Affinage

GTF3C1

General transcription factor 3C polypeptide 1 · UniProt Q12789

Round 2 corrected
Length
2109 aa
Mass
238.9 kDa
Annotated
2026-04-28
40 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2000 High

    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

    PMID:11118217

    Open questions at the time
    • 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
  2. 2010 High

    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

    PMID:20543138

    Open questions at the time
    • 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
  3. 2013 High

    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

    PMID:24113281

    Open questions at the time
    • 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
  4. 2023 High

    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

    PMID:37418517

    Open questions at the time
    • 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
  5. 2024 High

    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

    PMID:37963603

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 1 GO:0005198 structural molecule activity 1 GO:0016740 transferase activity 1 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 2
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-162582 Signal Transduction 1 R-HSA-4839726 Chromatin organization 1
Partners
GTF3C2GTF3C3GTF3C4GTF3C5GTF3C6MTORNF1SIRT7
Complex memberships
TFIIIC2

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 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. 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 The EMBO journal High 11118217
2009 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. Biochemical co-purification and characterization of IGHMBP2 complexes; genetic modifier rescue experiment in nmd mice Human molecular genetics Medium 19299493
2010 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. ChIP (chromatin immunoprecipitation), proximity ligation assay, in vitro kinase assay for Maf1 phosphorylation, TOS motif analysis Proceedings of the National Academy of Sciences of the United States of America High 20543138
2013 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. Affinity purification mass spectrometry (AP-MS), reciprocal immunoisolation from nuclear fractions, ChIP, siRNA knockdown with tRNA level measurement Molecular & cellular proteomics : MCP High 24113281
2023 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. Cryo-electron microscopy (cryo-EM) structure determination of the six-subunit human TFIIIC complex in unbound and tRNA gene-bound states Science advances High 37418517
2024 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. 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 of biochemistry High 37963603

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2010 Network organization of the human autophagy system. Nature 1286 20562859
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2018 DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 379 29656893
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2011 A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 269 21654808
2016 The cell proliferation antigen Ki-67 organises heterochromatin. eLife 265 26949251
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2010 mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proceedings of the National Academy of Sciences of the United States of America 187 20543138
2014 Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Molecular cell 173 25544563
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2019 H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids. Nature cell biology 162 30804502
2013 Sirtuin 7 plays a role in ribosome biogenesis and protein synthesis. Molecular & cellular proteomics : MCP 94 24113281
2009 Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery. Human molecular genetics 68 19299493
2000 Nuclear factor 1 (NF1) affects accurate termination and multiple-round transcription by human RNA polymerase III. The EMBO journal 27 11118217
2020 Novel candidate genes in esophageal atresia/tracheoesophageal fistula identified by exome sequencing. European journal of human genetics : EJHG 18 32641753
2023 Structural insights into human TFIIIC promoter recognition. Science advances 15 37418517
2014 Application of quantitative trait locus mapping and transcriptomics to studies of the senescence-accelerated phenotype in rats. BMC genomics 7 25563673
2024 The Largest Subunit of Human TFIIIC Complex, TFIIIC220, a Lysine Acetyltransferase Targets Histone H3K18. Journal of biochemistry 2 37963603
2025 Manganese exposure: a study on apoptosis and Ferroptosis in mouse Leydig and Sertoli cells. Toxicology research 0 40718854
2025 LncRNA GTF3C1 promotes diabetic corneal wound healing by regulating GABARAP and PTEN to augment autophagy. Eye and vision (London, England) 0 40790772
2001 Comparative mapping of five coding DNA sequences on cattle chromosomes 7 and 25. Cytogenetics and cell genetics 0 12063399