{"gene":"POLR3F","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1997,"finding":"The C34 subunit (RPC34/POLR3F) of yeast RNA polymerase III interacts with TFIIIB70, and mutations in RPC34 that impair this interaction also impair specific transcription of pol III genes. Purified mutant pol III enzymes showed normal catalytic activity on non-specific templates but were defective in specific transcription: one mutant (C34-1124) reduced pol III affinity for pre-initiation complexes, while a second (C34-1109) was defective in open complex formation during initiation. This demonstrates that C34 is a major determinant in pol III recruitment by the pre-initiation complex and also acts at a subsequent step required for formation of an initiation-competent polymerase.","method":"In vitro mutagenesis of RPC34; purification of mutant pol III; in vitro transcription assays on poly[d(A-T)] and specific pol III gene templates; complementation by increasing pol III concentration","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified mutant enzymes, multiple orthogonal functional assays (non-specific vs. specific transcription, titration), and dissection of two mechanistically distinct steps","pmids":["9312031"],"is_preprint":false},{"year":1999,"finding":"The C-terminal extension of yeast TFIIIB70 (BRF) contains conserved regions II and III that are required for interaction with the C34 subunit (POLR3F ortholog) of RNA pol III. Mutations in region II of TFIIIB70 that impair C34 binding are co-lethal with rpc34 mutations, establishing a genetically essential TFIIIB70–C34 interface. Separately, region II mutations impair TBP binding and TFIIIB assembly, and mutations in the TFIIIB70–C34 interface impair in vitro transcription of the SUP4 tRNA gene.","method":"Extensive mutagenesis of TFIIIB70; co-lethality (genetic epistasis) with rpc34 alleles; in vitro binding assays; suppression by TBP overexpression; in vitro transcription of SUP4 tRNA gene","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic epistasis, direct binding assays, and in vitro transcription, multiple orthogonal methods in one study","pmids":["10329159"],"is_preprint":false},{"year":2020,"finding":"Citrus MAF1 (CsMAF1) binds predominantly to the WH1 domain of the Pol III C34 subunit (CsC34, ortholog of POLR3F). The phosphoregulatory region of CsMAF1 (loop-3 and α-helix-2) contributes to this interaction, and phosphorylation of this region (including Ser45, phosphorylated by a citrus AGC1 kinase) decreases CsMAF1 affinity for CsC34, leading to Pol III derepression. Additionally, the C-terminal region of TFIIIB component BRF1 competes with CsMAF1 for binding to CsC34, indicating that CsC34 is a shared docking site for both MAF1-mediated repression and TFIIIB-mediated activation.","method":"NMR structural analysis of CsMAF1; pulldown/binding assays between CsMAF1 and CsC34; phosphorylation assays with AGC1 kinase; competition assays with BRF1 C-terminal region; mutagenesis of Ser45","journal":"The Plant cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (structural data, binding assays, kinase assay, competition assay) but single lab and plant ortholog rather than mammalian protein","pmids":["32641350"],"is_preprint":false}],"current_model":"POLR3F (RPC34/C34) is a subunit of RNA polymerase III that directly contacts TFIIIB70 (BRF) via its interaction surface and the WH1 domain serves as a docking site for MAF1-mediated repression; it plays dual roles in transcription initiation — facilitating pol III recruitment to pre-initiation complexes and enabling open complex formation — and its activity is regulated by phosphorylation-controlled MAF1 binding, with TFIIIB BRF1 competing with MAF1 for the same C34 interface."},"narrative":{"mechanistic_narrative":"POLR3F (RPC34/C34) is a subunit of RNA polymerase III that serves as a central determinant of pol III recruitment and initiation competence by docking the enzyme onto the pre-initiation complex through direct contact with TFIIIB [PMID:9312031, PMID:10329159]. Mutational analysis of the yeast subunit resolves two mechanistically distinct contributions: one C34 surface mediates pol III affinity for the pre-initiation complex, while a second is required for open complex formation during initiation, with catalytic activity on non-specific templates remaining intact [PMID:9312031]. The C34–TFIIIB interface is genetically essential, mapping to conserved regions II and III of the TFIIIB70 (BRF) C-terminal extension whose mutation is co-lethal with rpc34 alleles and impairs specific tRNA gene transcription [PMID:10329159]. C34 additionally acts as a regulatory hub: its WH1 domain is the principal docking site for the repressor MAF1, and TFIIIB BRF1 competes with MAF1 for this same interface, coupling MAF1 phosphorylation status to pol III derepression and TFIIIB-mediated activation [PMID:32641350].","teleology":[{"year":1997,"claim":"Established that C34 is not merely a structural subunit but a functional determinant linking pol III to its initiation machinery, distinguishing recruitment from a downstream initiation step.","evidence":"In vitro mutagenesis of RPC34, purification of mutant pol III, and transcription assays comparing non-specific vs. specific templates in yeast","pmids":["9312031"],"confidence":"High","gaps":["Did not define the structural surface of C34 contacting the pre-initiation complex","Mechanism of open complex formation defect at residue level not resolved","Not extended to mammalian POLR3F"]},{"year":1999,"claim":"Mapped the partner side of the interaction, showing the C34 docking site on TFIIIB70 (BRF) is genetically essential and required for specific transcription.","evidence":"Mutagenesis of TFIIIB70 with reciprocal co-lethality against rpc34 alleles, binding assays, and in vitro transcription of the SUP4 tRNA gene in yeast","pmids":["10329159"],"confidence":"High","gaps":["Did not provide an atomic-resolution structure of the C34–TFIIIB70 interface","Did not establish how the same interface is regulated"]},{"year":2020,"claim":"Identified the C34 WH1 domain as a shared docking platform for both the repressor MAF1 and activating TFIIIB BRF1, revealing a phosphorylation-gated competitive switch controlling pol III activity.","evidence":"NMR analysis of CsMAF1, pulldown and competition assays with CsC34 and BRF1 C-terminus, and AGC1 kinase phosphorylation assays in citrus (plant ortholog)","pmids":["32641350"],"confidence":"Medium","gaps":["Single lab and plant ortholog rather than mammalian POLR3F","Structural detail of the C34 WH1 surface engaging MAF1 versus BRF1 not fully resolved","In vivo consequences of the competitive switch on pol III gene programs not quantified"]},{"year":null,"claim":"Whether the recruitment, open-complex, and MAF1/BRF1 regulatory functions defined in yeast and plants are conserved at the mammalian POLR3F protein remains open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct functional or structural characterization of human POLR3F in the available corpus","MAF1-mediated regulation of the human C34 interface not tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"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":[0,1,2]}],"complexes":["RNA polymerase III"],"partners":["BRF1","MAF1","TFIIIB70"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H1D9","full_name":"DNA-directed RNA polymerase III subunit RPC6","aliases":["DNA-directed RNA polymerase III subunit F","RNA polymerase III 39 kDa subunit","RPC39"],"length_aa":316,"mass_kda":35.7,"function":"DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates (PubMed:20413673, PubMed:21358628, 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. Part of POLR3C/RPC3-POLR3F/RPC6-POLR3G/RPC7 heterotrimer that coordinates the dynamics of Pol III stalk and clamp modules during the transition from apo to elongation state (PubMed:20413673, PubMed:33558764, PubMed:33558766). Pol III plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses, including varicella zoster virus. Acts as a nuclear and cytosolic DNA sensor detecting AT-rich DNA, 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, PubMed:30211253). Preferentially binds double-stranded DNA (dsDNA) (PubMed:21358628)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9H1D9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/POLR3F","classification":"Common Essential","n_dependent_lines":1201,"n_total_lines":1208,"dependency_fraction":0.9942052980132451},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000132664","cell_line_id":"CID000714","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"POLR1C","stoichiometry":10.0},{"gene":"POLR2E","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":"POLR3C","stoichiometry":10.0},{"gene":"POLR3D","stoichiometry":10.0},{"gene":"POLR3E","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000714","total_profiled":1310},"omim":[{"mim_id":"619872","title":"IMMUNODEFICIENCY 101 (VARICELLA ZOSTER VIRUS-SPECIFIC); IMD101","url":"https://www.omim.org/entry/619872"},{"mim_id":"617456","title":"POLYMERASE III, RNA, SUBUNIT G; POLR3G","url":"https://www.omim.org/entry/617456"},{"mim_id":"617455","title":"POLYMERASE III, RNA, SUBUNIT F; POLR3F","url":"https://www.omim.org/entry/617455"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/POLR3F"},"hgnc":{"alias_symbol":["RPC39","RPC6","C34"],"prev_symbol":[]},"alphafold":{"accession":"Q9H1D9","domains":[{"cath_id":"1.10.10.10","chopping":"14-78","consensus_level":"high","plddt":81.8894,"start":14,"end":78},{"cath_id":"1.10.10.10","chopping":"86-163","consensus_level":"high","plddt":87.2083,"start":86,"end":163},{"cath_id":"1.10.10","chopping":"171-271","consensus_level":"high","plddt":91.0456,"start":171,"end":271},{"cath_id":"-","chopping":"280-314","consensus_level":"medium","plddt":90.6011,"start":280,"end":314}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H1D9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H1D9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H1D9-F1-predicted_aligned_error_v6.png","plddt_mean":84.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=POLR3F","jax_strain_url":"https://www.jax.org/strain/search?query=POLR3F"},"sequence":{"accession":"Q9H1D9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H1D9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H1D9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H1D9"}},"corpus_meta":[{"pmid":"15640162","id":"PMC_15640162","title":"Different from the HIV fusion inhibitor C34, the anti-HIV drug Fuzeon (T-20) inhibits HIV-1 entry by targeting multiple sites in gp41 and gp120.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15640162","citation_count":203,"is_preprint":false},{"pmid":"9312031","id":"PMC_9312031","title":"Dual role of the C34 subunit of RNA polymerase III in transcription initiation.","date":"1997","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9312031","citation_count":94,"is_preprint":false},{"pmid":"16550351","id":"PMC_16550351","title":"Maternal transfer of complement components C3-1, C3-3, C3-4, C4, C5, C7, Bf, and Df to offspring in rainbow trout (Oncorhynchus mykiss).","date":"2006","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/16550351","citation_count":93,"is_preprint":false},{"pmid":"12895697","id":"PMC_12895697","title":"HIV-1 resistance to the gp41-dependent fusion inhibitor C-34.","date":"2003","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/12895697","citation_count":62,"is_preprint":false},{"pmid":"18809675","id":"PMC_18809675","title":"Albumin-conjugated C34 peptide HIV-1 fusion inhibitor: equipotent to C34 and T-20 in vitro with sustained activity in SCID-hu Thy/Liv mice.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18809675","citation_count":60,"is_preprint":false},{"pmid":"23565220","id":"PMC_23565220","title":"Conjugation of cholesterol to HIV-1 fusion inhibitor C34 increases peptide-membrane interactions potentiating its action.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23565220","citation_count":53,"is_preprint":false},{"pmid":"10329159","id":"PMC_10329159","title":"Mutagenesis of yeast TFIIIB70 reveals C-terminal residues critical for interaction with TBP and C34.","date":"1999","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10329159","citation_count":44,"is_preprint":false},{"pmid":"34727285","id":"PMC_34727285","title":"TLR4-IN-C34 Inhibits Lipopolysaccharide-Stimulated Inflammatory Responses via Downregulating TLR4/MyD88/NF-κB/NLRP3 Signaling Pathway and Reducing ROS Generation in BV2 Cells.","date":"2021","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/34727285","citation_count":34,"is_preprint":false},{"pmid":"29016144","id":"PMC_29016144","title":"Alismanin A, a Triterpenoid with a C34 Skeleton from Alisma orientale as a Natural Agonist of Human Pregnane X Receptor.","date":"2017","source":"Organic letters","url":"https://pubmed.ncbi.nlm.nih.gov/29016144","citation_count":33,"is_preprint":false},{"pmid":"15828842","id":"PMC_15828842","title":"Differential inhibition of HIV-1 and SIV envelope-mediated cell fusion by C34 peptides derived from the C-terminal heptad repeat of gp41 from diverse strains of HIV-1, HIV-2, and SIV.","date":"2005","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15828842","citation_count":28,"is_preprint":false},{"pmid":"11430410","id":"PMC_11430410","title":"Variant toxin B and a functional toxin A produced by Clostridium difficile C34.","date":"2001","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/11430410","citation_count":27,"is_preprint":false},{"pmid":"31562169","id":"PMC_31562169","title":"Heterologous Expression of a Cryptic Gene Cluster from Streptomyces leeuwenhoekii C34T Yields a Novel Lasso Peptide, Leepeptin.","date":"2019","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31562169","citation_count":22,"is_preprint":false},{"pmid":"8255761","id":"PMC_8255761","title":"Anticodon bases C34 and C35 are major, positive, identity elements in Saccharomyces cerevisiae tRNA(Trp).","date":"1993","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8255761","citation_count":15,"is_preprint":false},{"pmid":"16250877","id":"PMC_16250877","title":"Development of anti-HIV agents targeting dynamic supramolecular mechanism: entry and fusion inhibitors based on CXCR4/CCR5 antagonists and gp41-C34-remodeling peptides.","date":"2005","source":"Current HIV research","url":"https://pubmed.ncbi.nlm.nih.gov/16250877","citation_count":14,"is_preprint":false},{"pmid":"30671980","id":"PMC_30671980","title":"Pharmacological inhibition of TLR4/NF-κB with TLR4-IN-C34 attenuated microcystin-leucine arginine toxicity in bovine Sertoli cells.","date":"2019","source":"Journal of applied toxicology : JAT","url":"https://pubmed.ncbi.nlm.nih.gov/30671980","citation_count":14,"is_preprint":false},{"pmid":"27155865","id":"PMC_27155865","title":"Glycosyl Phosphatidylinositol-Anchored C34 Peptide Derived From Human Immunodeficiency Virus Type 1 Gp41 Is a Potent Entry Inhibitor.","date":"2016","source":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27155865","citation_count":14,"is_preprint":false},{"pmid":"17255952","id":"PMC_17255952","title":"C34, a membrane fusion inhibitor, blocks HIV infection of langerhans cells and viral transmission to T cells.","date":"2007","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/17255952","citation_count":12,"is_preprint":false},{"pmid":"31012222","id":"PMC_31012222","title":"Dimeric C34 Derivatives Linked through Disulfide Bridges as New HIV-1 Fusion Inhibitors.","date":"2019","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31012222","citation_count":12,"is_preprint":false},{"pmid":"22252805","id":"PMC_22252805","title":"Preexposure prophylaxis with albumin-conjugated C34 peptide HIV-1 fusion inhibitor in SCID-hu Thy/Liv mice.","date":"2012","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/22252805","citation_count":12,"is_preprint":false},{"pmid":"32702985","id":"PMC_32702985","title":"Bungsteroid A: One Unusual C34 Pentacyclic Steroid Analogue from Zanthoxylum bungeanum Maxim.","date":"2020","source":"The Journal of organic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32702985","citation_count":12,"is_preprint":false},{"pmid":"15803807","id":"PMC_15803807","title":"Clinical significance and neuropathology of primary MADD in C34-T and G468-T mutations of the AMPD1 gene.","date":"2005","source":"Clinical neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/15803807","citation_count":11,"is_preprint":false},{"pmid":"31459949","id":"PMC_31459949","title":"Synthesis and Biological Activities of Aplyronine A Analogues toward the Development of Antitumor Protein-Protein Interaction Inducers between Actin and Tubulin: Conjugation of the C1-C9 Macrolactone Part and the C24-C34 Side Chain.","date":"2019","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/31459949","citation_count":11,"is_preprint":false},{"pmid":"29578590","id":"PMC_29578590","title":"Analysis of metabolic networks of Streptomyces leeuwenhoekii C34 by means of a genome scale model: Prediction of modifications that enhance the production of specialized metabolites.","date":"2018","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/29578590","citation_count":10,"is_preprint":false},{"pmid":"28842581","id":"PMC_28842581","title":"A first-in-human study of the novel HIV-fusion inhibitor C34-PEG4-Chol.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28842581","citation_count":9,"is_preprint":false},{"pmid":"26506247","id":"PMC_26506247","title":"The C34 Peptide Fusion Inhibitor Binds to the Six-Helix Bundle Core Domain of HIV-1 gp41 by Displacement of the C-Terminal Helical Repeat Region.","date":"2015","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26506247","citation_count":9,"is_preprint":false},{"pmid":"22032937","id":"PMC_22032937","title":"The effect of SAMe and betaine on Hepa 1-6, C34 and E47 liver cell survival in vitro.","date":"2011","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22032937","citation_count":9,"is_preprint":false},{"pmid":"26109003","id":"PMC_26109003","title":"Molecular weight-dependent degradation of D-lactate-containing polyesters by polyhydroxyalkanoate depolymerases from Variovorax sp. C34 and Alcaligenes faecalis T1.","date":"2015","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/26109003","citation_count":9,"is_preprint":false},{"pmid":"36152840","id":"PMC_36152840","title":"Pharmacological inhibition of toll-like receptor 4 with TLR4-IN-C34 modulates the intestinal flora homeostasis and the MyD88/NF-κB axis in ulcerative colitis.","date":"2022","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36152840","citation_count":8,"is_preprint":false},{"pmid":"36474570","id":"PMC_36474570","title":"TLR4-IN-C34 protects against acute kidney injury via modulating TLR4/MyD88/NF-κb axis, MAPK, and apoptosis.","date":"2022","source":"Iranian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36474570","citation_count":7,"is_preprint":false},{"pmid":"32641350","id":"PMC_32641350","title":"The MAF1 Phosphoregulatory Region Controls MAF1 Interaction with the RNA Polymerase III C34 Subunit and Transcriptional Repression in Plants.","date":"2020","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/32641350","citation_count":7,"is_preprint":false},{"pmid":"34553712","id":"PMC_34553712","title":"The C29-C34 parts of antitumor macrolide aplyronine A serve as versatile actin-affinity tags.","date":"2021","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34553712","citation_count":7,"is_preprint":false},{"pmid":"25393106","id":"PMC_25393106","title":"Molecular dynamics studies of the inhibitor C34 binding to the wild-type and mutant HIV-1 gp41: inhibitory and drug resistant mechanism.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25393106","citation_count":6,"is_preprint":false},{"pmid":"39336102","id":"PMC_39336102","title":"A New Chimeric Antibody against the HIV-1 Fusion Inhibitory Peptide MT-C34 with a High Affinity and Fc-Mediated Cellular Cytotoxicity.","date":"2024","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/39336102","citation_count":5,"is_preprint":false},{"pmid":"40122407","id":"PMC_40122407","title":"Benzo[a]phenoxazine derivative C34 efficacy against fluconazole-resistant Candida spp.","date":"2025","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/40122407","citation_count":3,"is_preprint":false},{"pmid":"16431293","id":"PMC_16431293","title":"Hyperleptinemia and its relation with peripheral C34(+)CD7(+) stem cells in renal transplant recipients.","date":"2005","source":"Transplant immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16431293","citation_count":3,"is_preprint":false},{"pmid":"40854507","id":"PMC_40854507","title":"TLR4-IN-C34 attenuates the progression of osteoarthritis through inhibiting inflammation, angiogenesis and pain.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40854507","citation_count":0,"is_preprint":false},{"pmid":"39709562","id":"PMC_39709562","title":"[Methods to Increase the Efficiency of Knock-in of a Construct Encoding the HIV-1 Fusion Inhibitor, MT-C34 Peptide, into the CXCR4 Locus in the CEM/R5 T Cell Line].","date":"2024","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/39709562","citation_count":0,"is_preprint":false},{"pmid":"40956005","id":"PMC_40956005","title":"Metabolic Engineering of Streptomyces leeuwenhoekii C34T to Increase Chaxamycin Production Based on the iVR1007 Genome-Scale Model.","date":"2025","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/40956005","citation_count":0,"is_preprint":false},{"pmid":"40718441","id":"PMC_40718441","title":"Neuroprotective Effects of Early TLR4 Blockade with Compound C34 in Temporal Lobe Epilepsy: Alleviation of Neuroinflammation and Apoptosis.","date":"2025","source":"Iranian journal of pharmaceutical research : IJPR","url":"https://pubmed.ncbi.nlm.nih.gov/40718441","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.25.25332126","title":"Treatment pathways of non-small cells lung cancer patients in the Czech Republic: an insight from administrative claims data","date":"2025-07-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.25.25332126","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.30.605930","title":"Structural insights into the assembly mechanism of the flagellar MS-ring with three different symmetries","date":"2024-07-31","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.30.605930","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.13.612944","title":"tRNA lysidinylation is essential for the minimal translation system found in the apicoplast of  <i>Plasmodium falciparum</i>","date":"2024-09-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.13.612944","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23043,"output_tokens":1580,"usd":0.046414,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7772,"output_tokens":1644,"usd":0.03998,"stage2_stop_reason":"end_turn"},"total_usd":0.086394,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about POLR3F (also known as RPC39, RPC6, C34 — the RNA polymerase III subunit).\n\nThe vast majority of papers use \"C34\" to refer to:\n- HIV fusion inhibitor peptide C34 (gp41-derived)\n- TLR4-IN-C34 (TLR4 inhibitor compound)\n- Various chemical compounds with C34 carbon skeletons\n- Clostridium difficile strain C34\n- Streptomyces leeuwenhoekii strain C34\n- tRNA anticodon positions C34/C35\n\nThe only papers genuinely about POLR3F (the RNA Pol III C34 subunit, RPC34/RPC6) are:\n- PMID:9312031 — \"Dual role of the C34 subunit of RNA polymerase III in transcription initiation\" (yeast RPC34, ortholog of human POLR3F)\n- PMID:10329159 — \"Mutagenesis of yeast TFIIIB70 reveals C-terminal residues critical for interaction with TBP and C34\" (mentions C34 subunit of pol III)\n- PMID:32641350 — \"The MAF1 Phosphoregulatory Region Controls MAF1 Interaction with the RNA Polymerase III C34 Subunit\" (plant ortholog CsC34, consistent with mammalian function)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"The C34 subunit (RPC34/POLR3F) of yeast RNA polymerase III interacts with TFIIIB70, and mutations in RPC34 that impair this interaction also impair specific transcription of pol III genes. Purified mutant pol III enzymes showed normal catalytic activity on non-specific templates but were defective in specific transcription: one mutant (C34-1124) reduced pol III affinity for pre-initiation complexes, while a second (C34-1109) was defective in open complex formation during initiation. This demonstrates that C34 is a major determinant in pol III recruitment by the pre-initiation complex and also acts at a subsequent step required for formation of an initiation-competent polymerase.\",\n      \"method\": \"In vitro mutagenesis of RPC34; purification of mutant pol III; in vitro transcription assays on poly[d(A-T)] and specific pol III gene templates; complementation by increasing pol III concentration\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified mutant enzymes, multiple orthogonal functional assays (non-specific vs. specific transcription, titration), and dissection of two mechanistically distinct steps\",\n      \"pmids\": [\"9312031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The C-terminal extension of yeast TFIIIB70 (BRF) contains conserved regions II and III that are required for interaction with the C34 subunit (POLR3F ortholog) of RNA pol III. Mutations in region II of TFIIIB70 that impair C34 binding are co-lethal with rpc34 mutations, establishing a genetically essential TFIIIB70–C34 interface. Separately, region II mutations impair TBP binding and TFIIIB assembly, and mutations in the TFIIIB70–C34 interface impair in vitro transcription of the SUP4 tRNA gene.\",\n      \"method\": \"Extensive mutagenesis of TFIIIB70; co-lethality (genetic epistasis) with rpc34 alleles; in vitro binding assays; suppression by TBP overexpression; in vitro transcription of SUP4 tRNA gene\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic epistasis, direct binding assays, and in vitro transcription, multiple orthogonal methods in one study\",\n      \"pmids\": [\"10329159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Citrus MAF1 (CsMAF1) binds predominantly to the WH1 domain of the Pol III C34 subunit (CsC34, ortholog of POLR3F). The phosphoregulatory region of CsMAF1 (loop-3 and α-helix-2) contributes to this interaction, and phosphorylation of this region (including Ser45, phosphorylated by a citrus AGC1 kinase) decreases CsMAF1 affinity for CsC34, leading to Pol III derepression. Additionally, the C-terminal region of TFIIIB component BRF1 competes with CsMAF1 for binding to CsC34, indicating that CsC34 is a shared docking site for both MAF1-mediated repression and TFIIIB-mediated activation.\",\n      \"method\": \"NMR structural analysis of CsMAF1; pulldown/binding assays between CsMAF1 and CsC34; phosphorylation assays with AGC1 kinase; competition assays with BRF1 C-terminal region; mutagenesis of Ser45\",\n      \"journal\": \"The Plant cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (structural data, binding assays, kinase assay, competition assay) but single lab and plant ortholog rather than mammalian protein\",\n      \"pmids\": [\"32641350\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"POLR3F (RPC34/C34) is a subunit of RNA polymerase III that directly contacts TFIIIB70 (BRF) via its interaction surface and the WH1 domain serves as a docking site for MAF1-mediated repression; it plays dual roles in transcription initiation — facilitating pol III recruitment to pre-initiation complexes and enabling open complex formation — and its activity is regulated by phosphorylation-controlled MAF1 binding, with TFIIIB BRF1 competing with MAF1 for the same C34 interface.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"POLR3F (RPC34/C34) is a subunit of RNA polymerase III that serves as a central determinant of pol III recruitment and initiation competence by docking the enzyme onto the pre-initiation complex through direct contact with TFIIIB [#0, #1]. Mutational analysis of the yeast subunit resolves two mechanistically distinct contributions: one C34 surface mediates pol III affinity for the pre-initiation complex, while a second is required for open complex formation during initiation, with catalytic activity on non-specific templates remaining intact [#0]. The C34–TFIIIB interface is genetically essential, mapping to conserved regions II and III of the TFIIIB70 (BRF) C-terminal extension whose mutation is co-lethal with rpc34 alleles and impairs specific tRNA gene transcription [#1]. C34 additionally acts as a regulatory hub: its WH1 domain is the principal docking site for the repressor MAF1, and TFIIIB BRF1 competes with MAF1 for this same interface, coupling MAF1 phosphorylation status to pol III derepression and TFIIIB-mediated activation [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that C34 is not merely a structural subunit but a functional determinant linking pol III to its initiation machinery, distinguishing recruitment from a downstream initiation step.\",\n      \"evidence\": \"In vitro mutagenesis of RPC34, purification of mutant pol III, and transcription assays comparing non-specific vs. specific templates in yeast\",\n      \"pmids\": [\"9312031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not define the structural surface of C34 contacting the pre-initiation complex\",\n        \"Mechanism of open complex formation defect at residue level not resolved\",\n        \"Not extended to mammalian POLR3F\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapped the partner side of the interaction, showing the C34 docking site on TFIIIB70 (BRF) is genetically essential and required for specific transcription.\",\n      \"evidence\": \"Mutagenesis of TFIIIB70 with reciprocal co-lethality against rpc34 alleles, binding assays, and in vitro transcription of the SUP4 tRNA gene in yeast\",\n      \"pmids\": [\"10329159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not provide an atomic-resolution structure of the C34–TFIIIB70 interface\",\n        \"Did not establish how the same interface is regulated\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified the C34 WH1 domain as a shared docking platform for both the repressor MAF1 and activating TFIIIB BRF1, revealing a phosphorylation-gated competitive switch controlling pol III activity.\",\n      \"evidence\": \"NMR analysis of CsMAF1, pulldown and competition assays with CsC34 and BRF1 C-terminus, and AGC1 kinase phosphorylation assays in citrus (plant ortholog)\",\n      \"pmids\": [\"32641350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab and plant ortholog rather than mammalian POLR3F\",\n        \"Structural detail of the C34 WH1 surface engaging MAF1 versus BRF1 not fully resolved\",\n        \"In vivo consequences of the competitive switch on pol III gene programs not quantified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the recruitment, open-complex, and MAF1/BRF1 regulatory functions defined in yeast and plants are conserved at the mammalian POLR3F protein remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct functional or structural characterization of human POLR3F in the available corpus\",\n        \"MAF1-mediated regulation of the human C34 interface not tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\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, 2]}\n    ],\n    \"complexes\": [\"RNA polymerase III\"],\n    \"partners\": [\"BRF1\", \"MAF1\", \"TFIIIB70\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}