Affinage

GTF3C4

General transcription factor 3C polypeptide 4 · UniProt Q9UKN8

Round 2 corrected
Length
822 aa
Mass
92.0 kDa
Annotated
2026-04-28
37 papers in source corpus 4 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GTF3C4 (hTFIIIC90) is a core subunit of the human TFIIIC2 DNA-binding subcomplex that is essential for RNA polymerase III transcription, bridging TFIIIC to TFIIIB and Pol III through direct physical interactions with multiple subunits of each complex (PMID:10523658). Beyond its structural role, GTF3C4 possesses intrinsic histone acetyltransferase activity specific for histone H3, linking the Pol III transcription machinery to chromatin modification (PMID:10523658). Loss of GTF3C4 induces cellular senescence marked by p16/p21 activation (PMID:32264951) and suppresses PI3K/AKT signaling, inhibiting breast cancer cell proliferation and promoting apoptosis (PMID:41649141).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1999 High

    Identification of hTFIIIC90 as a TFIIIC2 subunit resolved how TFIIIC bridges TFIIIB and Pol III at the preinitiation complex, establishing that a single subunit physically contacts components of all three assemblies and is absolutely required for Pol III transcription.

    Evidence cDNA cloning, immunodepletion/reconstitution of in vitro Pol III transcription, and co-immunoprecipitation with TFIIIC, TFIIIB, and Pol III subunits

    PMID:10523658

    Open questions at the time
    • Structural basis of the multi-subunit bridging interactions remains unresolved
    • In vivo ChIP-based occupancy at Pol III promoters was not assessed
    • Whether the bridging function is rate-limiting for Pol III transcription in cells is unknown
  2. 1999 High

    Demonstration that hTFIIIC90 has intrinsic histone H3 acetyltransferase activity revealed an unexpected enzymatic function for a general transcription factor subunit, suggesting TFIIIC may directly modify chromatin at Pol III-transcribed loci.

    Evidence In vitro HAT assay with purified protein and defined histone substrates

    PMID:10523658

    Open questions at the time
    • Specific H3 lysine residues targeted have not been identified
    • In vivo HAT activity and its functional contribution to Pol III transcription are untested
    • No catalytic-dead mutant has been characterized
  3. 2007 Medium

    Identification of the sixth TFIIIC subunit (TFIIIC35) as a direct GTF3C4 interactor, and demonstration that complete TFIIIC retains transcription activity, confirmed the subunit composition and functional integrity of the holo-complex.

    Evidence GST pulldown of TFIIIC35–hTFIIIC90 interaction and affinity purification of epitope-tagged TFIIIC with in vitro VA1 transcription assay

    PMID:17409385

    Open questions at the time
    • Stoichiometry and architecture of the six-subunit complex remain unresolved
    • Whether the TFIIIC35–GTF3C4 interaction is required for HAT activity is unknown
  4. 2020 Medium

    Loss-of-function studies revealed that GTF3C4 depletion triggers cellular senescence with activation of the p16/p21 axis, extending its role beyond Pol III transcription to cell proliferation control.

    Evidence siRNA knockdown with quantification of cell number, p16/p21 expression, and senescence morphology

    PMID:32264951

    Open questions at the time
    • Whether senescence results from impaired Pol III transcription or a Pol III-independent function is undetermined
    • Rescue experiments re-expressing GTF3C4 were not reported
    • Relevance to in vivo tissue homeostasis is unknown
  5. 2026 Medium

    Identification of GTF3C4 as the direct target of the anti-cancer compound bufalin, and demonstration that GTF3C4 knockdown suppresses PI3K/AKT signaling, positioned GTF3C4 upstream of a major pro-survival pathway in breast cancer cells.

    Evidence LiP-MS target identification, validated by CETSA, DARTS, and SPR; siRNA knockdown with PI3K/AKT pathway and proliferation/apoptosis readouts in breast cancer cell lines

    PMID:41649141

    Open questions at the time
    • Mechanism connecting GTF3C4 to PI3K/AKT activation is uncharacterized
    • Whether bufalin binding inhibits GTF3C4 HAT or scaffolding function is unknown
    • Findings are from a single study in breast cancer cell lines and lack in vivo validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for GTF3C4's multi-subunit bridging role within the Pol III preinitiation complex, the specific histone residues and genomic loci modified by its HAT activity in vivo, and the molecular pathway through which GTF3C4 regulates PI3K/AKT signaling and cellular senescence.
  • No high-resolution structure of GTF3C4 within TFIIIC or the Pol III PIC exists
  • In vivo HAT target sites and catalytic residues are uncharacterized
  • Causal relationship between Pol III transcription defects and senescence/PI3K signaling has not been dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140223 general transcription initiation factor activity 2 GO:0016740 transferase activity 1 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 2 R-HSA-162582 Signal Transduction 1 R-HSA-4839726 Chromatin organization 1
Partners
BDP1GTF3C1GTF3C2GTF3C5GTF3C6POLR3EPOLR3G
Complex memberships
TFIIICTFIIIC2

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 hTFIIIC90 (GTF3C4) was cloned and shown to be a bona fide subunit of the TFIIIC2 DNA-binding subcomplex of human TFIIIC, required absolutely for RNA polymerase III transcription. Immunodepletion and immunoprecipitation studies demonstrated that hTFIIIC90 physically interacts with the TFIIIC subunits hTFIIIC220, hTFIIIC110, and hTFIIIC63, the TFIIIB subunit hTFIIIB90, and the RNA polymerase III subunits hRPC39 and hRPC62, suggesting it bridges TFIIIB and Pol III recruitment to the preinitiation complex. cDNA cloning, immunodepletion, immunoprecipitation, in vitro RNA polymerase III transcription assay Molecular and cellular biology High 10523658
1999 hTFIIIC90 (GTF3C4) possesses an intrinsic histone acetyltransferase (HAT) activity with substrate specificity for histone H3, as demonstrated by in vitro HAT assays. In vitro histone acetyltransferase assay Molecular and cellular biology High 10523658
2007 TFIIIC35, the sixth subunit of human TFIIIC, specifically interacts with hTFIIIC90 (GTF3C4) in vitro, and affinity-purified TFIIIC containing epitope-tagged TFIIIC35 (which includes GTF3C4) is active in binding to and transcribing the VA1 gene in vitro, confirming GTF3C4's presence and function in the intact TFIIIC complex. In vitro binding assay (GST pulldown), affinity purification of epitope-tagged TFIIIC, in vitro transcription assay The Journal of biological chemistry Medium 17409385
2020 siRNA-mediated knockdown of GTF3C4 induces cellular senescence markers, including decreased cell number, activation of p16/p21, and morphological changes resembling senescence, placing GTF3C4 as a regulator whose loss triggers senescence. siRNA knockdown with readouts of cell number, p16/p21 activation, and cellular morphology Genome biology Medium 32264951
2026 GTF3C4 was identified as the direct molecular target of the anti-cancer compound bufalin using Limited Proteolysis-Mass Spectrometry. Direct binding of bufalin to GTF3C4 was validated by cell thermal shift assay, drug affinity response target stability (DARTS) assay, and surface plasmon resonance. GTF3C4 knockdown suppresses the PI3K/AKT signaling pathway and inhibits breast cancer cell proliferation while promoting apoptosis, placing GTF3C4 upstream of PI3K/AKT in breast cancer cells. Limited proteolysis-mass spectrometry (LiP-MS), cell thermal shift assay (CETSA), DARTS assay, surface plasmon resonance, siRNA knockdown with PI3K/AKT pathway readouts and proliferation/apoptosis assays Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 41649141

Source papers

Stage 0 corpus · 37 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
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
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
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
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
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2013 Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions. Science signaling 383 24255178
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
2020 A multidimensional systems biology analysis of cellular senescence in aging and disease. Genome biology 303 32264951
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2011 A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 269 21654808
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
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
2020 Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer. Molecular cell 159 32416067
2018 MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis. Molecular cell 152 30415952
2011 Maintenance of silent chromatin through replication requires SWI/SNF-like chromatin remodeler SMARCAD1. Molecular cell 148 21549307
2014 The central role of EED in the orchestration of polycomb group complexes. Nature communications 131 24457600
2013 A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity. PLoS genetics 131 23349634
2007 Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach. Cell cycle (Georgetown, Tex.) 127 17314511
1999 The TFIIIC90 subunit of TFIIIC interacts with multiple components of the RNA polymerase III machinery and contains a histone-specific acetyltransferase activity. Molecular and cellular biology 86 10523658
2007 Identification, molecular cloning, and characterization of the sixth subunit of human transcription factor TFIIIC. The Journal of biological chemistry 35 17409385
2024 NS1-mediated enhancement of MVC transcription and replication promoted by KAT5/H4K12ac. Journal of virology 8 38349085
2022 Overdominant expression of related genes of ion homeostasis improves K+ content advantage in hybrid tobacco leaves. BMC plant biology 7 35820807
2024 CRISPR-Cas9 screening develops an epigenetic and transcriptional gene signature for risk stratification and target prediction in neuroblastoma. Frontiers in cell and developmental biology 2 39175876
2026 Bufalin Inhibits the PI3K/AKT Pathway by Targeting GTF3C4 to Impede Breast Cancer Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41649141