{"gene":"TADA1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2026,"finding":"TADA1 is a non-enzymatic subunit of the SAGA CORE module required for KAT2A (GCN5) protein stability. Loss of TADA1 disrupts SAGA complex integrity, releasing non-chromatin-bound KAT2A that is degraded by the proteasome via the E3 ligase UBR5 and deubiquitinase OTUD5, resulting in reduced H3K9 acetylation. An intact CORE module containing TADA1 is also required for the stability of numerous other SAGA components.","method":"Fluorescence-based KAT2A stability reporter, systematic CRISPR knockout, proteomic profiling, focused CRISPR screen of ubiquitin-proteasome system genes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assay, proteomics, focused CRISPR screen) in a single rigorous study establishing mechanism of KAT2A stabilization by TADA1","pmids":["42009663"],"is_preprint":false},{"year":2023,"finding":"Hfi1 (the Cryptococcus neoformans ortholog of TADA1) forms part of the SAGA complex CORE module and is required for complex structural integrity; loss of Hfi1 alters histone acetylation and deubiquitination of several histone residues and affects transcription of other SAGA subunit genes.","method":"Gene deletion (hfi1Δ mutant), histone modification analysis, transcriptional profiling, virulence assay in murine inhalation model","journal":"Journal of fungi (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined histone-modification and transcriptional phenotypes, but single lab and ortholog (fungal pathogen) rather than direct human protein study","pmids":["38132798"],"is_preprint":false},{"year":2004,"finding":"HFI1 (yeast ortholog of TADA1) is required for effective repair of ionizing radiation-induced DNA damage; deletion of HFI1 causes clear X-ray sensitivity in yeast without substantial UV sensitivity.","method":"Genome-wide Saccharomyces deletion mutant screen; multipoint survival-vs.-dose X-ray assays in haploid and homozygous diploid strains; co-segregation analysis","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined loss-of-function phenotype (radiation sensitivity) confirmed by co-segregation in multiple strain backgrounds, single lab","pmids":["15371366"],"is_preprint":false},{"year":2009,"finding":"SRM12/HFI1 (yeast ortholog of TADA1) participates in DNA damage checkpoint control; the srm12/hfi1-srm mutation shortens cell-cycle arrest in response to DNA damage and influences checkpoint arrest at G1/S and S phases.","method":"Genetic analysis of srm12/hfi1 mutants; cell-cycle arrest assays with DNA-damaging agents in Saccharomyces cerevisiae","journal":"Genetika","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined checkpoint phenotypes by genetic analysis, but single lab and single method (genetic/cell-cycle arrest assay)","pmids":["19507699"],"is_preprint":false},{"year":2003,"finding":"HFI1 (yeast ortholog of TADA1) mediates important regulatory protein-protein interactions in yeast and is required for normal mitochondrial genome stability, chromosome maintenance, and plasmid maintenance; hfi1-srm mutations decrease spontaneous rho(-) mitochondrial mutagenesis and affect mitotic transmission fidelity.","method":"Yeast genetic analysis; characterization of spontaneous rho(-) mutants; chromosome and plasmid loss assays; radiation sensitivity assays","journal":"Yeast (Chichester, England)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic phenotypic characterization without molecular mechanism detail; single lab, single study","pmids":["12898711"],"is_preprint":false},{"year":2018,"finding":"miR-7702 directly targets TADA1 mRNA in human colorectal cancer cells (but not mouse cells), suppressing TADA1 protein expression and consequently reducing cell migration and invasion; this was confirmed by dual luciferase reporter assay.","method":"Dual luciferase reporter assay, transfection-based overexpression/knockdown, cell migration and invasion assays, species comparison (human vs. mouse cells)","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, reporter assay confirms miRNA-target interaction, but no direct mechanistic characterization of TADA1 protein function itself","pmids":["30210694"],"is_preprint":false}],"current_model":"TADA1 is a non-enzymatic structural subunit of the SAGA complex CORE module that is required for the stability of the catalytic subunit KAT2A (GCN5) and the integrity of the broader SAGA complex; loss of TADA1 causes proteasomal degradation of unassembled KAT2A (via UBR5/OTUD5), reduced H3K9 acetylation, and progressive disassembly of SAGA; orthologous studies in yeast and fungi further link TADA1/Hfi1 to DNA damage checkpoint control, radiation resistance, and mitochondrial genome stability."},"narrative":{"mechanistic_narrative":"TADA1 is a non-enzymatic structural subunit of the SAGA complex CORE module that maintains the integrity of the complex and the stability of its catalytic histone acetyltransferase subunit KAT2A (GCN5) [PMID:42009663]. In the absence of TADA1, SAGA integrity is disrupted and non-chromatin-bound KAT2A is degraded by the proteasome through the E3 ligase UBR5 and the deubiquitinase OTUD5, lowering H3K9 acetylation; an intact TADA1-containing CORE module is likewise required for the stability of numerous other SAGA components [PMID:42009663]. This SAGA-scaffolding role is conserved in fungi, where the ortholog Hfi1 is required for complex structural integrity and normal histone acetylation/deubiquitination and influences transcription of other SAGA subunit genes [PMID:38132798]. Beyond chromatin regulation, yeast ortholog studies link this function to genome maintenance, including X-ray-induced DNA damage repair [PMID:15371366], DNA damage checkpoint control at G1/S and S phases [PMID:19507699], and mitochondrial genome and chromosome stability [PMID:12898711].","teleology":[{"year":2003,"claim":"Established the first functional readout for the gene by showing the yeast ortholog mediates regulatory protein interactions and is required for mitochondrial and chromosome stability, framing it as a maintenance factor beyond transcription.","evidence":"Yeast genetic analysis of hfi1-srm mutants with rho(-) mutagenesis, chromosome and plasmid loss assays","pmids":["12898711"],"confidence":"Low","gaps":["Genetic phenotypes only; no molecular mechanism linking the protein to genome stability","No connection drawn to SAGA at this stage","Single lab, single study"]},{"year":2004,"claim":"Tested whether the ortholog contributes to DNA damage responses and showed its loss confers selective X-ray sensitivity, implicating it specifically in ionizing-radiation damage repair rather than UV repair.","evidence":"Genome-wide Saccharomyces deletion screen with survival-vs-dose X-ray assays and co-segregation analysis","pmids":["15371366"],"confidence":"Medium","gaps":["Does not define the molecular pathway through which it acts in repair","Radiation-sensitivity phenotype not mechanistically connected to chromatin acetylation"]},{"year":2009,"claim":"Refined the genome-maintenance role by showing the ortholog participates in DNA damage checkpoint control, with mutants shortening cell-cycle arrest at G1/S and S phases.","evidence":"Genetic analysis and cell-cycle arrest assays with DNA-damaging agents in S. cerevisiae","pmids":["19507699"],"confidence":"Medium","gaps":["Mechanism connecting checkpoint control to SAGA function not established","Single method (genetic/arrest assay)"]},{"year":2018,"claim":"Addressed regulation of the human gene by identifying miR-7702 as a direct repressor of TADA1 mRNA, linking TADA1 levels to colorectal cancer cell migration and invasion.","evidence":"Dual luciferase reporter assay, overexpression/knockdown, migration/invasion assays in human vs mouse cells","pmids":["30210694"],"confidence":"Low","gaps":["Reporter confirms miRNA targeting but does not characterize TADA1 protein function","Mechanistic basis for the migration/invasion phenotype unresolved","Single lab"]},{"year":2023,"claim":"Placed the ortholog firmly within the SAGA CORE module, showing it is required for complex structural integrity and for normal histone acetylation/deubiquitination and SAGA subunit gene expression.","evidence":"hfi1Δ deletion in Cryptococcus neoformans with histone modification analysis, transcriptional profiling, and murine virulence assay","pmids":["38132798"],"confidence":"Medium","gaps":["Fungal ortholog rather than direct human protein study","Does not resolve how the subunit confers structural stability mechanistically"]},{"year":2026,"claim":"Defined the human protein's molecular role: a non-enzymatic CORE module subunit that stabilizes KAT2A and the broader SAGA complex, with its loss triggering UBR5/OTUD5-mediated proteasomal degradation of unassembled KAT2A and loss of H3K9 acetylation.","evidence":"Fluorescence-based KAT2A stability reporter, systematic CRISPR knockout, proteomics, and focused ubiquitin-proteasome CRISPR screen in human cells","pmids":["42009663"],"confidence":"High","gaps":["No structural model of how TADA1 contacts and protects KAT2A within CORE","Connection between SAGA-scaffolding role and the genome-maintenance phenotypes seen in orthologs untested in human cells"]},{"year":null,"claim":"Whether the human SAGA-stabilizing function of TADA1 mechanistically underlies the DNA damage checkpoint, radiation-resistance, and mitochondrial genome-stability phenotypes observed in orthologs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No human study links TADA1/SAGA integrity to DNA repair or checkpoint control","Structural basis of CORE module stabilization undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1]}],"complexes":["SAGA complex (CORE module)"],"partners":["KAT2A","UBR5","OTUD5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96BN2","full_name":"Transcriptional adapter 1","aliases":["SPT3-associated factor 42","STAF42","Transcriptional adapter 1-like protein"],"length_aa":335,"mass_kda":37.4,"function":"Probably involved in transcriptional regulation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96BN2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TADA1","classification":"Not Classified","n_dependent_lines":367,"n_total_lines":1208,"dependency_fraction":0.3038079470198676},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MED19","stoichiometry":10.0},{"gene":"TAF12","stoichiometry":10.0},{"gene":"TRRAP","stoichiometry":10.0},{"gene":"ENY2","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2},{"gene":"SF3B3","stoichiometry":0.2},{"gene":"SF3B5","stoichiometry":0.2},{"gene":"TBP","stoichiometry":0.2},{"gene":"USP22","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TADA1","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Focal adhesion sites","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TADA1"},"hgnc":{"alias_symbol":["STAF42","ADA1","hADA1","HFI1"],"prev_symbol":["TADA1L"]},"alphafold":{"accession":"Q96BN2","domains":[{"cath_id":"-","chopping":"1-75","consensus_level":"medium","plddt":86.8801,"start":1,"end":75},{"cath_id":"-","chopping":"196-232_250-271","consensus_level":"medium","plddt":79.4558,"start":196,"end":271},{"cath_id":"-","chopping":"293-329","consensus_level":"high","plddt":85.9043,"start":293,"end":329}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BN2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BN2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BN2-F1-predicted_aligned_error_v6.png","plddt_mean":77.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TADA1","jax_strain_url":"https://www.jax.org/strain/search?query=TADA1"},"sequence":{"accession":"Q96BN2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96BN2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96BN2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BN2"}},"corpus_meta":[{"pmid":"24336571","id":"PMC_24336571","title":"Genome-scale CRISPR-Cas9 knockout screening in human cells.","date":"2013","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24336571","citation_count":4103,"is_preprint":false},{"pmid":"30078747","id":"PMC_30078747","title":"Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients.","date":"2018","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/30078747","citation_count":733,"is_preprint":false},{"pmid":"27431290","id":"PMC_27431290","title":"Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield.","date":"2016","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/27431290","citation_count":202,"is_preprint":false},{"pmid":"15371366","id":"PMC_15371366","title":"X-ray survival characteristics and genetic analysis for nine Saccharomyces deletion mutants that show altered radiation sensitivity.","date":"2004","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15371366","citation_count":57,"is_preprint":false},{"pmid":"11139490","id":"PMC_11139490","title":"Genetic evidence for a morphogenetic function of the Saccharomyces cerevisiae Pho85 cyclin-dependent kinase.","date":"2001","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11139490","citation_count":46,"is_preprint":false},{"pmid":"31218106","id":"PMC_31218106","title":"Loss of ZNF587B and SULF1 contributed to cisplatin resistance in ovarian cancer cell lines based on Genome-scale CRISPR/Cas9 screening.","date":"2019","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/31218106","citation_count":37,"is_preprint":false},{"pmid":"32953492","id":"PMC_32953492","title":"LINC00511 promotes lung squamous cell carcinoma proliferation and migration via inhibiting miR-150-5p and activating TADA1.","date":"2020","source":"Translational lung cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32953492","citation_count":24,"is_preprint":false},{"pmid":"30555512","id":"PMC_30555512","title":"Elucidating the Role of Chromatin State and Transcription Factors on the Regulation of the Yeast Metabolic Cycle: A Multi-Omic Integrative Approach.","date":"2018","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30555512","citation_count":11,"is_preprint":false},{"pmid":"30210694","id":"PMC_30210694","title":"Species-specific function of microRNA-7702 in human colorectal cancer cells via targeting TADA1.","date":"2018","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/30210694","citation_count":9,"is_preprint":false},{"pmid":"27510152","id":"PMC_27510152","title":"Application of ADA1 as a new marker enzyme in sandwich ELISA to study the effect of adenosine on activated monocytes.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27510152","citation_count":9,"is_preprint":false},{"pmid":"33675375","id":"PMC_33675375","title":"Genetic and functional analysis of the Zn(II)2Cys6 transcription factor HADA-1 in Hypsizygus marmoreus.","date":"2021","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/33675375","citation_count":8,"is_preprint":false},{"pmid":"38437001","id":"PMC_38437001","title":"Weighted single step GWAS reveals genomic regions associated with economic traits in Murrah buffaloes.","date":"2024","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38437001","citation_count":6,"is_preprint":false},{"pmid":"19504185","id":"PMC_19504185","title":"Design and assessment of a potent sodium channel blocking derivative of mexiletine for minimizing experimental neuropathic pain in several rat models.","date":"2009","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/19504185","citation_count":6,"is_preprint":false},{"pmid":"12898711","id":"PMC_12898711","title":"NET1 and HFI1 genes of yeast mediate both chromosome maintenance and mitochondrial rho(-) mutagenesis.","date":"2003","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/12898711","citation_count":4,"is_preprint":false},{"pmid":"38132798","id":"PMC_38132798","title":"SAGA Complex Subunit Hfi1 Is Important in the Stress Response and Pathogenesis of Cryptococcus neoformans.","date":"2023","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38132798","citation_count":3,"is_preprint":false},{"pmid":"33395458","id":"PMC_33395458","title":"Analysis of potential virulence genes and competence to transformation in Haemophilus influenzae biotype aegyptius associated with Brazilian Purpuric Fever.","date":"2020","source":"Genetics and molecular 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Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/38568320","citation_count":2,"is_preprint":false},{"pmid":"19507699","id":"PMC_19507699","title":"[Participation of SRM5/CDC28, SRM8/NET1, and SRM12/HFI1 genes in checkpoint control in yeast Saccharomyces cerevisiae].","date":"2009","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/19507699","citation_count":1,"is_preprint":false},{"pmid":"40816512","id":"PMC_40816512","title":"Expression of CMK2 is controlled by the general stress-response transcriptional factor Msn2 through a single STRE site in budding yeast.","date":"2025","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/40816512","citation_count":1,"is_preprint":false},{"pmid":"42009663","id":"PMC_42009663","title":"Disruption of the SAGA CORE triggers collateral degradation of KAT2A.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42009663","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11312,"output_tokens":1540,"usd":0.028518,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8345,"output_tokens":2318,"usd":0.049837,"stage2_stop_reason":"end_turn"},"total_usd":0.078355,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2026,\n      \"finding\": \"TADA1 is a non-enzymatic subunit of the SAGA CORE module required for KAT2A (GCN5) protein stability. Loss of TADA1 disrupts SAGA complex integrity, releasing non-chromatin-bound KAT2A that is degraded by the proteasome via the E3 ligase UBR5 and deubiquitinase OTUD5, resulting in reduced H3K9 acetylation. An intact CORE module containing TADA1 is also required for the stability of numerous other SAGA components.\",\n      \"method\": \"Fluorescence-based KAT2A stability reporter, systematic CRISPR knockout, proteomic profiling, focused CRISPR screen of ubiquitin-proteasome system genes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assay, proteomics, focused CRISPR screen) in a single rigorous study establishing mechanism of KAT2A stabilization by TADA1\",\n      \"pmids\": [\"42009663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hfi1 (the Cryptococcus neoformans ortholog of TADA1) forms part of the SAGA complex CORE module and is required for complex structural integrity; loss of Hfi1 alters histone acetylation and deubiquitination of several histone residues and affects transcription of other SAGA subunit genes.\",\n      \"method\": \"Gene deletion (hfi1Δ mutant), histone modification analysis, transcriptional profiling, virulence assay in murine inhalation model\",\n      \"journal\": \"Journal of fungi (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined histone-modification and transcriptional phenotypes, but single lab and ortholog (fungal pathogen) rather than direct human protein study\",\n      \"pmids\": [\"38132798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HFI1 (yeast ortholog of TADA1) is required for effective repair of ionizing radiation-induced DNA damage; deletion of HFI1 causes clear X-ray sensitivity in yeast without substantial UV sensitivity.\",\n      \"method\": \"Genome-wide Saccharomyces deletion mutant screen; multipoint survival-vs.-dose X-ray assays in haploid and homozygous diploid strains; co-segregation analysis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined loss-of-function phenotype (radiation sensitivity) confirmed by co-segregation in multiple strain backgrounds, single lab\",\n      \"pmids\": [\"15371366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SRM12/HFI1 (yeast ortholog of TADA1) participates in DNA damage checkpoint control; the srm12/hfi1-srm mutation shortens cell-cycle arrest in response to DNA damage and influences checkpoint arrest at G1/S and S phases.\",\n      \"method\": \"Genetic analysis of srm12/hfi1 mutants; cell-cycle arrest assays with DNA-damaging agents in Saccharomyces cerevisiae\",\n      \"journal\": \"Genetika\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined checkpoint phenotypes by genetic analysis, but single lab and single method (genetic/cell-cycle arrest assay)\",\n      \"pmids\": [\"19507699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HFI1 (yeast ortholog of TADA1) mediates important regulatory protein-protein interactions in yeast and is required for normal mitochondrial genome stability, chromosome maintenance, and plasmid maintenance; hfi1-srm mutations decrease spontaneous rho(-) mitochondrial mutagenesis and affect mitotic transmission fidelity.\",\n      \"method\": \"Yeast genetic analysis; characterization of spontaneous rho(-) mutants; chromosome and plasmid loss assays; radiation sensitivity assays\",\n      \"journal\": \"Yeast (Chichester, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic phenotypic characterization without molecular mechanism detail; single lab, single study\",\n      \"pmids\": [\"12898711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-7702 directly targets TADA1 mRNA in human colorectal cancer cells (but not mouse cells), suppressing TADA1 protein expression and consequently reducing cell migration and invasion; this was confirmed by dual luciferase reporter assay.\",\n      \"method\": \"Dual luciferase reporter assay, transfection-based overexpression/knockdown, cell migration and invasion assays, species comparison (human vs. mouse cells)\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, reporter assay confirms miRNA-target interaction, but no direct mechanistic characterization of TADA1 protein function itself\",\n      \"pmids\": [\"30210694\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TADA1 is a non-enzymatic structural subunit of the SAGA complex CORE module that is required for the stability of the catalytic subunit KAT2A (GCN5) and the integrity of the broader SAGA complex; loss of TADA1 causes proteasomal degradation of unassembled KAT2A (via UBR5/OTUD5), reduced H3K9 acetylation, and progressive disassembly of SAGA; orthologous studies in yeast and fungi further link TADA1/Hfi1 to DNA damage checkpoint control, radiation resistance, and mitochondrial genome stability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TADA1 is a non-enzymatic structural subunit of the SAGA complex CORE module that maintains the integrity of the complex and the stability of its catalytic histone acetyltransferase subunit KAT2A (GCN5) [#0]. In the absence of TADA1, SAGA integrity is disrupted and non-chromatin-bound KAT2A is degraded by the proteasome through the E3 ligase UBR5 and the deubiquitinase OTUD5, lowering H3K9 acetylation; an intact TADA1-containing CORE module is likewise required for the stability of numerous other SAGA components [#0]. This SAGA-scaffolding role is conserved in fungi, where the ortholog Hfi1 is required for complex structural integrity and normal histone acetylation/deubiquitination and influences transcription of other SAGA subunit genes [#1]. Beyond chromatin regulation, yeast ortholog studies link this function to genome maintenance, including X-ray-induced DNA damage repair [#2], DNA damage checkpoint control at G1/S and S phases [#3], and mitochondrial genome and chromosome stability [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the first functional readout for the gene by showing the yeast ortholog mediates regulatory protein interactions and is required for mitochondrial and chromosome stability, framing it as a maintenance factor beyond transcription.\",\n      \"evidence\": \"Yeast genetic analysis of hfi1-srm mutants with rho(-) mutagenesis, chromosome and plasmid loss assays\",\n      \"pmids\": [\"12898711\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Genetic phenotypes only; no molecular mechanism linking the protein to genome stability\",\n        \"No connection drawn to SAGA at this stage\",\n        \"Single lab, single study\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Tested whether the ortholog contributes to DNA damage responses and showed its loss confers selective X-ray sensitivity, implicating it specifically in ionizing-radiation damage repair rather than UV repair.\",\n      \"evidence\": \"Genome-wide Saccharomyces deletion screen with survival-vs-dose X-ray assays and co-segregation analysis\",\n      \"pmids\": [\"15371366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not define the molecular pathway through which it acts in repair\",\n        \"Radiation-sensitivity phenotype not mechanistically connected to chromatin acetylation\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Refined the genome-maintenance role by showing the ortholog participates in DNA damage checkpoint control, with mutants shortening cell-cycle arrest at G1/S and S phases.\",\n      \"evidence\": \"Genetic analysis and cell-cycle arrest assays with DNA-damaging agents in S. cerevisiae\",\n      \"pmids\": [\"19507699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting checkpoint control to SAGA function not established\",\n        \"Single method (genetic/arrest assay)\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Addressed regulation of the human gene by identifying miR-7702 as a direct repressor of TADA1 mRNA, linking TADA1 levels to colorectal cancer cell migration and invasion.\",\n      \"evidence\": \"Dual luciferase reporter assay, overexpression/knockdown, migration/invasion assays in human vs mouse cells\",\n      \"pmids\": [\"30210694\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Reporter confirms miRNA targeting but does not characterize TADA1 protein function\",\n        \"Mechanistic basis for the migration/invasion phenotype unresolved\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed the ortholog firmly within the SAGA CORE module, showing it is required for complex structural integrity and for normal histone acetylation/deubiquitination and SAGA subunit gene expression.\",\n      \"evidence\": \"hfi1\\u0394 deletion in Cryptococcus neoformans with histone modification analysis, transcriptional profiling, and murine virulence assay\",\n      \"pmids\": [\"38132798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Fungal ortholog rather than direct human protein study\",\n        \"Does not resolve how the subunit confers structural stability mechanistically\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined the human protein's molecular role: a non-enzymatic CORE module subunit that stabilizes KAT2A and the broader SAGA complex, with its loss triggering UBR5/OTUD5-mediated proteasomal degradation of unassembled KAT2A and loss of H3K9 acetylation.\",\n      \"evidence\": \"Fluorescence-based KAT2A stability reporter, systematic CRISPR knockout, proteomics, and focused ubiquitin-proteasome CRISPR screen in human cells\",\n      \"pmids\": [\"42009663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of how TADA1 contacts and protects KAT2A within CORE\",\n        \"Connection between SAGA-scaffolding role and the genome-maintenance phenotypes seen in orthologs untested in human cells\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the human SAGA-stabilizing function of TADA1 mechanistically underlies the DNA damage checkpoint, radiation-resistance, and mitochondrial genome-stability phenotypes observed in orthologs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No human study links TADA1/SAGA integrity to DNA repair or checkpoint control\",\n        \"Structural basis of CORE module stabilization undetermined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"SAGA complex (CORE module)\"],\n    \"partners\": [\"KAT2A\", \"UBR5\", \"OTUD5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}