{"gene":"GTF3C1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2000,"finding":"Nuclear Factor 1 (NF1) was purified to apparent homogeneity from a VA1 terminator-binding fraction (previously designated TFIIIC1/TFIIIC1') and found to interact specifically with two subunits of human TFIIIC2: TFIIIC220 (GTF3C1) and TFIIIC110. NF1 acts in conjunction with TFIIIC to promote accurate termination by RNA polymerase III and to facilitate multiple-round transcription (reinitiation) on the VA1 gene; immunodepletion of NF1 dramatically reduced Pol III transcription from a VA1 template.","method":"Biochemical purification to homogeneity, peptide sequence analysis, immunodepletion with anti-NF1 antibodies, in vitro Pol III transcription assay, site-directed mutation of NF1-binding site in VA1 terminator","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro transcription, protein purification to homogeneity, mutagenesis, and immunodepletion all in one study","pmids":["11118217"],"is_preprint":false},{"year":2009,"finding":"TFIIIC220 (GTF3C1) was identified as a component of IGHMBP2-containing complexes by biochemical co-purification. These complexes also include tRNAs (particularly tRNA(Tyr)), the ABT1 protein, and the helicases Reptin and Pontin, suggesting that GTF3C1/TFIIIC220 participates in a multi-protein assembly linking tRNA transcription machinery to the translational apparatus.","method":"Biochemical co-purification and characterization of IGHMBP2 complexes; genetic modifier rescue experiment in nmd mice","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 — co-purification from a single lab; no reciprocal immunoprecipitation specifically targeting GTF3C1","pmids":["19299493"],"is_preprint":false},{"year":2010,"finding":"mTOR kinase associates with TFIIIC (which contains GTF3C1/TFIIIC220) at tRNA and 5S rRNA genes in mammalian cells. TFIIIC contains a TOR signaling motif (TOS motif) that facilitates its physical association with mTOR. mTOR is recruited to Pol III-transcribed gene loci via this interaction with TFIIIC, where it phosphorylates the Pol III repressor Maf1 at serine 75 to relieve Pol III repression. Proximity ligation assays confirmed the nuclear mTOR–TFIIIC interaction.","method":"ChIP (chromatin immunoprecipitation), proximity ligation assay, in vitro kinase assay for Maf1 phosphorylation, TOS motif analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, PLA, in vitro kinase assay) from a single lab, with clear functional readout","pmids":["20543138"],"is_preprint":false},{"year":2013,"finding":"SIRT7 interacts specifically with GTF3C1 (TFIIIC220) and five out of six subunits of the TFIIIC2 complex (but not TFIIIA or TFIIIB), as determined by affinity purification mass spectrometry and reciprocal immunoisolations from nuclear fractions. SIRT7 is recruited to Pol III target genes (tRNA genes) by ChIP, and SIRT7 knockdown reduces tRNA levels, suggesting SIRT7 modulates Pol III transcription through its interaction with the TFIIIC2 complex including GTF3C1.","method":"Affinity purification mass spectrometry (AP-MS), reciprocal immunoisolation from nuclear fractions, ChIP, siRNA knockdown with tRNA level measurement","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 2 — reciprocal isolations, ChIP, and functional knockdown with defined molecular readout; multiple orthogonal methods","pmids":["24113281"],"is_preprint":false},{"year":2023,"finding":"Cryo-electron microscopy structures of the six-subunit human TFIIIC complex, unbound and bound to a tRNA gene promoter, revealed that GTF3C1 (TFIIIC220) forms an integral structural part of both the τA and τB modules of TFIIIC, connecting the two subcomplexes via a ~550-amino acid flexible linker. The τB module recognizes the B-box via DNA shape and sequence readout through assembly of multiple winged-helix domains; high-affinity B-box recognition anchors TFIIIC to promoter DNA and permits scanning for low-affinity A-boxes and TFIIIB recruitment for Pol III activation.","method":"Cryo-electron microscopy (cryo-EM) structure determination of the six-subunit human TFIIIC complex in unbound and tRNA gene-bound states","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structures with functional interpretation of domain architecture and DNA recognition mechanism","pmids":["37418517"],"is_preprint":false},{"year":2024,"finding":"Purified recombinant human TFIIIC220 (GTF3C1) possesses intrinsic lysine acetyltransferase activity, acetylating core histones H3, H4, and H2A in vitro. A putative catalytic domain was mapped within TFIIIC220; mutagenesis of critical residues in the putative acetyl-CoA binding 'P loop' drastically reduced this acetyltransferase activity. Knockdown of TFIIIC220 in mammalian cells dramatically reduced global H3K18 acetylation levels, which was rescued by overexpression of the acetyltransferase domain alone, identifying H3K18 as a primary physiological substrate.","method":"In vitro acetyltransferase assay with purified recombinant protein, site-directed mutagenesis of the P-loop, siRNA knockdown in mammalian cell lines, rescue with acetyltransferase domain overexpression, immunoblotting for H3K18ac","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay with mutagenesis, combined with knockdown and domain rescue in cells; multiple orthogonal methods","pmids":["37963603"],"is_preprint":false}],"current_model":"GTF3C1 (TFIIIC220) is the largest subunit of the six-subunit human TFIIIC2 transcription factor complex, structurally bridging the τA and τB DNA-recognition modules via a long flexible linker to mediate tRNA gene promoter recognition by RNA Pol III; it harbors intrinsic lysine acetyltransferase activity that targets H3K18 to relieve chromatin repression, interacts with mTOR (via a TOS motif) to couple nutrient signaling to Pol III transcription, binds NF1 to facilitate accurate Pol III termination and reinitiation, and associates with SIRT7 as part of a regulatory layer modulating Pol III output."},"narrative":{"teleology":[{"year":2000,"claim":"The question of how Pol III achieves accurate termination and efficient reinitiation was addressed by identifying NF1 as a factor that physically contacts GTF3C1 and TFIIIC110, establishing that TFIIIC subunit interactions are required for these late-stage transcription events.","evidence":"Biochemical purification to homogeneity, peptide sequencing, immunodepletion, and in vitro Pol III transcription/termination assays on VA1 templates","pmids":["11118217"],"confidence":"High","gaps":["Which domain(s) of GTF3C1 mediate the NF1 interaction remains unmapped","Whether NF1-dependent reinitiation operates at all Pol III gene classes or only type-II genes is untested"]},{"year":2010,"claim":"How nutrient signaling reaches Pol III-transcribed genes was unknown; this work showed that mTOR is physically recruited to tRNA and 5S rRNA loci through a TOS motif in TFIIIC, where it phosphorylates the Pol III repressor Maf1, establishing a direct signaling conduit from mTOR to Pol III output.","evidence":"ChIP at tRNA/5S genes, proximity ligation assay for nuclear mTOR–TFIIIC interaction, in vitro kinase assay for Maf1-S75 phosphorylation, TOS motif analysis","pmids":["20543138"],"confidence":"High","gaps":["The precise TFIIIC subunit(s) harboring the functional TOS motif were not individually mapped to GTF3C1 versus other subunits","Whether mTOR also directly phosphorylates TFIIIC subunits at chromatin remains untested"]},{"year":2013,"claim":"The regulatory logic governing Pol III output was expanded by demonstrating that SIRT7, an NAD+-dependent deacetylase, specifically associates with GTF3C1 and the TFIIIC2 complex at tRNA genes and positively influences tRNA levels, revealing a deacetylase-based regulatory layer at Pol III loci.","evidence":"Affinity purification mass spectrometry, reciprocal immunoisolation from nuclear fractions, ChIP at tRNA genes, siRNA knockdown with tRNA quantification","pmids":["24113281"],"confidence":"High","gaps":["The direct substrate of SIRT7 within TFIIIC (GTF3C1 or histone marks) is not identified","Whether SIRT7 counteracts the acetyltransferase activity of GTF3C1 itself is unknown"]},{"year":2023,"claim":"How TFIIIC recognizes bipartite intragenic promoters was structurally resolved: cryo-EM structures revealed that GTF3C1 spans both the τA and τB modules via a long flexible linker, with τB using winged-helix domains for B-box DNA shape/sequence readout, establishing the architectural basis for promoter scanning and TFIIIB recruitment.","evidence":"Cryo-EM of the six-subunit human TFIIIC in unbound and tRNA gene-bound states","pmids":["37418517"],"confidence":"High","gaps":["The flexible linker region of GTF3C1 is poorly resolved; its conformational dynamics during scanning are inferred, not directly observed","How TFIIIC transitions from scanning to stable TFIIIB recruitment is not captured structurally"]},{"year":2024,"claim":"Whether TFIIIC possesses intrinsic chromatin-modifying activity was answered: GTF3C1 was shown to harbor a bona fide acetyltransferase domain that acetylates H3K18, providing a direct mechanism by which TFIIIC relieves chromatin repression at its own target genes independently of recruited HATs.","evidence":"In vitro acetyltransferase assay with recombinant GTF3C1, P-loop mutagenesis, siRNA knockdown of GTF3C1 in mammalian cells with domain-rescue of H3K18ac levels","pmids":["37963603"],"confidence":"High","gaps":["Whether H3K18ac by GTF3C1 is restricted to Pol III loci or also marks Pol II-associated CTCF/boundary elements where TFIIIC localizes is untested","The relationship between GTF3C1 acetyltransferase activity and the SIRT7-mediated regulatory axis has not been examined"]},{"year":null,"claim":"A unified model integrating GTF3C1's structural scaffolding, intrinsic acetyltransferase activity, mTOR-mediated nutrient sensing, SIRT7-dependent regulation, and NF1-mediated termination/reinitiation at individual Pol III loci in vivo remains to be constructed.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide dissection of which GTF3C1 functions (scaffolding vs. acetyltransferase vs. mTOR recruitment) are rate-limiting for Pol III output at individual loci","Whether disease-associated mutations in GTF3C1 have been reported and how they map to functional domains is unexplored in the timeline","The interplay between SIRT7 deacetylase activity and GTF3C1 acetyltransferase activity on shared histone substrates has not been tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[5]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,3,4]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2,4]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,3,4,5]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]}],"complexes":["TFIIIC2"],"partners":["NF1","SIRT7","MTOR","GTF3C2","GTF3C3","GTF3C4","GTF3C5","GTF3C6"],"other_free_text":[]},"mechanistic_narrative":"GTF3C1 (TFIIIC220) is the largest subunit of the six-subunit human TFIIIC2 complex and serves as a central scaffold for RNA polymerase III promoter recognition, nutrient-responsive transcriptional regulation, and chromatin modification at Pol III-transcribed loci. Cryo-EM structures show that GTF3C1 bridges the τA and τB DNA-recognition modules of TFIIIC via a ~550-amino acid flexible linker, enabling B-box-anchored scanning for A-box elements and subsequent TFIIIB recruitment to activate Pol III transcription [PMID:37418517]. GTF3C1 harbors intrinsic lysine acetyltransferase activity that targets histone H3K18 to relieve chromatin repression at tRNA genes, as demonstrated by in vitro enzymatic assays, P-loop mutagenesis, and cellular knockdown-rescue experiments [PMID:37963603]. Beyond its structural and enzymatic roles, GTF3C1 couples nutrient signaling to Pol III output by recruiting mTOR to tRNA and 5S rRNA gene loci via a TOS motif, facilitating mTOR-dependent phosphorylation of the Pol III repressor Maf1 [PMID:20543138], and interacts with NF1 to promote accurate Pol III termination and reinitiation [PMID:11118217] and with the deacetylase SIRT7 to modulate tRNA transcription levels [PMID:24113281]."},"prefetch_data":{"uniprot":{"accession":"Q12789","full_name":"General transcription factor 3C polypeptide 1","aliases":["TF3C-alpha","TFIIIC box B-binding subunit","Transcription factor IIIC 220 kDa subunit","TFIIIC 220 kDa subunit","TFIIIC220","Transcription factor IIIC subunit alpha"],"length_aa":2109,"mass_kda":238.9,"function":"Required for RNA polymerase III-mediated transcription. Component of TFIIIC that initiates transcription complex assembly on tRNA and is required for transcription of 5S rRNA and other stable nuclear and cytoplasmic RNAs. Binds to the box B promoter element","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q12789/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/GTF3C1","classification":"Common Essential","n_dependent_lines":1050,"n_total_lines":1208,"dependency_fraction":0.8692052980132451},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GTF3C1","total_profiled":1310},"omim":[{"mim_id":"611784","title":"GENERAL TRANSCRIPTION FACTOR 3C, POLYPEPTIDE 6; GTF3C6","url":"https://www.omim.org/entry/611784"},{"mim_id":"604902","title":"BRF1 SUBUNIT OF RNA POLYMERASE III TRANSCRIPTION INITIATION FACTOR; BRF1","url":"https://www.omim.org/entry/604902"},{"mim_id":"604883","title":"GENERAL TRANSCRIPTION FACTOR 3C, POLYPEPTIDE 2; GTF3C2","url":"https://www.omim.org/entry/604883"},{"mim_id":"603246","title":"GENERAL TRANSCRIPTION FACTOR 3C, POLYPEPTIDE 1; GTF3C1","url":"https://www.omim.org/entry/603246"},{"mim_id":"600502","title":"IMMUNOGLOBULIN MU-BINDING PROTEIN 2; IGHMBP2","url":"https://www.omim.org/entry/600502"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GTF3C1"},"hgnc":{"alias_symbol":["TFIIIC220"],"prev_symbol":[]},"alphafold":{"accession":"Q12789","domains":[{"cath_id":"-","chopping":"2-245","consensus_level":"medium","plddt":83.5808,"start":2,"end":245},{"cath_id":"-","chopping":"265-336","consensus_level":"high","plddt":79.4676,"start":265,"end":336},{"cath_id":"1.10.10.10","chopping":"358-437","consensus_level":"medium","plddt":81.6648,"start":358,"end":437},{"cath_id":"-","chopping":"790-817_892-1054_1090-1131","consensus_level":"medium","plddt":82.3233,"start":790,"end":1131},{"cath_id":"-","chopping":"1252-1381","consensus_level":"medium","plddt":83.3325,"start":1252,"end":1381},{"cath_id":"1.10.10.10","chopping":"1708-1821_1977-2055_2079-2108","consensus_level":"medium","plddt":83.0573,"start":1708,"end":2108}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12789","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12789-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12789-F1-predicted_aligned_error_v6.png","plddt_mean":64.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GTF3C1","jax_strain_url":"https://www.jax.org/strain/search?query=GTF3C1"},"sequence":{"accession":"Q12789","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12789.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12789/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12789"}},"corpus_meta":[{"pmid":"24113281","id":"PMC_24113281","title":"Sirtuin 7 plays a role in ribosome biogenesis and protein synthesis.","date":"2013","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/24113281","citation_count":94,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19299493","id":"PMC_19299493","title":"Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19299493","citation_count":68,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11118217","id":"PMC_11118217","title":"Nuclear factor 1 (NF1) affects accurate termination and multiple-round transcription by human RNA polymerase III.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11118217","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32641753","id":"PMC_32641753","title":"Novel candidate genes in esophageal atresia/tracheoesophageal fistula identified by exome sequencing.","date":"2020","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/32641753","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37418517","id":"PMC_37418517","title":"Structural insights into human TFIIIC promoter recognition.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37418517","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25563673","id":"PMC_25563673","title":"Application of quantitative trait locus mapping and transcriptomics to studies of the senescence-accelerated phenotype in rats.","date":"2014","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/25563673","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37963603","id":"PMC_37963603","title":"The Largest Subunit of Human TFIIIC Complex, TFIIIC220, a Lysine Acetyltransferase Targets Histone H3K18.","date":"2024","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37963603","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40790772","id":"PMC_40790772","title":"LncRNA GTF3C1 promotes diabetic corneal wound healing by regulating GABARAP and PTEN to augment autophagy.","date":"2025","source":"Eye and vision (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40790772","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40718854","id":"PMC_40718854","title":"Manganese exposure: a study on apoptosis and Ferroptosis in mouse Leydig and Sertoli cells.","date":"2025","source":"Toxicology research","url":"https://pubmed.ncbi.nlm.nih.gov/40718854","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12063399","id":"PMC_12063399","title":"Comparative mapping of five coding DNA sequences on cattle chromosomes 7 and 25.","date":"2001","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12063399","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17081983","id":"PMC_17081983","title":"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17081983","citation_count":2861,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16169070","id":"PMC_16169070","title":"A human protein-protein interaction network: a resource for annotating the proteome.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16169070","citation_count":1704,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16964243","id":"PMC_16964243","title":"A probability-based approach for high-throughput protein phosphorylation analysis and site localization.","date":"2006","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/16964243","citation_count":1336,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20562859","id":"PMC_20562859","title":"Network organization of the human autophagy system.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20562859","citation_count":1286,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15302935","id":"PMC_15302935","title":"Large-scale characterization of HeLa cell nuclear phosphoproteins.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15302935","citation_count":1159,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20360068","id":"PMC_20360068","title":"Systematic analysis of human protein complexes identifies chromosome segregation proteins.","date":"2010","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20360068","citation_count":421,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29656893","id":"PMC_29656893","title":"DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/29656893","citation_count":379,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28611215","id":"PMC_28611215","title":"Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28611215","citation_count":282,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21654808","id":"PMC_21654808","title":"A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/21654808","citation_count":269,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26949251","id":"PMC_26949251","title":"The cell proliferation antigen Ki-67 organises heterochromatin.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26949251","citation_count":265,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21900206","id":"PMC_21900206","title":"A directed protein interaction network for investigating intracellular signal transduction.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21900206","citation_count":258,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29568061","id":"PMC_29568061","title":"An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29568061","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20543138","id":"PMC_20543138","title":"mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20543138","citation_count":187,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25544563","id":"PMC_25544563","title":"Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/25544563","citation_count":173,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32807901","id":"PMC_32807901","title":"UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32807901","citation_count":168,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30804502","id":"PMC_30804502","title":"H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30804502","citation_count":162,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6373,"output_tokens":1406,"usd":0.020105},"stage2":{"model":"claude-opus-4-6","input_tokens":4644,"output_tokens":1869,"usd":0.104917},"total_usd":0.301796,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":18169,"output_tokens":3152,"usd":0.050894},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5509,"output_tokens":2255,"usd":0.12588}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of the six-subunit human TFIIIC complex (unbound and bound to a tRNA gene) revealed that GTF3C1 (TFIIIC220) forms an integral part of both the τA and τB modules, connecting them via a ~550-amino acid flexible linker, and that the τB module recognizes the B-box via DNA shape and sequence readout through multiple winged-helix domains, providing a structural mechanism for high-affinity B-box anchoring and scanning for low-affinity A-boxes.\",\n      \"method\": \"Cryo-electron microscopy with structural analysis of TFIIIC bound to tRNA gene promoter\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures with functional domain mapping, single rigorous study with multiple structural states\",\n      \"pmids\": [\"37418517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Purified recombinant human TFIIIC220 (GTF3C1) acetylates core histones H3, H4, and H2A in vitro, with a putative catalytic acetyltransferase domain identified; mutation of critical residues in the putative acetyl-CoA binding P-loop drastically reduced catalytic activity, and knockdown of TFIIIC220 in mammalian cells reduced global H3K18 acetylation, which was rescued by overexpression of the acetyltransferase domain.\",\n      \"method\": \"In vitro acetyltransferase assay with recombinant protein, active-site mutagenesis, siRNA knockdown with rescue experiment\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution plus mutagenesis plus cellular knockdown/rescue with specific histone mark readout\",\n      \"pmids\": [\"37963603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SIRT7 interacts specifically with GTF3C1 (TFIIIC220), a component of the Pol III transcription factor TFIIIC2 complex, as determined by affinity purification mass spectrometry and reciprocal immunoaffinity purification; SIRT7 also interacts with five out of six TFIIIC2 subunits and localizes to Pol III target genes by ChIP, with SIRT7 knockdown reducing tRNA levels, suggesting SIRT7 regulates Pol III transcription through the TFIIIC2 complex.\",\n      \"method\": \"Affinity purification mass spectrometry, reciprocal Co-IP, ChIP assay, siRNA knockdown with tRNA level measurement\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus MS plus ChIP plus functional KD, multiple orthogonal methods in single study\",\n      \"pmids\": [\"24113281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GTF3C1 (TFIIIC220, referred to as transcription factor IIIC-220 kDa) is part of IGHMBP2-containing complexes, as identified by biochemical co-purification; this places GTF3C1 in a complex relevant to tRNA transcription and the translational machinery.\",\n      \"method\": \"Biochemical co-purification/co-immunoprecipitation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single co-purification identifying GTF3C1 as part of a complex, moderate functional context but limited mechanistic follow-up for GTF3C1 specifically\",\n      \"pmids\": [\"19299493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Nuclear factor 1 (NF1) interacts specifically with two subunits of human TFIIIC2, including TFIIIC220 (GTF3C1), as demonstrated by binding assays, and this interaction affects both termination and reinitiation of transcription by RNA Pol III on the VA1 gene.\",\n      \"method\": \"Protein interaction assay (NF1 binding to TFIIIC220), immunodepletion, in vitro transcription assay with mutant templates\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical interaction validated with immunodepletion and functional transcription assay, but GTF3C1 is one of two interacting subunits identified\",\n      \"pmids\": [\"11118217\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GTF3C1 (TFIIIC220) is the largest subunit of the six-subunit human TFIIIC complex that bridges the τA and τB modules via a flexible linker to enable promoter recognition at tRNA genes (cryo-EM); it possesses intrinsic lysine acetyltransferase activity targeting histone H3K18 to relieve chromatin-mediated repression of Pol III transcription; it interacts with SIRT7 (a regulator of Pol III activity) and NF1 (to facilitate accurate termination and reinitiation), and is found in IGHMBP2-containing complexes linked to the translational machinery.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEPT papers.\n\n**Classification:**\n\n- Paper [1] (PMID:24113281): KEEP — describes SIRT7 interaction with GTF3C1 (TFIIIC220), a component of TFIIIC2 complex\n- Paper [2] (PMID:19299493): KEEP — describes TFIIIC220 (GTF3C1) as part of IGHMBP2-containing complexes\n- Paper [3] (PMID:11118217): KEEP — describes NF1 interaction with TFIIIC220 (GTF3C1) and TFIIIC110 subunits\n- Paper [4] (PMID:32641753): EXCLUDE — pure genetic association/exome sequencing study, no mechanistic findings about GTF3C1\n- Paper [5] (PMID:37418517): KEEP — cryo-EM structure of human TFIIIC complex including TFIIIC220 (GTF3C1)\n- Paper [6] (PMID:25563673): EXCLUDE — expression/QTL study, no mechanistic findings\n- Paper [7] (PMID:37963603): KEEP — characterizes acetyltransferase activity of TFIIIC220 (GTF3C1)\n- Paper [8] (PMID:40790772): EXCLUDE — Case (B) alt-locus product: describes lncRNA GTF3C1, not the canonical protein\n- Paper [9] (PMID:40718854): EXCLUDE — mentions Gtf3c1 as a dysregulated gene, no mechanistic study of the protein\n- Paper [10] (PMID:12063399): EXCLUDE — comparative mapping study only, no mechanistic findings\n\n**Additional curated papers:**\n- PMID:17081983: EXCLUDE — large phosphoproteomics screen; GTF3C1 mentioned only as phosphorylation detection, no mechanism\n- PMID:16169070: EXCLUDE — large Y2H screen, GTF3C1 mentioned in network context only\n- PMID:12477932, PMID:14702039, PMID:15489334: EXCLUDE — cDNA sequencing projects\n- PMID:16964243, PMID:15302935: EXCLUDE — phosphoproteomics screens\n- PMID:20562859: EXCLUDE — autophagy network, GTF3C1 not specifically studied mechanistically\n- PMID:26186194, PMID:28514442, PMID:33961781: EXCLUDE — large interactome screens, no specific GTF3C1 mechanism\n- PMID:26496610: EXCLUDE — global interactome, no specific GTF3C1 mechanism\n- PMID:25416956: EXCLUDE — interactome map, no specific GTF3C1 mechanism\n- PMID:29507755: EXCLUDE — m6A methylation, not about GTF3C1\n- PMID:21873635: EXCLUDE — GO annotation methodology\n- PMID:35271311: EXCLUDE — subcellular localization resource, no specific GTF3C1 mechanism\n- PMID:20360068: EXCLUDE — chromosome segregation complexes, not specifically GTF3C1\n- PMID:26344197: EXCLUDE — metazoan complexes survey, not specifically GTF3C1\n- PMID:29656893: EXCLUDE — DNA repair/shieldin, not GTF3C1\n- PMID:34079125: EXCLUDE — BioID map, not specifically GTF3C1\n- PMID:28611215: EXCLUDE — HNRNPL/prostate cancer, not GTF3C1\n- PMID:21654808: EXCLUDE — cyclin D1/DNA repair, not GTF3C1\n- PMID:26949251: EXCLUDE — Ki-67, not GTF3C1\n- PMID:21900206: EXCLUDE — signaling network, not specifically GTF3C1\n- PMID:29568061: EXCLUDE — MAC-tag methodology, not specifically GTF3C1\n- PMID:20543138: KEEP — describes mTOR association with TFIIIC (including GTF3C1/TFIIIC220) at tRNA genes\n- PMID:25544563: EXCLUDE — KSHV-host interactions, not specifically GTF3C1\n- PMID:32807901: EXCLUDE — UFMylation/p53, not GTF3C1\n- PMID:30804502: EXCLUDE — BRCA1-BARD1/H4K20me0, not GTF3C1\n- PMID:22939629: EXCLUDE — human protein complexes census, not specifically GTF3C1\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Nuclear Factor 1 (NF1) was purified to apparent homogeneity from a VA1 terminator-binding fraction (previously designated TFIIIC1/TFIIIC1') and found to interact specifically with two subunits of human TFIIIC2: TFIIIC220 (GTF3C1) and TFIIIC110. NF1 acts in conjunction with TFIIIC to promote accurate termination by RNA polymerase III and to facilitate multiple-round transcription (reinitiation) on the VA1 gene; immunodepletion of NF1 dramatically reduced Pol III transcription from a VA1 template.\",\n      \"method\": \"Biochemical purification to homogeneity, peptide sequence analysis, immunodepletion with anti-NF1 antibodies, in vitro Pol III transcription assay, site-directed mutation of NF1-binding site in VA1 terminator\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro transcription, protein purification to homogeneity, mutagenesis, and immunodepletion all in one study\",\n      \"pmids\": [\"11118217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TFIIIC220 (GTF3C1) was identified as a component of IGHMBP2-containing complexes by biochemical co-purification. These complexes also include tRNAs (particularly tRNA(Tyr)), the ABT1 protein, and the helicases Reptin and Pontin, suggesting that GTF3C1/TFIIIC220 participates in a multi-protein assembly linking tRNA transcription machinery to the translational apparatus.\",\n      \"method\": \"Biochemical co-purification and characterization of IGHMBP2 complexes; genetic modifier rescue experiment in nmd mice\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-purification from a single lab; no reciprocal immunoprecipitation specifically targeting GTF3C1\",\n      \"pmids\": [\"19299493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"mTOR kinase associates with TFIIIC (which contains GTF3C1/TFIIIC220) at tRNA and 5S rRNA genes in mammalian cells. TFIIIC contains a TOR signaling motif (TOS motif) that facilitates its physical association with mTOR. mTOR is recruited to Pol III-transcribed gene loci via this interaction with TFIIIC, where it phosphorylates the Pol III repressor Maf1 at serine 75 to relieve Pol III repression. Proximity ligation assays confirmed the nuclear mTOR–TFIIIC interaction.\",\n      \"method\": \"ChIP (chromatin immunoprecipitation), proximity ligation assay, in vitro kinase assay for Maf1 phosphorylation, TOS motif analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, PLA, in vitro kinase assay) from a single lab, with clear functional readout\",\n      \"pmids\": [\"20543138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SIRT7 interacts specifically with GTF3C1 (TFIIIC220) and five out of six subunits of the TFIIIC2 complex (but not TFIIIA or TFIIIB), as determined by affinity purification mass spectrometry and reciprocal immunoisolations from nuclear fractions. SIRT7 is recruited to Pol III target genes (tRNA genes) by ChIP, and SIRT7 knockdown reduces tRNA levels, suggesting SIRT7 modulates Pol III transcription through its interaction with the TFIIIC2 complex including GTF3C1.\",\n      \"method\": \"Affinity purification mass spectrometry (AP-MS), reciprocal immunoisolation from nuclear fractions, ChIP, siRNA knockdown with tRNA level measurement\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal isolations, ChIP, and functional knockdown with defined molecular readout; multiple orthogonal methods\",\n      \"pmids\": [\"24113281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-electron microscopy structures of the six-subunit human TFIIIC complex, unbound and bound to a tRNA gene promoter, revealed that GTF3C1 (TFIIIC220) forms an integral structural part of both the τA and τB modules of TFIIIC, connecting the two subcomplexes via a ~550-amino acid flexible linker. The τB module recognizes the B-box via DNA shape and sequence readout through assembly of multiple winged-helix domains; high-affinity B-box recognition anchors TFIIIC to promoter DNA and permits scanning for low-affinity A-boxes and TFIIIB recruitment for Pol III activation.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) structure determination of the six-subunit human TFIIIC complex in unbound and tRNA gene-bound states\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structures with functional interpretation of domain architecture and DNA recognition mechanism\",\n      \"pmids\": [\"37418517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Purified recombinant human TFIIIC220 (GTF3C1) possesses intrinsic lysine acetyltransferase activity, acetylating core histones H3, H4, and H2A in vitro. A putative catalytic domain was mapped within TFIIIC220; mutagenesis of critical residues in the putative acetyl-CoA binding 'P loop' drastically reduced this acetyltransferase activity. Knockdown of TFIIIC220 in mammalian cells dramatically reduced global H3K18 acetylation levels, which was rescued by overexpression of the acetyltransferase domain alone, identifying H3K18 as a primary physiological substrate.\",\n      \"method\": \"In vitro acetyltransferase assay with purified recombinant protein, site-directed mutagenesis of the P-loop, siRNA knockdown in mammalian cell lines, rescue with acetyltransferase domain overexpression, immunoblotting for H3K18ac\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with mutagenesis, combined with knockdown and domain rescue in cells; multiple orthogonal methods\",\n      \"pmids\": [\"37963603\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GTF3C1 (TFIIIC220) is the largest subunit of the six-subunit human TFIIIC2 transcription factor complex, structurally bridging the τA and τB DNA-recognition modules via a long flexible linker to mediate tRNA gene promoter recognition by RNA Pol III; it harbors intrinsic lysine acetyltransferase activity that targets H3K18 to relieve chromatin repression, interacts with mTOR (via a TOS motif) to couple nutrient signaling to Pol III transcription, binds NF1 to facilitate accurate Pol III termination and reinitiation, and associates with SIRT7 as part of a regulatory layer modulating Pol III output.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GTF3C1 (TFIIIC220) is the largest subunit of the six-subunit human TFIIIC complex and serves as the architectural scaffold that bridges the τA and τB subcomplexes via a ~550-amino-acid flexible linker, enabling promoter recognition at tRNA genes through B-box anchoring and A-box scanning [PMID:37418517]. Beyond its structural role, GTF3C1 possesses intrinsic lysine acetyltransferase activity: it acetylates histones H3, H4, and H2A in vitro, with specificity for H3K18 in cells, thereby relieving chromatin-mediated repression of RNA Polymerase III transcription [PMID:37963603]. GTF3C1 physically interacts with the NAD⁺-dependent deacetylase SIRT7, which localizes to Pol III target genes and positively regulates tRNA levels through the TFIIIC complex [PMID:24113281], and with nuclear factor 1 (NF1), which modulates Pol III termination and reinitiation [PMID:11118217].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying that NF1 binds TFIIIC220 established that factors outside the core Pol III machinery can modulate transcription termination and reinitiation through direct contact with TFIIIC subunits.\",\n      \"evidence\": \"Protein interaction assays, immunodepletion, and in vitro transcription on the VA1 gene template\",\n      \"pmids\": [\"11118217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The relative contribution of NF1–GTF3C1 versus NF1–other TFIIIC subunit interactions was not resolved\",\n        \"In vivo relevance of NF1-mediated termination/reinitiation regulation was not tested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Co-purification of GTF3C1 with IGHMBP2-containing complexes linked TFIIIC to the translational machinery, suggesting a broader role for TFIIIC beyond Pol III promoter recognition.\",\n      \"evidence\": \"Biochemical co-purification/co-immunoprecipitation from human cells\",\n      \"pmids\": [\"19299493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single co-purification without reciprocal validation for GTF3C1 specifically\",\n        \"Functional consequence of the IGHMBP2–GTF3C1 interaction was not determined\",\n        \"Whether GTF3C1 participates in translation-related functions remains untested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that SIRT7 interacts with GTF3C1 and localizes to Pol III genes revealed a regulatory axis whereby a sirtuin deacetylase modulates tRNA transcription through the TFIIIC complex.\",\n      \"evidence\": \"Affinity purification mass spectrometry, reciprocal co-IP, ChIP at Pol III loci, and siRNA knockdown with tRNA quantification\",\n      \"pmids\": [\"24113281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SIRT7 deacetylates GTF3C1 itself or histones acetylated by GTF3C1 was not resolved\",\n        \"The specific domains of GTF3C1 mediating the SIRT7 interaction were not mapped\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cryo-EM structures of human TFIIIC bound to a tRNA gene resolved how GTF3C1 bridges the τA and τB modules and how the τB module reads B-box DNA, providing the first atomic-level model of promoter scanning and recognition by TFIIIC.\",\n      \"evidence\": \"Cryo-electron microscopy of unbound and DNA-bound TFIIIC at near-atomic resolution\",\n      \"pmids\": [\"37418517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The structure of the full flexible linker connecting τA and τB was not resolved\",\n        \"How GTF3C1 conformational dynamics contribute to promoter scanning in vivo remains unclear\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying GTF3C1 as an acetyltransferase that targets H3K18 established a direct enzymatic mechanism by which TFIIIC relieves chromatin repression at its own target genes, unifying its promoter-binding and chromatin-remodeling functions.\",\n      \"evidence\": \"In vitro acetyltransferase assays with recombinant GTF3C1, active-site mutagenesis, siRNA knockdown with H3K18ac rescue in mammalian cells\",\n      \"pmids\": [\"37963603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Genome-wide contribution of GTF3C1 acetyltransferase activity versus other H3K18 acetyltransferases (e.g., p300) is not delineated\",\n        \"Whether GTF3C1 acetyltransferase activity is regulated by SIRT7 deacetylation has not been tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GTF3C1's acetyltransferase activity is coordinated with its structural role in promoter scanning, and whether SIRT7-mediated deacetylation directly antagonizes GTF3C1 catalytic output at specific loci, remain central open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vivo structure of the full TFIIIC–TFIIIB–Pol III pre-initiation complex including the GTF3C1 linker\",\n        \"Acetyltransferase domain regulation by post-translational modifications or interacting partners is unknown\",\n        \"Whether GTF3C1 acetylates non-histone substrates has not been explored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"TFIIIC (human six-subunit complex)\"\n    ],\n    \"partners\": [\n      \"SIRT7\",\n      \"NF1\",\n      \"IGHMBP2\",\n      \"GTF3C2\",\n      \"GTF3C3\",\n      \"GTF3C4\",\n      \"GTF3C5\",\n      \"GTF3C6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"GTF3C1 (TFIIIC220) is the largest subunit of the six-subunit human TFIIIC2 complex and serves as a central scaffold for RNA polymerase III promoter recognition, nutrient-responsive transcriptional regulation, and chromatin modification at Pol III-transcribed loci. Cryo-EM structures show that GTF3C1 bridges the τA and τB DNA-recognition modules of TFIIIC via a ~550-amino acid flexible linker, enabling B-box-anchored scanning for A-box elements and subsequent TFIIIB recruitment to activate Pol III transcription [PMID:37418517]. GTF3C1 harbors intrinsic lysine acetyltransferase activity that targets histone H3K18 to relieve chromatin repression at tRNA genes, as demonstrated by in vitro enzymatic assays, P-loop mutagenesis, and cellular knockdown-rescue experiments [PMID:37963603]. Beyond its structural and enzymatic roles, GTF3C1 couples nutrient signaling to Pol III output by recruiting mTOR to tRNA and 5S rRNA gene loci via a TOS motif, facilitating mTOR-dependent phosphorylation of the Pol III repressor Maf1 [PMID:20543138], and interacts with NF1 to promote accurate Pol III termination and reinitiation [PMID:11118217] and with the deacetylase SIRT7 to modulate tRNA transcription levels [PMID:24113281].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The question of how Pol III achieves accurate termination and efficient reinitiation was addressed by identifying NF1 as a factor that physically contacts GTF3C1 and TFIIIC110, establishing that TFIIIC subunit interactions are required for these late-stage transcription events.\",\n      \"evidence\": \"Biochemical purification to homogeneity, peptide sequencing, immunodepletion, and in vitro Pol III transcription/termination assays on VA1 templates\",\n      \"pmids\": [\"11118217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which domain(s) of GTF3C1 mediate the NF1 interaction remains unmapped\",\n        \"Whether NF1-dependent reinitiation operates at all Pol III gene classes or only type-II genes is untested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"How nutrient signaling reaches Pol III-transcribed genes was unknown; this work showed that mTOR is physically recruited to tRNA and 5S rRNA loci through a TOS motif in TFIIIC, where it phosphorylates the Pol III repressor Maf1, establishing a direct signaling conduit from mTOR to Pol III output.\",\n      \"evidence\": \"ChIP at tRNA/5S genes, proximity ligation assay for nuclear mTOR–TFIIIC interaction, in vitro kinase assay for Maf1-S75 phosphorylation, TOS motif analysis\",\n      \"pmids\": [\"20543138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The precise TFIIIC subunit(s) harboring the functional TOS motif were not individually mapped to GTF3C1 versus other subunits\",\n        \"Whether mTOR also directly phosphorylates TFIIIC subunits at chromatin remains untested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The regulatory logic governing Pol III output was expanded by demonstrating that SIRT7, an NAD+-dependent deacetylase, specifically associates with GTF3C1 and the TFIIIC2 complex at tRNA genes and positively influences tRNA levels, revealing a deacetylase-based regulatory layer at Pol III loci.\",\n      \"evidence\": \"Affinity purification mass spectrometry, reciprocal immunoisolation from nuclear fractions, ChIP at tRNA genes, siRNA knockdown with tRNA quantification\",\n      \"pmids\": [\"24113281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The direct substrate of SIRT7 within TFIIIC (GTF3C1 or histone marks) is not identified\",\n        \"Whether SIRT7 counteracts the acetyltransferase activity of GTF3C1 itself is unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How TFIIIC recognizes bipartite intragenic promoters was structurally resolved: cryo-EM structures revealed that GTF3C1 spans both the τA and τB modules via a long flexible linker, with τB using winged-helix domains for B-box DNA shape/sequence readout, establishing the architectural basis for promoter scanning and TFIIIB recruitment.\",\n      \"evidence\": \"Cryo-EM of the six-subunit human TFIIIC in unbound and tRNA gene-bound states\",\n      \"pmids\": [\"37418517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The flexible linker region of GTF3C1 is poorly resolved; its conformational dynamics during scanning are inferred, not directly observed\",\n        \"How TFIIIC transitions from scanning to stable TFIIIB recruitment is not captured structurally\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether TFIIIC possesses intrinsic chromatin-modifying activity was answered: GTF3C1 was shown to harbor a bona fide acetyltransferase domain that acetylates H3K18, providing a direct mechanism by which TFIIIC relieves chromatin repression at its own target genes independently of recruited HATs.\",\n      \"evidence\": \"In vitro acetyltransferase assay with recombinant GTF3C1, P-loop mutagenesis, siRNA knockdown of GTF3C1 in mammalian cells with domain-rescue of H3K18ac levels\",\n      \"pmids\": [\"37963603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether H3K18ac by GTF3C1 is restricted to Pol III loci or also marks Pol II-associated CTCF/boundary elements where TFIIIC localizes is untested\",\n        \"The relationship between GTF3C1 acetyltransferase activity and the SIRT7-mediated regulatory axis has not been examined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified model integrating GTF3C1's structural scaffolding, intrinsic acetyltransferase activity, mTOR-mediated nutrient sensing, SIRT7-dependent regulation, and NF1-mediated termination/reinitiation at individual Pol III loci in vivo remains to be constructed.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genome-wide dissection of which GTF3C1 functions (scaffolding vs. acetyltransferase vs. mTOR recruitment) are rate-limiting for Pol III output at individual loci\",\n        \"Whether disease-associated mutations in GTF3C1 have been reported and how they map to functional domains is unexplored in the timeline\",\n        \"The interplay between SIRT7 deacetylase activity and GTF3C1 acetyltransferase activity on shared histone substrates has not been tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"TFIIIC2\"\n    ],\n    \"partners\": [\n      \"NF1\",\n      \"SIRT7\",\n      \"MTOR\",\n      \"GTF3C2\",\n      \"GTF3C3\",\n      \"GTF3C4\",\n      \"GTF3C5\",\n      \"GTF3C6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}