [6] (PMID: 30830215) is about POLR3H in humans — a clinical/genetic study, but it includes functional experiments (mouse knockout, point mutation mice with phenotypic readouts). It establishes that loss-of-function causes embryonic lethality and that a missense mutation causes fertility defects — these are loss-of-function experiments with defined phenotypic readouts.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"The yeast gene YKL1 encodes the RNA Polymerase III subunit C25 (ortholog of human POLR3H/RPC8). C25 is present in submolar ratios in Pol III, easily dissociates from the enzyme, is essential for cell growth and viability, but is not required for transcription in certain in vitro assays. It is related in sequence to the RNA Polymerase II subunit RPB7. A C25 conditional mutant grown at the nonpermissive temperature synthesizes tRNA at reduced rates relative to 5.8S rRNA, a hallmark of all characterized RNA Polymerase III mutants.\",\n      \"method\": \"Gene identification by sequence homology to RPB7; SDS-PAGE mobility matching; conditional mutant analysis (temperature-sensitive growth) with tRNA and 5.8S rRNA synthesis assay; dissociation studies from purified Pol III\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (sequence analysis, biochemical dissociation, in vivo conditional mutant with specific RNA synthesis readouts) in a focused study; foundational characterization paper\",\n      \"pmids\": [\"8065349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A homozygous missense mutation (p.Asp50Gly) in POLR3H causes primary ovarian insufficiency in humans. Complete loss-of-function (knockout) of Polr3h in mice caused early embryonic lethality, establishing that POLR3H is essential for embryonic development. Mice carrying the homozygous point mutation (Polr3hD50G) were viable but showed delayed pubertal development, decreased fertility, small litter sizes, and decreased expression of ovarian Foxo3a with lower numbers of primary follicles.\",\n      \"method\": \"Whole-exome sequencing in human families; CRISPR/Cas9-generated mouse knockout (lethal) and knock-in point mutation lines; phenotypic analysis of pubertal timing, fertility, litter size; ovarian follicle counting; Foxo3a expression assay\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal human genetics plus two independent CRISPR mouse models (null and point mutation) with multiple defined phenotypic readouts (lethality, puberty, fertility, follicle counts, gene expression)\",\n      \"pmids\": [\"30830215\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"POLR3H (RPC8/C25) is an essential subunit of RNA Polymerase III that is present in submolar ratios and dissociates easily from the enzyme; it is required for normal tRNA synthesis in vivo (but not in certain cell-free transcription assays), is indispensable for embryonic development, and its partial loss of function impairs reproductive development and ovarian folliculogenesis, at least in part through reduced Foxo3a expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"POLR3H (RPC8/C25) is an essential subunit of RNA Polymerase III, the enzyme responsible for synthesizing tRNAs and other small RNAs, and is required for normal tRNA synthesis in vivo [#0]. Within Pol III it is present in submolar ratios and dissociates readily from the purified enzyme, and although a conditional mutant of the yeast ortholog C25 specifically reduces tRNA synthesis relative to 5.8S rRNA, the subunit is dispensable for transcription in certain in vitro assays [#0]. POLR3H is indispensable for development: complete loss of function causes early embryonic lethality in mice, whereas a homozygous missense mutation (p.Asp50Gly) is compatible with viability but impairs reproductive development, producing delayed puberty, reduced fertility, and fewer primary ovarian follicles in association with decreased ovarian Foxo3a expression [#1]. In humans, this same POLR3H mutation causes primary ovarian insufficiency [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that POLR3H corresponds to a conserved, dissociable subunit of RNA Polymerase III essential for viability and for normal tRNA synthesis, defining its core enzymatic context.\",\n      \"evidence\": \"Yeast gene identification by sequence homology to RPB7, biochemical dissociation from purified Pol III, and temperature-sensitive conditional mutant analysis scoring tRNA versus 5.8S rRNA synthesis\",\n      \"pmids\": [\"8065349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Why the subunit is dispensable in certain in vitro transcription assays yet required in vivo is unresolved\",\n        \"The structural basis for its submolar stoichiometry and easy dissociation is not defined\",\n        \"Its sequence relationship to RPB7 implies but does not demonstrate a specific molecular role within Pol III\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected POLR3H function to mammalian development and human disease, showing the subunit is essential for embryogenesis and that hypomorphic missense alleles selectively disrupt reproductive development.\",\n      \"evidence\": \"Whole-exome sequencing in human families plus CRISPR/Cas9 mouse null (lethal) and knock-in point-mutation lines, with phenotyping of puberty, fertility, follicle counts, and Foxo3a expression\",\n      \"pmids\": [\"30830215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The mechanism linking POLR3H/Pol III activity to reduced Foxo3a expression in the ovary is not established\",\n        \"Whether the p.Asp50Gly allele alters Pol III assembly, stability, or transcriptional output is undefined\",\n        \"Tissue-specific basis for the ovarian/reproductive vulnerability is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How POLR3H contributes mechanistically to Pol III transcription and how its partial loss translates into the Foxo3a-associated folliculogenesis defect remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of POLR3H within the human Pol III complex in the corpus\",\n        \"No direct link between specific Pol III transcript changes and the reproductive phenotype\",\n        \"No biochemical characterization of how the p.Asp50Gly substitution perturbs subunit function\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"RNA Polymerase III\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}