Affinage

GTF3C5

General transcription factor 3C polypeptide 5 · UniProt Q9Y5Q8

Round 2 corrected
Length
519 aa
Mass
59.6 kDa
Annotated
2026-04-28
44 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GTF3C5 (TFIIIC63) is a core subunit of the TFIIIC2 DNA-binding subcomplex of human TFIIIC, where it directly contacts TFIIIC102, TFIIIC35, TFIIIB90, and the RNA polymerase III subunit RPC62, thereby coupling promoter recognition at class III genes to recruitment of both TFIIIB and Pol III (PMID:10373544, PMID:17409385). Beyond its canonical role in Pol III transcription, GTF3C5 controls nuclear architecture in neurons by tethering activity-dependent genes away from transcription factories in the resting state; its depletion causes spontaneous gene relocation, ectopic transcription, and exuberant dendritic growth (PMID:23966877). Biallelic loss-of-function variants in GTF3C5 cause a multisystem developmental disorder in humans, with patient cells showing reduced TFIIIC63 protein, diminished genome-wide TFIIIC chromatin occupancy, and partial loss of Pol III binding, and gtf3c5-null zebrafish recapitulate the developmental phenotype (PMID:38520561).

Mechanistic history

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

    Cloning of hTFIIIC63 established that a single TFIIIC2 subunit bridges promoter recognition (via TFIIIC102) and Pol III machinery recruitment (via TFIIIB90 and RPC62), answering how the TFIIIC DNA-binding subcomplex couples A-box recognition to transcription initiation.

    Evidence cDNA cloning, GST pulldown, co-immunoprecipitation, and TPR-repeat mutagenesis in human cells

    PMID:10373544

    Open questions at the time
    • No structural information on TFIIIC63 or its binding interfaces
    • In vivo relevance of each interaction not tested by loss-of-function
    • Whether TFIIIC63 contributes to promoter selectivity beyond A-box genes was unknown
  2. 2002 Medium

    Detection of a GTF3C5 ortholog at nuclear pore complexes in a light mRNA-associated complex raised the possibility of a post-transcriptional function, expanding the protein's known localization beyond transcription sites.

    Evidence Immuno-electron microscopy, gel filtration, and co-immunoprecipitation in Chironomus tentans

    PMID:12006668

    Open questions at the time
    • Observation restricted to a dipteran ortholog; not confirmed for human GTF3C5
    • Functional significance of the nuclear-pore association was not demonstrated
    • Whether this reflects moonlighting or transit of TFIIIC during assembly is unclear
  3. 2007 High

    Identification of TFIIIC35 as a direct binding partner of GTF3C5 completed the subunit-interaction map of human TFIIIC and confirmed that GTF3C5 resides in a transcriptionally active holocomplex.

    Evidence GST pulldown, affinity purification from epitope-tagged cell line, in vitro transcription of the VA1 gene

    PMID:17409385

    Open questions at the time
    • Stoichiometry and structural arrangement of the TFIIIC holocomplex remain unresolved
    • Whether TFIIIC35–GTF3C5 interaction is required for all Pol III gene classes was untested
  4. 2013 High

    Loss-of-function experiments in neurons revealed that GTF3C5 constrains nuclear architecture by preventing activity-dependent genes from entering transcription factories in the resting state, establishing a non-canonical, Pol III-independent role in gene regulation and neuronal morphology.

    Evidence shRNA knockdown in cortical neurons, ChIP-seq, gene relocation assays, dendritic morphology analysis

    PMID:23966877

    Open questions at the time
    • Mechanism by which GTF3C5/TFIIIC tethers Pol II genes to non-factory sites is unknown
    • Whether the dendritic growth phenotype is direct or secondary to ectopic transcription was not resolved
    • Relevance of this architectural role outside neurons not tested
  5. 2024 High

    Discovery that biallelic GTF3C5 variants cause a human developmental disorder proved the gene is essential for embryonic development and showed that partial TFIIIC63 loss leads to genome-wide reduction in both TFIIIC and Pol III chromatin occupancy.

    Evidence Patient lymphoblastoid cell lines (western blot, ChIP-seq for TFIIIC63 and Pol III), yeast complementation with patient variants, zebrafish gtf3c5 knockout

    PMID:38520561

    Open questions at the time
    • Which specific Pol III target genes drive the developmental phenotype is unknown
    • Whether the nuclear-architecture role contributes to the human disease phenotype has not been examined
    • No therapeutic or rescue strategy has been tested in patient-derived cells

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how GTF3C5 mechanistically distinguishes its canonical Pol III transcription role from its architectural role at Pol II gene loci, and whether these functions are separable or jointly disrupted in disease.
  • No separation-of-function mutants exist for architectural versus transcriptional roles
  • No high-resolution structure of TFIIIC63 or its interaction interfaces has been reported
  • Tissue-specific requirements for GTF3C5 beyond neurons and early development are uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0140223 general transcription initiation factor activity 2
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1643685 Disease 1 R-HSA-4839726 Chromatin organization 1
Partners
BDP1DNMT3LGTF3C2GTF3C6POLR3F
Complex memberships
TFIIICTFIIIC2 subcomplex

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 hTFIIIC63 (GTF3C5) was cloned and characterized as a subunit of the TFIIIC2 DNA-binding subcomplex of human TFIIIC. In vitro binding assays and mutagenesis showed that hTFIIIC63 interacts with hTFIIIC102 (via TPR repeats of TFIIIC102), with hTFIIIB90, and with hRPC62, facilitating recruitment of both TFIIIB and RNA polymerase III to class III gene promoters. These interactions parallel those of its yeast ortholog yTFIIIC95. cDNA cloning, in vitro binding assays (GST pulldown, co-immunoprecipitation), mutagenesis of TPR repeats Molecular and cellular biology High 10373544
2002 A TFIIICalpha-like protein (p2D10) in Chironomus tentans (ortholog of GTF3C5/TFIIICalpha) was found not only at transcription sites but also at nuclear pore complexes and in the nucleoplasm. Gel filtration and co-immunoprecipitation identified a light p2D10-containing complex that includes RNA and the mRNA trafficking proteins RAE1 and hrp65, suggesting a posttranscriptional/mRNA trafficking role in addition to its transcription function. Immunoelectron microscopy, gel filtration chromatography, co-immunoprecipitation Molecular biology of the cell Medium 12006668
2007 TFIIIC35 (the sixth subunit of human TFIIIC) specifically interacts with GTF3C5 (TFIIIC63) and, to a lesser extent, with TFIIIC90 in vitro. Affinity-purified TFIIIC from an epitope-tagged TFIIIC35 cell line was active in DNA binding and in transcription of the VA1 gene in vitro, confirming GTF3C5 is part of the active TFIIIC holocomplex. In vitro binding assays (GST pulldown), affinity purification, in vitro transcription assay The Journal of biological chemistry High 17409385
2013 Silencing of Gtf3c5 (the TFIIIC63 subunit) in non-stimulated cortical neurons induced uncontrolled relocation of activity-dependent genes to transcription factories and their transcription without stimulation, mimicking the effect of chronic depolarization. Gtf3c5 knockdown also dramatically increased dendritic length and branching. This demonstrates that GTF3C5/TFIIIC controls nuclear architecture by tethering activity-dependent genes away from transcription factories in resting neurons. shRNA knockdown, genome-wide ChIP-seq, fluorescence microscopy (gene relocation assay), neuronal morphology analysis PLoS genetics High 23966877
2014 GTF3C5 protein was identified as a direct interactor of DNMT3L (DNA methyltransferase 3-like) using transcription factor protein arrays. Notably, GTF3C5 interacted with DNMT3L but not with DNMT3A or DNMT3B, suggesting it may help recruit DNMT3L/DNMT3B complexes to specific genomic loci for targeted de novo DNA methylation. Transcription factor protein array, interaction specificity confirmed by differential binding to DNMT3A/B vs DNMT3L Biochimie Low 24952347
2024 Biallelic loss-of-function variants in GTF3C5 cause a multisystem developmental disorder in humans. Lymphoblastoid cell lines from affected individuals showed reduced TFIIIC63 protein levels, reduced genome-wide TFIIIC63 chromatin binding, and partial reduction (~40%) of RNA polymerase III occupancy at Pol III target sites. Yeast with subject-specific variants showed temperature sensitivity and impaired growth. gtf3c5 mutant zebrafish exhibited a smaller body, head, and eyes, demonstrating an essential developmental role. Patient-derived lymphoblastoid cell lines, western blotting, ChIP-seq (TFIIIC63 and Pol III), yeast complementation/temperature sensitivity assay, zebrafish knockout morphology Human genetics High 38520561

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
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
2020 A reference map of the human binary protein interactome. Nature 849 32296183
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
2010 An atlas of combinatorial transcriptional regulation in mouse and man. Cell 573 20211142
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
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
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
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
2007 Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Molecular cell 367 17643375
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2018 K63 ubiquitylation triggers proteasomal degradation by seeding branched ubiquitin chains. Proceedings of the National Academy of Sciences of the United States of America 227 29378950
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
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
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
2020 Interactome analysis reveals that lncRNA HULC promotes aerobic glycolysis through LDHA and PKM2. Nature communications 167 32572027
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2013 Binding of TFIIIC to sine elements controls the relocation of activity-dependent neuronal genes to transcription factories. PLoS genetics 64 23966877
1999 Cloning and characterization of two evolutionarily conserved subunits (TFIIIC102 and TFIIIC63) of human TFIIIC and their involvement in functional interactions with TFIIIB and RNA polymerase III. Molecular and cellular biology 60 10373544
2019 Machine Learning Classifiers for Endometriosis Using Transcriptomics and Methylomics Data. Frontiers in genetics 37 31552087
2007 Identification, molecular cloning, and characterization of the sixth subunit of human transcription factor TFIIIC. The Journal of biological chemistry 35 17409385
2014 DNMT3L interacts with transcription factors to target DNMT3L/DNMT3B to specific DNA sequences: role of the DNMT3L/DNMT3B/p65-NFκB complex in the (de-)methylation of TRAF1. Biochimie 30 24952347
2020 Genome-wide meta-analysis associates GPSM1 with type 2 diabetes, a plausible gene involved in skeletal muscle function. Journal of human genetics 9 31959871
2022 Whole-exome sequencing identifies novel protein-altering variants associated with serum apolipoprotein and lipid concentrations. Genome medicine 8 36419110
2022 Network Meta-Analysis of Chicken Microarray Data following Avian Influenza Challenge-A Comparison of Highly and Lowly Pathogenic Strains. Genes 6 35327988
2002 Evidence for a posttranscriptional role of a TFIIICalpha-like protein in Chironomus tentans. Molecular biology of the cell 5 12006668
2022 Monogenic causes of pigmentary mosaicism. Human genetics 3 35503477
2025 Genome-wide analysis defines genetic determinants of MPN subtypes and identifies a sex-specific association at CDH22/CD40. Blood 2 41026930
2024 Biallelic variants in GTF3C5, a regulator of RNA polymerase III-mediated transcription, cause a multisystem developmental disorder. Human genetics 2 38520561
2023 Exploring lncRNAs associated with human pancreatic islet cell death induced by transfer of adoptive lymphocytes in a humanized mouse model. Frontiers in endocrinology 1 38027148
2026 African-specific genetic loci determine iron status and risk of severe malaria and bacteremia in African children. Nature communications 0 41946712