{"gene":"GTF2H5","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2004,"finding":"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.","method":"Quantitative proteomics (SILAC), chromatin immunoprecipitation (ChIP), in vitro transcription assay, UV sensitivity assay, genetic analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (quantitative proteomics, ChIP, in vitro transcription), identification replicated with functional validation in yeast model","pmids":["15220919"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Immunoblot and immunofluorescence analysis of TFIIH levels in patient-derived TTD-A cells","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (immunoblot, immunofluorescence) in patient cells, single lab","pmids":["11062469"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Fluorescent antibody labeling, ATPase stimulation assay, XPA recruitment assay, overexpression complementation in TTD-XPD cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vitro ATPase assay, fluorescence imaging, genetic complementation) in a single rigorous study","pmids":["16427011"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Fluorescence microscopy (live-cell imaging of GFP-tagged TTDA), FRAP, fluorescence recovery kinetics in cells treated with UV and transcription inhibitors","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell FRAP with biologically active tagged protein, multiple conditions tested, clear mechanistic conclusion","pmids":["16669699"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Cell-free NER assay with purified Tfb5, protein-protein interaction assay, UV survival assay, tfb5 deletion mutant analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro NER reconstitution with purified protein complementation, protein interaction mapping, and genetic analysis in a single study","pmids":["17215295"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Strand-specific NER analysis using repair assays in yeast deletion mutants (tfb5, rad26, rpb9, rad7 combinations)","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis using multiple double and triple mutants, strand-specific repair assays, single lab","pmids":["17644494"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Drosophila transgenic overexpression, genetic suppression assay, UV survival assay, DNA repair efficiency measurement (CPD/6-4PP levels)","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in intact multicellular organism with multiple alleles tested, functional repair assay, TFIIH level measurement","pmids":["19008953"],"is_preprint":false},{"year":2010,"finding":"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.","method":"X-ray crystallography of Tfb5-Tfb2C complex","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure at 1.7 Å resolution, two crystal forms solved, single lab","pmids":["20606254"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Tripartite split-GFP system in living cells, fluorescence microscopy, UV damage recruitment assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel in vivo split-GFP interaction assay plus UV recruitment imaging, single lab, single study","pmids":["23729738"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Ttda knock-out mouse generation, NER assay in mouse embryonic fibroblasts, UV and oxidant sensitivity assays, genetic comparison of null vs patient-mutant cells","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse model with multiple phenotypic assays (NER, oxidant sensitivity, embryonic viability), clear mechanistic conclusion distinguishing null from hypomorphic patient mutations","pmids":["23637614"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Molecular dynamics simulation, fragment-based drug screening (>3000 compounds), biophysical binding assays, quantitative live-cell TFIIH imaging","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biophysical methods and live-cell imaging, single lab, novel mechanistic finding about dimerization","pmids":["30068551"],"is_preprint":false},{"year":2021,"finding":"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.","method":"C. elegans knockout analysis, NER assay, TFIIH stability measurement, transcriptional stress experiments, tissue-specific imaging","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout in metazoan model, multiple assays (NER, TFIIH stability, transcriptional challenge), cross-species validation of mammalian findings","pmids":["34824371"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"Experimental neurology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, cancer cell line context with unclear direct mechanistic validation; p53 promoter binding method not clearly specified in abstract, functional consequence without pathway reconstitution","pmids":["32540359"],"is_preprint":false}],"current_model":"GTF2H5 (TTDA/p8/TFB5) encodes the smallest (8 kDa, 71 amino acid) tenth subunit of the TFIIH transcription/repair complex, which stabilizes overall TFIIH architecture by shifting from a free homodimer to a heterodimer with the p52 subunit upon TFIIH incorporation; in NER it stimulates XPB ATPase activity (together with XPC-hHR23B) to open damaged DNA and enable XPA recruitment, is recruited to UV damage sites via a NER-specific dynamic interaction with TFIIH, and is essential for both global genomic and transcription-coupled NER in multiple organisms, while being dispensable for basal transcription under normal conditions."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2000,"claim":"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","pmids":["11062469"],"confidence":"Medium","gaps":["Did not identify the subunit/gene responsible","Mechanism of how reduced TFIIH preferentially impairs repair not resolved"]},{"year":2004,"claim":"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","pmids":["15220919"],"confidence":"High","gaps":["Did not define the molecular partner within TFIIH","Relative contribution to transcription vs repair unresolved"]},{"year":2006,"claim":"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","pmids":["16427011","16669699"],"confidence":"High","gaps":["Structural basis of XPB stimulation not resolved","How free vs bound pools are regulated upon damage unclear"]},{"year":2007,"claim":"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","pmids":["17215295","17644494"],"confidence":"Medium","gaps":["Atomic detail of the Tfb5-Tfb2 contact not yet resolved","Mechanistic basis for partial TC-NER dispensability unclear"]},{"year":2008,"claim":"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","pmids":["19008953"],"confidence":"High","gaps":["Did not establish stoichiometry of stabilization","Direct biochemical interaction with XPD not shown"]},{"year":2010,"claim":"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","pmids":["20606254"],"confidence":"High","gaps":["Structure of full TFIIH-incorporated subunit absent","Conformational changes upon incorporation not captured"]},{"year":2013,"claim":"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","pmids":["23729738","23637614"],"confidence":"High","gaps":["Molecular defect distinguishing null from patient phenotypes not fully defined","Mechanism of the oxidative-damage repair role unresolved"]},{"year":2018,"claim":"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","pmids":["30068551"],"confidence":"Medium","gaps":["In vivo relevance of the homodimer not established","Functional state of the homodimeric pool unclear"]},{"year":2021,"claim":"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","pmids":["34824371"],"confidence":"High","gaps":["Molecular basis of conditional transcriptional requirement not defined","Tissue-specific differences in TFIIH fragility unexplained"]},{"year":null,"claim":"Whether GTF2H5 has TFIIH-independent functions, such as direct transcriptional regulation of target genes, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,4,10]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,4,9,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,10]}],"complexes":["TFIIH"],"partners":["GTF2H4","XPB","XPD"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6ZYL4","full_name":"General transcription factor IIH subunit 5","aliases":["General transcription factor IIH polypeptide 5","TFB5 ortholog","TFIIH basal transcription factor complex TTD-A subunit","TFIIH subunit p8"],"length_aa":71,"mass_kda":8.1,"function":"Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. Necessary for the stability of the TFIIH complex and for the presence of normal levels of TFIIH in the cell","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q6ZYL4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GTF2H5","classification":"Not Classified","n_dependent_lines":75,"n_total_lines":1208,"dependency_fraction":0.062086092715231786},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDC7","stoichiometry":10.0},{"gene":"CDK7","stoichiometry":10.0},{"gene":"CETN2","stoichiometry":0.2},{"gene":"TJP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GTF2H5","total_profiled":1310},"omim":[{"mim_id":"616395","title":"TRICHOTHIODYSTROPHY 3, PHOTOSENSITIVE; TTD3","url":"https://www.omim.org/entry/616395"},{"mim_id":"608780","title":"GENERAL TRANSCRIPTION FACTOR IIH, POLYPEPTIDE 5; GTF2H5","url":"https://www.omim.org/entry/608780"},{"mim_id":"601760","title":"GENERAL TRANSCRIPTION FACTOR IIH, POLYPEPTIDE 4; GTF2H4","url":"https://www.omim.org/entry/601760"},{"mim_id":"601675","title":"TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE; TTD1","url":"https://www.omim.org/entry/601675"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GTF2H5"},"hgnc":{"alias_symbol":["FLJ30544","bA120J8.2","TTD-A","TFB5","TFIIH","TTDA"],"prev_symbol":["C6orf175","TTD"]},"alphafold":{"accession":"Q6ZYL4","domains":[{"cath_id":"3.30.70.1220","chopping":"6-68","consensus_level":"high","plddt":71.1595,"start":6,"end":68}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZYL4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZYL4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZYL4-F1-predicted_aligned_error_v6.png","plddt_mean":68.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GTF2H5","jax_strain_url":"https://www.jax.org/strain/search?query=GTF2H5"},"sequence":{"accession":"Q6ZYL4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZYL4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZYL4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZYL4"}},"corpus_meta":[{"pmid":"15220919","id":"PMC_15220919","title":"Identification of TFB5, a new component of general transcription and DNA repair factor IIH.","date":"2004","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15220919","citation_count":129,"is_preprint":false},{"pmid":"11062469","id":"PMC_11062469","title":"Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD-A trichothiodystrophy disorder.","date":"2000","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11062469","citation_count":107,"is_preprint":false},{"pmid":"16427011","id":"PMC_16427011","title":"p8/TTD-A as a repair-specific TFIIH subunit.","date":"2006","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16427011","citation_count":90,"is_preprint":false},{"pmid":"16669699","id":"PMC_16669699","title":"Dynamic interaction of TTDA with TFIIH is stabilized by nucleotide excision repair in living cells.","date":"2006","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/16669699","citation_count":74,"is_preprint":false},{"pmid":"23637614","id":"PMC_23637614","title":"Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23637614","citation_count":33,"is_preprint":false},{"pmid":"8371115","id":"PMC_8371115","title":"Identification of the L-tartrate dehydratase genes (ttdA and ttdB) of Escherichia coli and evolutionary relationship with the class I fumarase genes.","date":"1993","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/8371115","citation_count":30,"is_preprint":false},{"pmid":"26463438","id":"PMC_26463438","title":"The NER-related gene GTF2H5 predicts survival in high-grade serous ovarian cancer patients.","date":"2015","source":"Journal of gynecologic 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required for stress response and pathogenicity in the tangerine pathotype of Alternaria alternata.","date":"2020","source":"Molecular plant pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32776683","citation_count":21,"is_preprint":false},{"pmid":"16804186","id":"PMC_16804186","title":"Functional identification of ygiP as a positive regulator of the ttdA-ttdB-ygjE operon.","date":"2006","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/16804186","citation_count":19,"is_preprint":false},{"pmid":"23729738","id":"PMC_23729738","title":"In vivo interactions of TTDA mutant proteins within TFIIH.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23729738","citation_count":16,"is_preprint":false},{"pmid":"17215295","id":"PMC_17215295","title":"Tfb5 interacts with Tfb2 and facilitates nucleotide excision repair in yeast.","date":"2007","source":"Nucleic acids 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Yeast lacking TFB5 grow slowly and are sensitive to UV radiation, phenocopying mutations in core TFIIH subunits.\",\n      \"method\": \"Quantitative proteomics (SILAC), chromatin immunoprecipitation (ChIP), in vitro transcription assay, UV sensitivity assay, genetic analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (quantitative proteomics, ChIP, in vitro transcription), identification replicated with functional validation in yeast model\",\n      \"pmids\": [\"15220919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoblot and immunofluorescence analysis of TFIIH levels in patient-derived TTD-A cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (immunoblot, immunofluorescence) in patient cells, single lab\",\n      \"pmids\": [\"11062469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Fluorescent antibody labeling, ATPase stimulation assay, XPA recruitment assay, overexpression complementation in TTD-XPD cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vitro ATPase assay, fluorescence imaging, genetic complementation) in a single rigorous study\",\n      \"pmids\": [\"16427011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Fluorescence microscopy (live-cell imaging of GFP-tagged TTDA), FRAP, fluorescence recovery kinetics in cells treated with UV and transcription inhibitors\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell FRAP with biologically active tagged protein, multiple conditions tested, clear mechanistic conclusion\",\n      \"pmids\": [\"16669699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-free NER assay with purified Tfb5, protein-protein interaction assay, UV survival assay, tfb5 deletion mutant analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro NER reconstitution with purified protein complementation, protein interaction mapping, and genetic analysis in a single study\",\n      \"pmids\": [\"17215295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Strand-specific NER analysis using repair assays in yeast deletion mutants (tfb5, rad26, rpb9, rad7 combinations)\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis using multiple double and triple mutants, strand-specific repair assays, single lab\",\n      \"pmids\": [\"17644494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Drosophila transgenic overexpression, genetic suppression assay, UV survival assay, DNA repair efficiency measurement (CPD/6-4PP levels)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in intact multicellular organism with multiple alleles tested, functional repair assay, TFIIH level measurement\",\n      \"pmids\": [\"19008953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography of Tfb5-Tfb2C complex\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure at 1.7 Å resolution, two crystal forms solved, single lab\",\n      \"pmids\": [\"20606254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Tripartite split-GFP system in living cells, fluorescence microscopy, UV damage recruitment assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel in vivo split-GFP interaction assay plus UV recruitment imaging, single lab, single study\",\n      \"pmids\": [\"23729738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Ttda knock-out mouse generation, NER assay in mouse embryonic fibroblasts, UV and oxidant sensitivity assays, genetic comparison of null vs patient-mutant cells\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse model with multiple phenotypic assays (NER, oxidant sensitivity, embryonic viability), clear mechanistic conclusion distinguishing null from hypomorphic patient mutations\",\n      \"pmids\": [\"23637614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Molecular dynamics simulation, fragment-based drug screening (>3000 compounds), biophysical binding assays, quantitative live-cell TFIIH imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biophysical methods and live-cell imaging, single lab, novel mechanistic finding about dimerization\",\n      \"pmids\": [\"30068551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"C. elegans knockout analysis, NER assay, TFIIH stability measurement, transcriptional stress experiments, tissue-specific imaging\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout in metazoan model, multiple assays (NER, TFIIH stability, transcriptional challenge), cross-species validation of mammalian findings\",\n      \"pmids\": [\"34824371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cancer cell line context with unclear direct mechanistic validation; p53 promoter binding method not clearly specified in abstract, functional consequence without pathway reconstitution\",\n      \"pmids\": [\"32540359\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GTF2H5 (TTDA/p8/TFB5) encodes the smallest (8 kDa, 71 amino acid) tenth subunit of the TFIIH transcription/repair complex, which stabilizes overall TFIIH architecture by shifting from a free homodimer to a heterodimer with the p52 subunit upon TFIIH incorporation; in NER it stimulates XPB ATPase activity (together with XPC-hHR23B) to open damaged DNA and enable XPA recruitment, is recruited to UV damage sites via a NER-specific dynamic interaction with TFIIH, and is essential for both global genomic and transcription-coupled NER in multiple organisms, while being dispensable for basal transcription under normal conditions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #4, #11]. 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 [#4, #7]. 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 [#1, #10]. 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 [#2]. 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 [#3, #11]. 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 [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that patient TTD-A defects act by destabilizing TFIIH rather than disabling its catalytic core, reframing the disease as one of complex abundance.\",\n      \"evidence\": \"Immunoblot and immunofluorescence of TFIIH levels in patient-derived TTD-A cells\",\n      \"pmids\": [\"11062469\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not identify the subunit/gene responsible\", \"Mechanism of how reduced TFIIH preferentially impairs repair not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"SILAC proteomics, ChIP, in vitro transcription and UV sensitivity assays in yeast\",\n      \"pmids\": [\"15220919\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not define the molecular partner within TFIIH\", \"Relative contribution to transcription vs repair unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro ATPase stimulation assay, XPA recruitment imaging, complementation in TTD-XPD cells; live-cell FRAP of GFP-TTDA\",\n      \"pmids\": [\"16427011\", \"16669699\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of XPB stimulation not resolved\", \"How free vs bound pools are regulated upon damage unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cell-free NER reconstitution with purified Tfb5, interaction mapping, and strand-specific repair assays in yeast deletion mutants\",\n      \"pmids\": [\"17215295\", \"17644494\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Atomic detail of the Tfb5-Tfb2 contact not yet resolved\", \"Mechanistic basis for partial TC-NER dispensability unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Drosophila transgenic overexpression, genetic suppression of p52/XPB alleles, and CPD/6-4PP repair measurement\",\n      \"pmids\": [\"19008953\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not establish stoichiometry of stabilization\", \"Direct biochemical interaction with XPD not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided the structural basis of the GTF2H5-p52 interaction at atomic resolution, explaining how the smallest subunit docks onto the TFIIH core.\",\n      \"evidence\": \"X-ray crystallography of the yeast Tfb5-Tfb2C complex at 1.7 Å\",\n      \"pmids\": [\"20606254\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structure of full TFIIH-incorporated subunit absent\", \"Conformational changes upon incorporation not captured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Tripartite split-GFP interaction assay and UV-damage recruitment imaging; Ttda knockout mouse with NER and oxidant sensitivity assays\",\n      \"pmids\": [\"23729738\", \"23637614\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular defect distinguishing null from patient phenotypes not fully defined\", \"Mechanism of the oxidative-damage repair role unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Molecular dynamics, fragment-based drug screening, biophysical binding, and quantitative live-cell TFIIH imaging\",\n      \"pmids\": [\"30068551\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"In vivo relevance of the homodimer not established\", \"Functional state of the homodimeric pool unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"C. elegans knockout with NER assays, TFIIH stability measurement, and transcriptional stress experiments\",\n      \"pmids\": [\"34824371\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular basis of conditional transcriptional requirement not defined\", \"Tissue-specific differences in TFIIH fragility unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether GTF2H5 has TFIIH-independent functions, such as direct transcriptional regulation of target genes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4, 10]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 4, 9, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"complexes\": [\"TFIIH\"],\n    \"partners\": [\"GTF2H4\", \"XPB\", \"XPD\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}