Affinage

GTF2H5

General transcription factor IIH subunit 5 · UniProt Q6ZYL4

Length
71 aa
Mass
8.1 kDa
Annotated
2026-06-10
26 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GTF2H5 (TTDA/p8/TFB5) encodes the smallest, tenth subunit of the TFIIH complex and functions principally as an architectural stabilizer required for nucleotide excision repair (NER) across yeast, Drosophila, C. elegans, and mammals (PMID:15220919, PMID:17215295, PMID:34824371). Rather than carrying intrinsic enzymatic activity, it lacks DNA-binding capacity and confers structural rigidity to the TFIIH core through a direct interaction with the p52/Tfb2 subunit, whose structural basis was resolved at high resolution (PMID:17215295, PMID:20606254). GTF2H5 transitions from a free homodimer to a heterodimeric state upon binding p52, and this incorporation maintains intracellular TFIIH concentration; loss or destabilization of GTF2H5 reduces total TFIIH levels and preferentially compromises repair function (PMID:11062469, PMID:30068551). Within NER, GTF2H5 stimulates the ATPase activity of XPB together with the damage-recognition factor XPC-hHR23B to open damaged DNA, an event required for downstream XPA recruitment (PMID:16427011). In living cells it partitions between a TFIIH-bound pool and a free shuttling fraction, with NER-specific lesions driving stable association with TFIIH, marking GTF2H5 as a subunit with a dedicated repair role that is largely dispensable for basal transcription under normal conditions (PMID:16669699, PMID:34824371). Complete disruption causes embryonic lethality and abolishes NER, including repair of oxidative damage, whereas the hypomorphic mutations found in trichothiodystrophy patients only partially inactivate the protein (PMID:23637614).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2000 Medium

    Established that patient TTD-A defects act by destabilizing TFIIH rather than disabling its catalytic core, reframing the disease as one of complex abundance.

    Evidence Immunoblot and immunofluorescence of TFIIH levels in patient-derived TTD-A cells

    PMID:11062469

    Open questions at the time
    • Did not identify the subunit/gene responsible
    • Mechanism of how reduced TFIIH preferentially impairs repair not resolved
  2. 2004 High

    Identified TFB5/GTF2H5 as a bona fide core TFIIH subunit, answering whether the protein is a stable component and linking it to both transcription and UV resistance.

    Evidence SILAC proteomics, ChIP, in vitro transcription and UV sensitivity assays in yeast

    PMID:15220919

    Open questions at the time
    • Did not define the molecular partner within TFIIH
    • Relative contribution to transcription vs repair unresolved
  3. 2006 High

    Defined the enzymatic contribution of GTF2H5 to NER and showed it is dedicated to repair, demonstrating it stimulates XPB ATPase to open DNA for XPA recruitment while being dispensable for RNA synthesis.

    Evidence In vitro ATPase stimulation assay, XPA recruitment imaging, complementation in TTD-XPD cells; live-cell FRAP of GFP-TTDA

    PMID:16427011 PMID:16669699

    Open questions at the time
    • Structural basis of XPB stimulation not resolved
    • How free vs bound pools are regulated upon damage unclear
  4. 2007 Medium

    Localized the interaction to the Tfb2/p52 subunit and showed GTF2H5 acts as an architectural stabilizer lacking DNA binding, while dissecting its differential roles in GG-NER versus TC-NER.

    Evidence Cell-free NER reconstitution with purified Tfb5, interaction mapping, and strand-specific repair assays in yeast deletion mutants

    PMID:17215295 PMID:17644494

    Open questions at the time
    • Atomic detail of the Tfb5-Tfb2 contact not yet resolved
    • Mechanistic basis for partial TC-NER dispensability unclear
  5. 2008 High

    Confirmed in an intact metazoan that GTF2H5 acts through p52 and XPD and that boosting its levels restores TFIIH and enhances repair, validating its stabilizing role genetically.

    Evidence Drosophila transgenic overexpression, genetic suppression of p52/XPB alleles, and CPD/6-4PP repair measurement

    PMID:19008953

    Open questions at the time
    • Did not establish stoichiometry of stabilization
    • Direct biochemical interaction with XPD not shown
  6. 2010 High

    Provided the structural basis of the GTF2H5-p52 interaction at atomic resolution, explaining how the smallest subunit docks onto the TFIIH core.

    Evidence X-ray crystallography of the yeast Tfb5-Tfb2C complex at 1.7 Å

    PMID:20606254

    Open questions at the time
    • Structure of full TFIIH-incorporated subunit absent
    • Conformational changes upon incorporation not captured
  7. 2013 High

    Demonstrated in living cells that the p52-GTF2H5 subcomplex is the incorporation unit for TFIIH and that patient mutations retain p52 binding, DNA localization, and UV recruitment, sharpening why patient alleles are hypomorphic.

    Evidence Tripartite split-GFP interaction assay and UV-damage recruitment imaging; Ttda knockout mouse with NER and oxidant sensitivity assays

    PMID:23637614 PMID:23729738

    Open questions at the time
    • Molecular defect distinguishing null from patient phenotypes not fully defined
    • Mechanism of the oxidative-damage repair role unresolved
  8. 2018 Medium

    Resolved the oligomeric switch underlying stabilization, showing free GTF2H5 is a homodimer that becomes a heterodimer on binding p52, and that disrupting this interface lowers TFIIH and transcription to TTD-A-like levels.

    Evidence Molecular dynamics, fragment-based drug screening, biophysical binding, and quantitative live-cell TFIIH imaging

    PMID:30068551

    Open questions at the time
    • In vivo relevance of the homodimer not established
    • Functional state of the homodimeric pool unclear
  9. 2021 High

    Confirmed across an additional metazoan that GTF2H5 promotes TFIIH stability tissue-wide and is essential for NER, while being uniquely compatible with life unless transcription is challenged, distinguishing it from other TFIIH subunits.

    Evidence C. elegans knockout with NER assays, TFIIH stability measurement, and transcriptional stress experiments

    PMID:34824371

    Open questions at the time
    • Molecular basis of conditional transcriptional requirement not defined
    • Tissue-specific differences in TFIIH fragility unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether GTF2H5 has TFIIH-independent functions, such as direct transcriptional regulation of target genes, remains unresolved.
  • The reported p53-promoter regulatory role in glioma is a single low-confidence study without pathway reconstitution
  • No mechanism linking TFIIH stabilization to direct promoter binding established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-74160 Gene expression (Transcription) 2
Partners
GTF2H4XPBXPD
Complex memberships
TFIIH

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 TFB5/GTF2H5 (yeast YDR079c-a) is a bona fide core component of TFIIH, required for efficient recruitment of TFIIH to promoters in vitro and in vivo, and is required for efficient transcription in vitro and normal induction of GAL genes. Yeast lacking TFB5 grow slowly and are sensitive to UV radiation, phenocopying mutations in core TFIIH subunits. Quantitative proteomics (SILAC), chromatin immunoprecipitation (ChIP), in vitro transcription assay, UV sensitivity assay, genetic analysis Nature genetics High 15220919
2000 TTD-A cells (carrying mutations in the GTF2H5 locus) contain a strong reduction in total TFIIH concentration despite having TFIIH that is active in both transcription and repair, indicating GTF2H5 mutations cause instability of the TFIIH complex rather than direct enzymatic defects. The reduction of TFIIH mainly affects repair function. Immunoblot and immunofluorescence analysis of TFIIH levels in patient-derived TTD-A cells Nature genetics Medium 11062469
2006 p8/GTF2H5 (the tenth subunit of TFIIH) plays a critical role in DNA repair by stimulating XPB ATPase activity together with the damage recognition factor XPC-hHR23B to trigger DNA opening; this opening is required for recruitment of XPA to the damage site. p8 is dispensable for RNA synthesis and does not interfere with the transcriptional function of CAK, although both p8 and CAK interact with XPD. p8 overexpression in TTD-XPD cells counteracts detrimental XPD mutations by restoring cellular TFIIH concentration. Fluorescent antibody labeling, ATPase stimulation assay, XPA recruitment assay, overexpression complementation in TTD-XPD cells Molecular cell High 16427011
2006 In living cells, TTDA/GTF2H5 exists in two kinetic pools: one fraction stably bound to TFIIH, and a free fraction that shuttles between cytoplasm and nucleus. Upon induction of NER-specific DNA lesions, the equilibrium shifts dramatically toward stable association of TTDA with TFIIH, while modulation of transcriptional activity does not shift this equilibrium, identifying TTDA as the first TFIIH subunit with a primarily NER-dedicated role in vivo. Fluorescence microscopy (live-cell imaging of GFP-tagged TTDA), FRAP, fluorescence recovery kinetics in cells treated with UV and transcription inhibitors PLoS biology High 16669699
2007 Yeast Tfb5/GTF2H5 directly participates in NER and interacts with the core TFIIH subunit Tfb2 (but not other NER proteins); this Tfb5-Tfb2 interaction correlates with cellular NER function. Tfb5 lacks intrinsic DNA binding activity and acts as an architectural stabilizer conferring structural rigidity to the core TFIIH complex. Cell-free NER assay with purified Tfb5, protein-protein interaction assay, UV survival assay, tfb5 deletion mutant analysis Nucleic acids research High 17215295
2007 Yeast Tfb5/GTF2H5 is essential for global genomic NER (GG-NER) but partially dispensable for Rad26-mediated transcription-coupled NER (TC-NER), especially in GG-NER deficient cells. Tfb5 is required for Rpb9-mediated TC-NER. Strand-specific NER analysis using repair assays in yeast deletion mutants (tfb5, rad26, rpb9, rad7 combinations) DNA repair Medium 17644494
2008 p8/TTDA/GTF2H5 overexpression in Drosophila suppresses lethality, developmental defects, and sterility caused by mutations in the p52 (Dmp52) TFIIH subunit, and restores TFIIH levels. Overexpression of p8 also suppresses a lethal allele of the Drosophila XPB homolog. Transgenic flies overexpressing p8 show enhanced repair of UV-induced cyclobutane pyrimidine dimers and 6-4 photoproducts. The genetic interaction demonstrates p8 interacts with p52 and XPD within TFIIH. Drosophila transgenic overexpression, genetic suppression assay, UV survival assay, DNA repair efficiency measurement (CPD/6-4PP levels) PLoS genetics High 19008953
2010 Crystal structure of the minimal complex between yeast Tfb5 (GTF2H5 ortholog) and the C-terminal region of Tfb2 was determined at 1.7 Å resolution, revealing the structural basis of the Tfb5-Tfb2 interaction within TFIIH core. X-ray crystallography of Tfb5-Tfb2C complex Acta crystallographica. Section D, Biological crystallography High 20606254
2013 TTDA/GTF2H5 interacts directly with TFIIH subunit p52 in living cells, and the p52-TTDA complex is incorporated into TFIIH. Both wild-type and TTD-A patient-mutated TTDA proteins interact with p52, bind DNA, and localize to UV-damaged DNA. Tripartite split-GFP system in living cells, fluorescence microscopy, UV damage recruitment assay Journal of cell science Medium 23729738
2013 Full disruption of TTDA/GTF2H5 in a mouse knock-out model causes embryonic lethality and complete NER deficiency in cells, whereas TTD-A patient mutations only partially inactivate TTDA function. TTDA-null cells are also highly sensitive to oxidizing agents, revealing a role in oxidative DNA damage repair. Ttda knock-out mouse generation, NER assay in mouse embryonic fibroblasts, UV and oxidant sensitivity assays, genetic comparison of null vs patient-mutant cells PLoS genetics High 23637614
2018 TTD-A/p8/GTF2H5 exists in a homodimeric state when free and shifts to a heterodimeric structure when binding to TFIIH partner (p52). Small molecules that bind to the p8 dimerization interface destabilize p8, reduce intracellular TFIIH concentration, and decrease basal transcriptional activity in mouse cells to levels similar to those in TTD-A individuals. Molecular dynamics simulation, fragment-based drug screening (>3000 compounds), biophysical binding assays, quantitative live-cell TFIIH imaging The Journal of biological chemistry Medium 30068551
2021 In C. elegans, GTF-2H5 (TTDA ortholog) promotes TFIIH stability in multiple tissues and is indispensable for NER, facilitating recruitment of TFIIH to DNA damage. Unlike depletion of other TFIIH subunits, GTF-2H5 deficiency is compatible with life under normal conditions, but when transcription is challenged, gtf-2h5 embryos die due to intrinsic TFIIH fragility. C. elegans knockout analysis, NER assay, TFIIH stability measurement, transcriptional stress experiments, tissue-specific imaging Communications biology High 34824371
2020 TTDA/GTF2H5 overexpression in glioma cells inhibits apoptosis and promotes cell growth, while knockdown has the opposite effect. TTDA interacts with the p53 gene promoter at the -1959 bp and -1530 bp regions, regulating p53 transcription and thereby inhibiting the p53-Bax/Bcl2 mitochondrial apoptosis pathway. Overexpression and shRNA knockdown in glioma cell lines, apoptosis assays, Bax/Bcl2/caspase-3 western blot, ChIP or promoter binding assay for p53 promoter interaction Experimental neurology Low 32540359

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Identification of TFB5, a new component of general transcription and DNA repair factor IIH. Nature genetics 129 15220919
2000 Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD-A trichothiodystrophy disorder. Nature genetics 107 11062469
2006 p8/TTD-A as a repair-specific TFIIH subunit. Molecular cell 90 16427011
2006 Dynamic interaction of TTDA with TFIIH is stabilized by nucleotide excision repair in living cells. PLoS biology 74 16669699
2013 Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality. PLoS genetics 33 23637614
1993 Identification of the L-tartrate dehydratase genes (ttdA and ttdB) of Escherichia coli and evolutionary relationship with the class I fumarase genes. Journal of general microbiology 30 8371115
2015 The NER-related gene GTF2H5 predicts survival in high-grade serous ovarian cancer patients. Journal of gynecologic oncology 28 26463438
2020 TTDA inhibited apoptosis by regulating the p53-Bax/Bcl2 axis in glioma. Experimental neurology 25 32540359
2008 p8/TTDA overexpression enhances UV-irradiation resistance and suppresses TFIIH mutations in a Drosophila trichothiodystrophy model. PLoS genetics 25 19008953
2014 TTDA: big impact of a small protein. Experimental cell research 23 25016283
2020 The basal transcription factor II H subunit Tfb5 is required for stress response and pathogenicity in the tangerine pathotype of Alternaria alternata. Molecular plant pathology 21 32776683
2006 Functional identification of ygiP as a positive regulator of the ttdA-ttdB-ygjE operon. Microbiology (Reading, England) 19 16804186
2013 In vivo interactions of TTDA mutant proteins within TFIIH. Journal of cell science 16 23729738
2007 Tfb5 interacts with Tfb2 and facilitates nucleotide excision repair in yeast. Nucleic acids research 16 17215295
2007 Synthesis, complexation and water exchange properties of Gd(III)-TTDA-mono and bis(amide) derivatives and their binding affinity to human serum albumin. Dalton transactions (Cambridge, England : 2003) 16 17592591
2014 Trichothiodystrophy group A: a first Japanese patient with a novel homozygous nonsense mutation in the GTF2H5 gene. The Journal of dermatology 11 24986372
2010 In vivo MR/optical imaging for gastrin releasing peptide receptor of prostate cancer tumor using Gd-TTDA-NP-BN-Cy5.5. Bioorganic & medicinal chemistry 11 20493715
2018 Small molecule-based targeting of TTD-A dimerization to control TFIIH transcriptional activity represents a potential strategy for anticancer therapy. The Journal of biological chemistry 10 30068551
2021 C. elegans TFIIH subunit GTF-2H5/TTDA is a non-essential transcription factor indispensable for DNA repair. Communications biology 9 34824371
2018 A case of severe trichothiodystrophy 3 in a neonate due to mutation in the GTF2H5 gene: Clinical report. European journal of medical genetics 6 30359777
2007 Tfb5 is partially dispensable for Rad26 mediated transcription coupled nucleotide excision repair in yeast. DNA repair 5 17644494
2010 Structure determination of the minimal complex between Tfb5 and Tfb2, two subunits of the yeast transcription/DNA-repair factor TFIIH: a retrospective study. Acta crystallographica. Section D, Biological crystallography 3 20606254
2024 GTF2H5 Identified as a crucial synthetic lethal target to counteract chemoresistance in colorectal cancer. Translational oncology 2 39173480
2023 Severe trichothiodystrophy and cardiac malformation in a newborn carrying a novel GTF2H5 homozygous truncating variant. Clinical genetics 2 37356817
2025 Trichothiodystrophy type 3 with a mutation in the GTF2H5 gene: A case report in Argentina. Archivos argentinos de pediatria 1 40168358
2026 Comparative roles of four TFIIH subunits (Tfb1, Tfb2, Tfb4 and Tfb5) in anti-UV and insecticidal processes of Beauveria bassiana. Pesticide biochemistry and physiology 0 41629034

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