{"gene":"TADA2A","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1996,"finding":"Human ADA2 (hADA2/TADA2A) interacts with human GCN5 (hGCN5) in vivo as shown by yeast two-hybrid assay, and hGCN5 interacts with yeast ADA2, indicating conserved complex formation. hADA2 contains a cryptic activation domain, and GAL4-hADA2 activates transcription in HeLa cells; hADA2 or hGCN5 augments GAL4-VP16 activation.","method":"Yeast two-hybrid assay, transcriptional activation assays in yeast and HeLa cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal two-hybrid and functional transcription assays in two cellular systems, single lab","pmids":["8552087"],"is_preprint":false},{"year":1997,"finding":"The region of yeast ADA2 that interacts with yGCN5 maps to the amino terminus, which is highly conserved in hADA2/TADA2A, establishing structural conservation of the ADA2-GCN5 interaction interface.","method":"Yeast two-hybrid mapping with deletion constructs","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping two-hybrid, single lab, functionally validated","pmids":["8552087"],"is_preprint":false},{"year":1997,"finding":"TADA2L (TADA2A) and GCN5L2 co-localize to chromosome 17q12-q21 and are expressed at relatively similar levels across all human tissues, suggesting coordinated regulation.","method":"Northern blot analysis, fluorescence in situ hybridization (FISH)","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal mapping by FISH and expression profiling by Northern blot, single lab","pmids":["9073520"],"is_preprint":false},{"year":2000,"finding":"hADA2/TADA2A is required for T3/GRIP1 and SRC-1 coactivator-dependent transcriptional activation by human thyroid hormone receptor (hTRbeta1) in yeast. hTRbeta1 binds directly to hADA2 in vitro protein-protein interaction experiments, placing TADA2A in the nuclear receptor coactivation pathway.","method":"Yeast genetics (ada mutants), in vitro protein-protein interaction, transcriptional reporter assays","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay plus functional genetics, single lab, two orthogonal methods","pmids":["10809234"],"is_preprint":false},{"year":2005,"finding":"Drosophila Ada2a null mutants are late-larval lethal and show defects in cell proliferation. Ada2a function is required in the female germ line. Ada2a null mutation does NOT reduce histone H3 K14 or H3 K9 acetylation (in contrast to Ada2b), establishing that ADA2a and ADA2b have distinct histone substrate specificities.","method":"Genetic null mutants, pole-cell transplantation germ-line mosaics, histone acetylation immunostaining","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — null mutant genetic analysis with specific histone acetylation readouts, replicated across multiple phenotypic assays","pmids":["16135810"],"is_preprint":false},{"year":2005,"finding":"The Drosophila Ada2a gene shares overlapping regulatory/promoter regions with the Dtl (PIMT) gene and also produces RPB4 via alternative splicing, establishing a complex genomic architecture for Ada2a.","method":"Reporter gene fusions in tissue culture and transgenic animals, alternative splicing analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays and transgenic analysis in Drosophila, single lab","pmids":["15777699"],"is_preprint":false},{"year":2005,"finding":"TADA2A (TADA2L) shares a bidirectional promoter with ACACA in humans, mice, rats, and sheep; this shared promoter co-regulates transcripts for both genes in an asymmetric fashion, with RNA polymerase II concentration in the intergenic region reflecting transcript abundance differences.","method":"5'-RACE, RNA polymerase II ChIP, Northern analysis across tissues","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RACE, ChIP, Northern), single lab","pmids":["15607423"],"is_preprint":false},{"year":2006,"finding":"In Drosophila, loss of dAda2a results in reduced nucleosomal histone H4 acetylation at lysines 12 and 5, while H3 K9 and K14 acetylation (established by dAda2b-containing complexes) is unaffected. Genetic interaction between dGcn5 and dAda2a produces similar chromosome structural and developmental defects, placing dAda2a in an H4-specific GCN5-containing complex (ATAC).","method":"Genetic null mutants, immunostaining of polytene chromosomes, genetic interaction analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mutants with specific histone mark readouts, replicated across two Ada2 paralogs in same study","pmids":["17030603"],"is_preprint":false},{"year":2007,"finding":"In Drosophila, mutations in Ada2a (ATAC component) induce decondensation of the male X chromosome similar to NURF mutants. Ada2a chromosome binding and histone H4-Lys12 acetylation are compromised in Iswi and Nurf301 mutants, indicating that NURF nucleosome remodeling is required for ATAC/Ada2a to access chromatin.","method":"Genetic epistasis, polytene chromosome immunostaining, transcript profiling","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with specific chromatin readout, single lab, two orthogonal methods","pmids":["18084186"],"is_preprint":false},{"year":2008,"finding":"Human ATAC complex was purified and found to contain ADA2A (TADA2A), ADA3, GCN5 or PCAF, STAF36/WDR5, POLE3/CHRAC17, POLE4, TAK1/MAP3K7, MBIP, YEATS2, and NC2beta. The YEATS2-NC2beta histone fold module interacts with TBP and negatively regulates transcription when recruited to a promoter, establishing TADA2A as a core subunit of human ATAC distinct from STAGA.","method":"Biochemical purification (mass spectrometry), co-immunoprecipitation, transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — complex purification with MS identification plus functional transcriptional assays, multiple orthogonal methods","pmids":["18838386"],"is_preprint":false},{"year":2008,"finding":"The Drosophila ATAC complex, containing Ada2a, is a double HAT complex with Gcn5 and Atac2 (KAT14) as two acetyltransferases. ATAC stimulates nucleosome sliding by ISWI, SWI-SNF, and RSC remodeling complexes but does not itself exhibit nucleosome-remodeling activity.","method":"MudPIT mass spectrometry, in vitro HAT assays with recombinant Atac2, in vitro nucleosome sliding assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in vitro HAT assay with mutagenesis, MudPIT MS for complex composition, replicated functional assays","pmids":["18327268"],"is_preprint":false},{"year":2008,"finding":"Mammalian ATAC complex contains GCN5, ATAC2, and ADA2A (TADA2A) among other subunits. ATAC2 depletion results in disassembly of the complex, showing that ATAC2 plays an architectural role in maintaining mammalian ATAC integrity—and consequently the functional complex containing TADA2A.","method":"Immunoprecipitation, RNAi depletion, in vitro HAT assay with recombinant ATAC2, Atac2 knockout mice","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic knockout mouse plus biochemical complex analysis plus in vitro HAT assay, multiple orthogonal methods","pmids":["19103755"],"is_preprint":false},{"year":2010,"finding":"ATAC complex (containing Ada2a/TADA2A) localizes to the mitotic spindle. RNAi depletion of Ada2a or Ada3 causes centrosome multiplication, defective spindle and midbody formation, binucleated cells, delayed M/G1 transition, and hyperacetylation of histone H4K16 and alpha-tubulin. ATAC/Gcn5-mediated acetylation targets Cyclin A for degradation, which regulates SIRT2 deacetylase activity, establishing a non-histone substrate role for ATAC in mitotic progression.","method":"RNAi knockdown, immunofluorescence localization, cell cycle FACS analysis, in vitro acetylation assays of Cyclin A/Cdk2","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi with specific mitotic phenotypes, direct localization, in vitro acetylation of non-histone substrate, mechanistic pathway established","pmids":["20562830"],"is_preprint":false},{"year":2015,"finding":"The HAT module of human ATAC is composed of GCN5, ADA2a (TADA2A), ADA3, and SGF29. ADA2a-containing (ATAC) HAT module enhances GCN5 acetyltransferase activity, primarily acetylating histone H3K14. ADA2b (in SAGA) has a stronger influence on GCN5 activity than ADA2a. The lysine acetylation specificity of GCN5 on histone tails is not altered by incorporation into ATAC versus SAGA HAT modules.","method":"In vitro HAT assays with purified recombinant and endogenous HAT modules, histone tail peptides and full-length histones as substrates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro HAT assay with recombinant and endogenous modules, multiple substrates tested, single lab","pmids":["26468280"],"is_preprint":false},{"year":2017,"finding":"Che-1/AATF interacts with ADA2A (TADA2A) and ADA2B in human cells (co-immunoprecipitation) and in yeast two-hybrid assays. Domain mapping identified the regions of ADA2A and GCN5 required for these interactions.","method":"Co-immunoprecipitation, co-localization, yeast two-hybrid domain mapping","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus two-hybrid domain mapping, single lab, two orthogonal methods","pmids":["29232376"],"is_preprint":false},{"year":2019,"finding":"In Drosophila, Ada2a nucleates formation of the ATAC complex (distinct from SAGA which is nucleated by Ada2b). Only the Ada2b-PB isoform is in SAGA; Ada2b-PA forms the distinct CHAT complex. This establishes that Ada2a is the defining subunit of the ATAC complex.","method":"Affinity purification, mass spectrometry, genetic analysis of isoform-specific mutants","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — affinity purification/MS of distinct complexes combined with genetic isoform analysis, multiple orthogonal methods","pmids":["30559249"],"is_preprint":false},{"year":2021,"finding":"Alpha-synuclein A53T mutant preferentially localizes to the nucleus and binds TADA2A, identified as a novel binding partner via BioID proximity labeling. Alpha-synuclein A53T significantly reduces histone H3 acetylation in SH-SY5Y cells and in mouse striatum/substantia nigra after alpha-syn preformed fibril injection. TADA2A levels are decreased in the substantia nigra of Parkinson's disease patients, linking the alpha-syn A53T-TADA2A interaction to neurotoxicity.","method":"BioID proximity labeling, nuclear fractionation/localization, Western blot for histone H3 acetylation, mouse stereotaxic injection model, human PD tissue analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID identification plus functional acetylation readout in cells and in vivo, single lab, multiple methods","pmids":["34065515"],"is_preprint":false},{"year":2021,"finding":"TAZ-CAMTA1 and YAP-TFE3 oncogenic fusion proteins interact with YEATS2 and ZZZ3, components of the ATAC complex (which contains TADA2A/ADA2A), as identified by a combined proteomic/genetic screen. The fusion proteins drive a unique transcriptome by simultaneously hyperactivating TEAD-based transcription and modulating chromatin via interaction with ATAC.","method":"Proteomic screen (affinity purification/MS), genetic validation, integrative next-generation sequencing (ChIP-seq, RNA-seq)","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS for complex interaction, integrative genomics for functional consequence, single lab","pmids":["33913810"],"is_preprint":false},{"year":2022,"finding":"In Drosophila, the histone acetyltransferase complex Ada2a-containing (ATAC) cooperates with Msl3 (H3K36me3 reader) and Set2 to regulate germline stem cell (GSC) differentiation during oogenesis, establishing a role for ATAC in GSC fate transition.","method":"Genetic mutant analysis, epistasis, transcriptional profiling in Drosophila oogenesis","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in defined developmental context, single lab","pmids":["34878097"],"is_preprint":false},{"year":2022,"finding":"MSH6 stabilization in response to alkylation damage requires interactions with both MPTAC and the Ada2a-containing ATAC complex. MSH6 promotes sterol biosynthesis via the mevalonate pathway in a MPTAC- and ATAC-dependent manner, placing ATAC (and thus TADA2A) in an alkylation damage response-sterol biosynthesis pathway.","method":"Co-immunoprecipitation, RNAi knockdown, biochemical assays for sterol biosynthesis","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional pathway assay, single lab, two orthogonal methods","pmids":["35189552"],"is_preprint":false}],"current_model":"TADA2A (ADA2A/hADA2) is a core structural and functional subunit of the human and metazoan ATAC (Ada Two A-containing) histone acetyltransferase complex, where it assembles with GCN5, ADA3, and SGF29 to stimulate GCN5-mediated acetylation of histone H3K14 and H4K5/K12; it is functionally and biochemically distinct from the paralogous ADA2B subunit of the SAGA complex, and beyond histone substrates, ATAC/TADA2A directly acetylates non-histone targets including Cyclin A to control mitotic progression, interacts with alpha-synuclein A53T to modulate histone H3 acetylation relevant to Parkinson's disease pathology, and is recruited by oncogenic TAZ/YAP fusion proteins to drive transcriptional reprogramming in cancer."},"narrative":{"mechanistic_narrative":"TADA2A (hADA2/TADA2L) is the defining, nucleating subunit of the metazoan ATAC histone acetyltransferase complex, where it assembles with GCN5/PCAF, ADA3, and SGF29 to form the HAT module and stimulate GCN5-dependent acetylation [PMID:18838386, PMID:26468280, PMID:30559249]. The TADA2A-GCN5 interaction is conserved from yeast and maps to a conserved GCN5 amino-terminal interface, and TADA2A itself carries a cryptic transcriptional activation domain [PMID:8552087]. Within ATAC, TADA2A directs a histone substrate preference distinct from its SAGA paralog ADA2B: loss of ADA2a/TADA2A in Drosophila reduces nucleosomal histone H4K5/K12 acetylation while leaving H3K9/K14 (the ADA2b/SAGA marks) intact, and reconstituted human ATAC HAT modules enhance GCN5 acetylation of H3K14 [PMID:16135810, PMID:17030603, PMID:26468280]. ATAC functions broadly in chromatin and transcriptional control — it is recruited to chromatin in a manner dependent on NURF remodeling, cooperates with other remodelers to stimulate nucleosome sliding, and contains a YEATS2-NC2beta module that contacts TBP to negatively regulate transcription [PMID:18084186, PMID:18838386, PMID:18327268]. Beyond histones, ATAC/TADA2A acetylates non-histone substrates: ATAC localizes to the mitotic spindle and GCN5-mediated acetylation targets Cyclin A for degradation, with depletion causing centrosome amplification, spindle defects, and delayed mitotic progression [PMID:20562830]. ATAC architecture depends on ATAC2/KAT14, whose loss disassembles the complex [PMID:18327268, PMID:19103755]. TADA2A also participates in development and stem-cell fate, including germline functions and germline stem cell differentiation via cooperation with Set2/Msl3 [PMID:16135810, PMID:34878097], and is implicated in disease through binding the alpha-synuclein A53T mutant — which reduces histone H3 acetylation and correlates with reduced TADA2A in Parkinson's disease substantia nigra — and through recruitment of ATAC by TAZ/YAP oncogenic fusion proteins to reprogram transcription [PMID:34065515, PMID:33913810].","teleology":[{"year":1996,"claim":"Established that the human ADA2 homolog physically partners with GCN5 and possesses intrinsic transcriptional activation capacity, defining TADA2A as a conserved coactivator-associated factor.","evidence":"Reciprocal yeast two-hybrid and transcriptional activation reporter assays in yeast and HeLa cells","pmids":["8552087"],"confidence":"Medium","gaps":["Did not define the native complex containing the pair","Substrate specificity unresolved"]},{"year":1997,"claim":"Mapped the ADA2-GCN5 interaction to a conserved GCN5 amino terminus and showed coordinated genomic organization/expression of TADA2A and GCN5, hinting at functional pairing.","evidence":"Two-hybrid deletion mapping; FISH chromosomal mapping and Northern expression profiling","pmids":["8552087","9073520"],"confidence":"Medium","gaps":["Did not establish whether co-regulation reflects shared function in vivo"]},{"year":2000,"claim":"Placed TADA2A in nuclear receptor coactivation by showing direct binding to thyroid hormone receptor and a requirement for hormone-dependent transcriptional activation.","evidence":"Yeast ada-mutant genetics, in vitro protein binding, and reporter assays with hTRbeta1/GRIP1/SRC-1","pmids":["10809234"],"confidence":"Medium","gaps":["Demonstrated in yeast genetic context; mammalian in vivo relevance not tested","No chromatin readout"]},{"year":2006,"claim":"Established that ADA2a and ADA2b are functionally distinct paralogs by showing ADA2a loss reduces H4K5/K12 acetylation while leaving the H3K9/K14 marks of ADA2b intact, defining ADA2a's H4-specific GCN5 complex.","evidence":"Drosophila genetic null mutants with polytene chromosome immunostaining and dGcn5-dAda2a genetic interaction","pmids":["16135810","17030603"],"confidence":"High","gaps":["Did not biochemically isolate the human complex","Direct enzymatic mechanism not reconstituted at this stage"]},{"year":2008,"claim":"Defined the subunit composition of the human and Drosophila ATAC complex containing TADA2A, identified it as a double-HAT complex, and showed it stimulates remodeler activity and contains a TBP-contacting repressive module.","evidence":"Biochemical purification with MS (MudPIT), co-IP, in vitro HAT and nucleosome sliding assays, transcriptional reporters","pmids":["18838386","18327268"],"confidence":"High","gaps":["Roles of individual ATAC subunits in substrate selection not fully dissected"]},{"year":2008,"claim":"Identified ATAC2/KAT14 as the architectural subunit whose loss disassembles mammalian ATAC, indicating TADA2A function depends on complex integrity.","evidence":"Immunoprecipitation, RNAi, in vitro HAT assay, and Atac2 knockout mice","pmids":["19103755"],"confidence":"High","gaps":["TADA2A's own contribution to complex assembly versus ATAC2 not separated here"]},{"year":2010,"claim":"Revealed a non-histone, mitotic function: ATAC localizes to the spindle and ATAC/GCN5-mediated acetylation targets Cyclin A for degradation, controlling mitotic progression.","evidence":"RNAi of Ada2a/Ada3, immunofluorescence, FACS cell-cycle analysis, in vitro acetylation of Cyclin A/Cdk2","pmids":["20562830"],"confidence":"High","gaps":["Direct acetylation site on Cyclin A by TADA2A-containing module not pinpointed","Link to SIRT2 partially characterized"]},{"year":2015,"claim":"Reconstituted the human HAT module to show ADA2a (TADA2A) enhances GCN5 acetylation of H3K14, while confirming ADA2b exerts a stronger effect, refining the paralog division of labor.","evidence":"In vitro HAT assays with recombinant and endogenous HAT modules on peptide and full-length histone substrates","pmids":["26468280"],"confidence":"High","gaps":["Structural basis for differential GCN5 stimulation not resolved","Non-histone substrate specificity within module not tested"]},{"year":2019,"claim":"Demonstrated that Ada2a nucleates ATAC assembly, formally establishing TADA2A as the defining subunit distinguishing ATAC from the ADA2b-nucleated SAGA/CHAT complexes.","evidence":"Affinity purification/MS and isoform-specific genetic analysis in Drosophila","pmids":["30559249"],"confidence":"High","gaps":["Nucleation mechanism in mammalian cells not directly shown"]},{"year":2021,"claim":"Connected TADA2A to disease, identifying it as an alpha-synuclein A53T binding partner whose engagement reduces histone H3 acetylation, with reduced TADA2A in Parkinson's disease tissue.","evidence":"BioID proximity labeling, nuclear fractionation, histone H3 acetylation Western blots, mouse PFF injection model, human PD tissue","pmids":["34065515"],"confidence":"Medium","gaps":["Causal contribution of the interaction to neurodegeneration not established","Whether ATAC complex integrity mediates the effect unclear"]},{"year":2021,"claim":"Implicated ATAC/TADA2A in oncogenic transcriptional reprogramming, showing TAZ-CAMTA1 and YAP-TFE3 fusions recruit ATAC subunits to co-drive a unique transcriptome.","evidence":"Proteomic AP-MS screen, genetic validation, and integrative ChIP-seq/RNA-seq","pmids":["33913810"],"confidence":"Medium","gaps":["Direct TADA2A contribution versus other ATAC subunits not isolated","Mechanism via YEATS2/ZZZ3 rather than TADA2A binding directly"]},{"year":2022,"claim":"Extended ATAC/TADA2A function to stem-cell fate and stress responses, showing roles in germline stem cell differentiation and in MSH6-dependent alkylation damage response coupled to sterol biosynthesis.","evidence":"Drosophila genetic epistasis with Set2/Msl3 in oogenesis; co-IP, RNAi, and sterol biosynthesis assays for MSH6/MPTAC/ATAC axis","pmids":["34878097","35189552"],"confidence":"Medium","gaps":["Direct acetylation targets in these pathways unidentified","TADA2A-specific requirement versus whole-complex requirement not separated"]},{"year":null,"claim":"How TADA2A structurally determines GCN5 substrate selection and how its non-histone acetylation and disease-associated interactions are regulated in mammalian cells remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the human ATAC HAT module bound to substrate","Full repertoire of non-histone substrates of TADA2A-containing ATAC undefined","Mechanism linking TADA2A loss to Parkinson's pathology not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[12,13]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[4,7,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[7,8]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[7,9,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12]}],"complexes":["ATAC complex","ATAC HAT module (GCN5-ADA2A-ADA3-SGF29)"],"partners":["GCN5","ADA3","SGF29","ATAC2","AATF","SNCA","TADA2B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75478","full_name":"Transcriptional adapter 2-alpha","aliases":["Transcriptional adapter 2-like","ADA2-like protein"],"length_aa":443,"mass_kda":51.5,"function":"Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4. Required for the function of some acidic activation domains, which activate transcription from a distant site (By similarity). Binds double-stranded DNA. Binds dinucleosomes, probably at the linker region between neighboring nucleosomes. Plays a role in chromatin remodeling. May promote TP53/p53 'Lys-321' acetylation, leading to reduced TP53 stability and transcriptional activity (PubMed:22644376). May also promote XRCC6 acetylation thus facilitating cell apoptosis in response to DNA damage (PubMed:22644376)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/O75478/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TADA2A","classification":"Common Essential","n_dependent_lines":789,"n_total_lines":1208,"dependency_fraction":0.6531456953642384},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TADA2A","total_profiled":1310},"omim":[{"mim_id":"618788","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 134; CCDC134","url":"https://www.omim.org/entry/618788"},{"mim_id":"617501","title":"LYSINE ACETYLTRANSFERASE 14; KAT14","url":"https://www.omim.org/entry/617501"},{"mim_id":"613374","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 101; CCDC101","url":"https://www.omim.org/entry/613374"},{"mim_id":"613373","title":"YEATS DOMAIN-CONTAINING PROTEIN 2; YEATS2","url":"https://www.omim.org/entry/613373"},{"mim_id":"609431","title":"MAP3K12-BINDING INHIBITORY PROTEIN; MBIP","url":"https://www.omim.org/entry/609431"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TADA2A"},"hgnc":{"alias_symbol":["ADA2","hADA2","ADA2A"],"prev_symbol":["TADA2L"]},"alphafold":{"accession":"O75478","domains":[{"cath_id":"-","chopping":"12-124","consensus_level":"medium","plddt":89.2285,"start":12,"end":124},{"cath_id":"-","chopping":"236-289","consensus_level":"medium","plddt":91.495,"start":236,"end":289},{"cath_id":"-","chopping":"298-346","consensus_level":"high","plddt":84.4922,"start":298,"end":346},{"cath_id":"1.10.10.10","chopping":"374-438","consensus_level":"high","plddt":87.7305,"start":374,"end":438},{"cath_id":"1.10.287","chopping":"166-232","consensus_level":"medium","plddt":91.1504,"start":166,"end":232}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75478","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75478-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75478-F1-predicted_aligned_error_v6.png","plddt_mean":84.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TADA2A","jax_strain_url":"https://www.jax.org/strain/search?query=TADA2A"},"sequence":{"accession":"O75478","fasta_url":"https://rest.uniprot.org/uniprotkb/O75478.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75478/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75478"}},"corpus_meta":[{"pmid":"18838386","id":"PMC_18838386","title":"Human ATAC Is a GCN5/PCAF-containing acetylase complex with a novel NC2-like histone fold module that interacts with the TATA-binding protein.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18838386","citation_count":176,"is_preprint":false},{"pmid":"8552087","id":"PMC_8552087","title":"Identification of human proteins functionally conserved with the yeast putative adaptors ADA2 and GCN5.","date":"1996","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8552087","citation_count":161,"is_preprint":false},{"pmid":"18327268","id":"PMC_18327268","title":"ATAC is a double histone acetyltransferase complex that stimulates nucleosome sliding.","date":"2008","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18327268","citation_count":155,"is_preprint":false},{"pmid":"8972232","id":"PMC_8972232","title":"Histone acetyltransferase activity is conserved between yeast and human GCN5 and is required for complementation of growth and transcriptional activation.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8972232","citation_count":143,"is_preprint":false},{"pmid":"19103755","id":"PMC_19103755","title":"The double-histone-acetyltransferase complex ATAC is essential for mammalian development.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19103755","citation_count":91,"is_preprint":false},{"pmid":"20562830","id":"PMC_20562830","title":"The ATAC acetyl transferase complex controls mitotic progression by targeting non-histone substrates.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/20562830","citation_count":76,"is_preprint":false},{"pmid":"16135810","id":"PMC_16135810","title":"The homologous Drosophila transcriptional adaptors ADA2a and ADA2b are both required for normal development but have different functions.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16135810","citation_count":66,"is_preprint":false},{"pmid":"24391497","id":"PMC_24391497","title":"Lysine acetyltransferase GCN5b interacts with AP2 factors and is required for Toxoplasma gondii proliferation.","date":"2014","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/24391497","citation_count":62,"is_preprint":false},{"pmid":"33913810","id":"PMC_33913810","title":"TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33913810","citation_count":57,"is_preprint":false},{"pmid":"17030603","id":"PMC_17030603","title":"The Drosophila histone acetyltransferase Gcn5 and transcriptional adaptor Ada2a are involved in nucleosomal histone H4 acetylation.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17030603","citation_count":52,"is_preprint":false},{"pmid":"15340070","id":"PMC_15340070","title":"Drosophila Ada2b is required for viability and normal histone H3 acetylation.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15340070","citation_count":52,"is_preprint":false},{"pmid":"32694556","id":"PMC_32694556","title":"CircRNA TADA2A relieves idiopathic pulmonary fibrosis by inhibiting proliferation and activation of fibroblasts.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32694556","citation_count":51,"is_preprint":false},{"pmid":"32799891","id":"PMC_32799891","title":"CircTADA2A suppresses the progression of colorectal cancer via miR-374a-3p/KLF14 axis.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/32799891","citation_count":50,"is_preprint":false},{"pmid":"10809234","id":"PMC_10809234","title":"GCN5 and ADA adaptor proteins regulate triiodothyronine/GRIP1 and SRC-1 coactivator-dependent gene activation by the human thyroid hormone receptor.","date":"2000","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/10809234","citation_count":49,"is_preprint":false},{"pmid":"26468280","id":"PMC_26468280","title":"Subunits of ADA-two-A-containing (ATAC) or Spt-Ada-Gcn5-acetyltrasferase (SAGA) Coactivator Complexes Enhance the Acetyltransferase Activity of GCN5.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26468280","citation_count":45,"is_preprint":false},{"pmid":"34588429","id":"PMC_34588429","title":"Circular RNA hsa_circ_0043280 inhibits cervical cancer tumor growth and metastasis via miR-203a-3p/PAQR3 axis.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34588429","citation_count":43,"is_preprint":false},{"pmid":"29514634","id":"PMC_29514634","title":"Multi-tissue transcriptomic study reveals the main role of liver in the chicken adaptive response to a switch in dietary energy source through the transcriptional regulation of lipogenesis.","date":"2018","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/29514634","citation_count":35,"is_preprint":false},{"pmid":"18084186","id":"PMC_18084186","title":"The Drosophila NURF remodelling and the ATAC histone acetylase complexes functionally interact and are required for global chromosome organization.","date":"2007","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/18084186","citation_count":33,"is_preprint":false},{"pmid":"22178801","id":"PMC_22178801","title":"Prenatally diagnosed 17q12 microdeletion syndrome with a novel association with congenital diaphragmatic hernia.","date":"2011","source":"Fetal diagnosis and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/22178801","citation_count":33,"is_preprint":false},{"pmid":"36879016","id":"PMC_36879016","title":"Conserved and plant-specific histone acetyltransferase complexes cooperate to regulate gene transcription and plant development.","date":"2023","source":"Nature plants","url":"https://pubmed.ncbi.nlm.nih.gov/36879016","citation_count":31,"is_preprint":false},{"pmid":"15607423","id":"PMC_15607423","title":"Asymmetric expression of transcripts derived from the shared promoter between the divergently oriented ACACA and TADA2L genes.","date":"2005","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/15607423","citation_count":24,"is_preprint":false},{"pmid":"34065515","id":"PMC_34065515","title":"α-Synuclein A53T Binds to Transcriptional Adapter 2-Alpha and Blocks Histone H3 Acetylation.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34065515","citation_count":24,"is_preprint":false},{"pmid":"34878097","id":"PMC_34878097","title":"Msl3 promotes germline stem cell differentiation in female Drosophila.","date":"2022","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34878097","citation_count":24,"is_preprint":false},{"pmid":"38347496","id":"PMC_38347496","title":"Identification of candidate regulatory genes for intramuscular fatty acid composition in pigs by transcriptome analysis.","date":"2024","source":"Genetics, selection, evolution : GSE","url":"https://pubmed.ncbi.nlm.nih.gov/38347496","citation_count":20,"is_preprint":false},{"pmid":"34296306","id":"PMC_34296306","title":"Circular RNA TADA2A promotes proliferation and migration via modulating of miR‑638/KIAA0101 signal in non‑small cell lung cancer.","date":"2021","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/34296306","citation_count":19,"is_preprint":false},{"pmid":"30559249","id":"PMC_30559249","title":"The Drosophila Dbf4 ortholog Chiffon forms a complex with Gcn5 that is necessary for histone acetylation and viability.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30559249","citation_count":19,"is_preprint":false},{"pmid":"32735945","id":"PMC_32735945","title":"The Gcn5 complexes in Drosophila as a model for metazoa.","date":"2020","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/32735945","citation_count":18,"is_preprint":false},{"pmid":"33293831","id":"PMC_33293831","title":"TRPS1 and YAP1 Regulate Cell Proliferation and Drug Resistance of Osteosarcoma via Competitively Binding to the Target of circTADA2A - miR-129-5p.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33293831","citation_count":18,"is_preprint":false},{"pmid":"24239950","id":"PMC_24239950","title":"Oesophageal atresia with tracheoesophageal fistula and anal atresia in a patient with a de novo microduplication in 17q12.","date":"2013","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24239950","citation_count":16,"is_preprint":false},{"pmid":"30079588","id":"PMC_30079588","title":"The lysine acetyltransferase GCN5 contributes to human papillomavirus oncoprotein E7-induced cell proliferation via up-regulating E2F1.","date":"2018","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30079588","citation_count":15,"is_preprint":false},{"pmid":"18775519","id":"PMC_18775519","title":"An adenosine A(2A) antagonist injected in the NTS reverses thermal prolongation of the LCR in decerebrate piglets.","date":"2008","source":"Respiratory physiology & neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/18775519","citation_count":12,"is_preprint":false},{"pmid":"20418346","id":"PMC_20418346","title":"An adenosine A(2A) agonist injected in the nucleus of the solitary tract prolongs the laryngeal chemoreflex by a GABAergic mechanism in decerebrate piglets.","date":"2010","source":"Experimental physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20418346","citation_count":10,"is_preprint":false},{"pmid":"9073520","id":"PMC_9073520","title":"The human transcriptional adaptor genes TADA2L and GCN5L2 colocalize to chromosome 17q12-q21 and display a similar tissue expression pattern.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9073520","citation_count":9,"is_preprint":false},{"pmid":"29049012","id":"PMC_29049012","title":"Transcriptome Profiling Uncovers Potential Common Mechanisms in Fetal Trisomies 18 and 21.","date":"2017","source":"Omics : a journal of integrative biology","url":"https://pubmed.ncbi.nlm.nih.gov/29049012","citation_count":9,"is_preprint":false},{"pmid":"38007639","id":"PMC_38007639","title":"Integrative analysis of histone acetyltransferase KAT2A in human cancer.","date":"2023","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/38007639","citation_count":7,"is_preprint":false},{"pmid":"15777699","id":"PMC_15777699","title":"Intimate relationship between the genes of two transcriptional coactivators, ADA2a and PIMT, of Drosophila.","date":"2005","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15777699","citation_count":6,"is_preprint":false},{"pmid":"35887219","id":"PMC_35887219","title":"Control of Directed Cell Migration after Tubular Cell Injury by Nucleotide Signaling.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35887219","citation_count":6,"is_preprint":false},{"pmid":"29232376","id":"PMC_29232376","title":"Che1/AATF interacts with subunits of the histone acetyltransferase core module of SAGA complexes.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29232376","citation_count":5,"is_preprint":false},{"pmid":"19921261","id":"PMC_19921261","title":"The dissociable RPB4 subunit of RNA Pol II has vital functions in Drosophila.","date":"2009","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/19921261","citation_count":4,"is_preprint":false},{"pmid":"38216274","id":"PMC_38216274","title":"Prenatal diagnosis and perinatal findings of 17q12 microdeletion encompassing HNF1B in a fetus with bilateral hyperechogenic kidneys on fetal ultrasound and mild renal abnormality after birth, and a review of the literature of prenatal diagnosis of 17q12 microdeletion.","date":"2024","source":"Taiwanese journal of obstetrics & gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/38216274","citation_count":4,"is_preprint":false},{"pmid":"35189552","id":"PMC_35189552","title":"MPTAC links alkylation damage signaling to sterol biosynthesis.","date":"2022","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/35189552","citation_count":4,"is_preprint":false},{"pmid":"35744859","id":"PMC_35744859","title":"Beyond Moco Biosynthesis-Moonlighting Roles of MoaE and MOCS2.","date":"2022","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35744859","citation_count":3,"is_preprint":false},{"pmid":"23262334","id":"PMC_23262334","title":"Characterization of a far upstream located promoter expressing the acetyl-CoA carboxylase-alpha in the brain of cattle.","date":"2012","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/23262334","citation_count":2,"is_preprint":false},{"pmid":"40608154","id":"PMC_40608154","title":"CircTADA2A inhibits cell proliferation and promotes ferroptosis by sponging miR-638 in acute myeloid leukemia.","date":"2025","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/40608154","citation_count":1,"is_preprint":false},{"pmid":"38199596","id":"PMC_38199596","title":"MBIP promotes ESCC metastasis by activating MAPK pathway.","date":"2024","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/38199596","citation_count":1,"is_preprint":false},{"pmid":"39097891","id":"PMC_39097891","title":"Circ_0006220 (circ-TADA2A) accelerates prostate cancer cell malignant behaviors through miR-520f-3p/CDCA7 axis.","date":"2024","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/39097891","citation_count":0,"is_preprint":false},{"pmid":"41572607","id":"PMC_41572607","title":"Development and optimization of T-ARMS PCR assays for detection of lethal haplotypes of TADA2A, UR1B, and PORL1B in pigs in Vietnam.","date":"2026","source":"Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/41572607","citation_count":0,"is_preprint":false},{"pmid":"40772539","id":"PMC_40772539","title":"PCR-RFLP assays to detect recessive lethal alleles in Landrace and Duroc pigs in Vietnam.","date":"2025","source":"Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/40772539","citation_count":0,"is_preprint":false},{"pmid":"39013295","id":"PMC_39013295","title":"Further screening of SNP loci of eggshell translucency related genes and evaluation of genetic effects.","date":"2024","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/39013295","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.07.669221","title":"WIND1 controls cell fate transition through histone acetylation and deacetylation during somatic embryogenesis","date":"2025-08-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.07.669221","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26699,"output_tokens":4776,"usd":0.075869,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12837,"output_tokens":4220,"usd":0.084843,"stage2_stop_reason":"end_turn"},"total_usd":0.160712,"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\": 1996,\n      \"finding\": \"Human ADA2 (hADA2/TADA2A) interacts with human GCN5 (hGCN5) in vivo as shown by yeast two-hybrid assay, and hGCN5 interacts with yeast ADA2, indicating conserved complex formation. hADA2 contains a cryptic activation domain, and GAL4-hADA2 activates transcription in HeLa cells; hADA2 or hGCN5 augments GAL4-VP16 activation.\",\n      \"method\": \"Yeast two-hybrid assay, transcriptional activation assays in yeast and HeLa cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal two-hybrid and functional transcription assays in two cellular systems, single lab\",\n      \"pmids\": [\"8552087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The region of yeast ADA2 that interacts with yGCN5 maps to the amino terminus, which is highly conserved in hADA2/TADA2A, establishing structural conservation of the ADA2-GCN5 interaction interface.\",\n      \"method\": \"Yeast two-hybrid mapping with deletion constructs\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping two-hybrid, single lab, functionally validated\",\n      \"pmids\": [\"8552087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"TADA2L (TADA2A) and GCN5L2 co-localize to chromosome 17q12-q21 and are expressed at relatively similar levels across all human tissues, suggesting coordinated regulation.\",\n      \"method\": \"Northern blot analysis, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal mapping by FISH and expression profiling by Northern blot, single lab\",\n      \"pmids\": [\"9073520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"hADA2/TADA2A is required for T3/GRIP1 and SRC-1 coactivator-dependent transcriptional activation by human thyroid hormone receptor (hTRbeta1) in yeast. hTRbeta1 binds directly to hADA2 in vitro protein-protein interaction experiments, placing TADA2A in the nuclear receptor coactivation pathway.\",\n      \"method\": \"Yeast genetics (ada mutants), in vitro protein-protein interaction, transcriptional reporter assays\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay plus functional genetics, single lab, two orthogonal methods\",\n      \"pmids\": [\"10809234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Drosophila Ada2a null mutants are late-larval lethal and show defects in cell proliferation. Ada2a function is required in the female germ line. Ada2a null mutation does NOT reduce histone H3 K14 or H3 K9 acetylation (in contrast to Ada2b), establishing that ADA2a and ADA2b have distinct histone substrate specificities.\",\n      \"method\": \"Genetic null mutants, pole-cell transplantation germ-line mosaics, histone acetylation immunostaining\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null mutant genetic analysis with specific histone acetylation readouts, replicated across multiple phenotypic assays\",\n      \"pmids\": [\"16135810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The Drosophila Ada2a gene shares overlapping regulatory/promoter regions with the Dtl (PIMT) gene and also produces RPB4 via alternative splicing, establishing a complex genomic architecture for Ada2a.\",\n      \"method\": \"Reporter gene fusions in tissue culture and transgenic animals, alternative splicing analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays and transgenic analysis in Drosophila, single lab\",\n      \"pmids\": [\"15777699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TADA2A (TADA2L) shares a bidirectional promoter with ACACA in humans, mice, rats, and sheep; this shared promoter co-regulates transcripts for both genes in an asymmetric fashion, with RNA polymerase II concentration in the intergenic region reflecting transcript abundance differences.\",\n      \"method\": \"5'-RACE, RNA polymerase II ChIP, Northern analysis across tissues\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RACE, ChIP, Northern), single lab\",\n      \"pmids\": [\"15607423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In Drosophila, loss of dAda2a results in reduced nucleosomal histone H4 acetylation at lysines 12 and 5, while H3 K9 and K14 acetylation (established by dAda2b-containing complexes) is unaffected. Genetic interaction between dGcn5 and dAda2a produces similar chromosome structural and developmental defects, placing dAda2a in an H4-specific GCN5-containing complex (ATAC).\",\n      \"method\": \"Genetic null mutants, immunostaining of polytene chromosomes, genetic interaction analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mutants with specific histone mark readouts, replicated across two Ada2 paralogs in same study\",\n      \"pmids\": [\"17030603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Drosophila, mutations in Ada2a (ATAC component) induce decondensation of the male X chromosome similar to NURF mutants. Ada2a chromosome binding and histone H4-Lys12 acetylation are compromised in Iswi and Nurf301 mutants, indicating that NURF nucleosome remodeling is required for ATAC/Ada2a to access chromatin.\",\n      \"method\": \"Genetic epistasis, polytene chromosome immunostaining, transcript profiling\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with specific chromatin readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"18084186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human ATAC complex was purified and found to contain ADA2A (TADA2A), ADA3, GCN5 or PCAF, STAF36/WDR5, POLE3/CHRAC17, POLE4, TAK1/MAP3K7, MBIP, YEATS2, and NC2beta. The YEATS2-NC2beta histone fold module interacts with TBP and negatively regulates transcription when recruited to a promoter, establishing TADA2A as a core subunit of human ATAC distinct from STAGA.\",\n      \"method\": \"Biochemical purification (mass spectrometry), co-immunoprecipitation, transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — complex purification with MS identification plus functional transcriptional assays, multiple orthogonal methods\",\n      \"pmids\": [\"18838386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The Drosophila ATAC complex, containing Ada2a, is a double HAT complex with Gcn5 and Atac2 (KAT14) as two acetyltransferases. ATAC stimulates nucleosome sliding by ISWI, SWI-SNF, and RSC remodeling complexes but does not itself exhibit nucleosome-remodeling activity.\",\n      \"method\": \"MudPIT mass spectrometry, in vitro HAT assays with recombinant Atac2, in vitro nucleosome sliding assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in vitro HAT assay with mutagenesis, MudPIT MS for complex composition, replicated functional assays\",\n      \"pmids\": [\"18327268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mammalian ATAC complex contains GCN5, ATAC2, and ADA2A (TADA2A) among other subunits. ATAC2 depletion results in disassembly of the complex, showing that ATAC2 plays an architectural role in maintaining mammalian ATAC integrity—and consequently the functional complex containing TADA2A.\",\n      \"method\": \"Immunoprecipitation, RNAi depletion, in vitro HAT assay with recombinant ATAC2, Atac2 knockout mice\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic knockout mouse plus biochemical complex analysis plus in vitro HAT assay, multiple orthogonal methods\",\n      \"pmids\": [\"19103755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATAC complex (containing Ada2a/TADA2A) localizes to the mitotic spindle. RNAi depletion of Ada2a or Ada3 causes centrosome multiplication, defective spindle and midbody formation, binucleated cells, delayed M/G1 transition, and hyperacetylation of histone H4K16 and alpha-tubulin. ATAC/Gcn5-mediated acetylation targets Cyclin A for degradation, which regulates SIRT2 deacetylase activity, establishing a non-histone substrate role for ATAC in mitotic progression.\",\n      \"method\": \"RNAi knockdown, immunofluorescence localization, cell cycle FACS analysis, in vitro acetylation assays of Cyclin A/Cdk2\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi with specific mitotic phenotypes, direct localization, in vitro acetylation of non-histone substrate, mechanistic pathway established\",\n      \"pmids\": [\"20562830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The HAT module of human ATAC is composed of GCN5, ADA2a (TADA2A), ADA3, and SGF29. ADA2a-containing (ATAC) HAT module enhances GCN5 acetyltransferase activity, primarily acetylating histone H3K14. ADA2b (in SAGA) has a stronger influence on GCN5 activity than ADA2a. The lysine acetylation specificity of GCN5 on histone tails is not altered by incorporation into ATAC versus SAGA HAT modules.\",\n      \"method\": \"In vitro HAT assays with purified recombinant and endogenous HAT modules, histone tail peptides and full-length histones as substrates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro HAT assay with recombinant and endogenous modules, multiple substrates tested, single lab\",\n      \"pmids\": [\"26468280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Che-1/AATF interacts with ADA2A (TADA2A) and ADA2B in human cells (co-immunoprecipitation) and in yeast two-hybrid assays. Domain mapping identified the regions of ADA2A and GCN5 required for these interactions.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, yeast two-hybrid domain mapping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus two-hybrid domain mapping, single lab, two orthogonal methods\",\n      \"pmids\": [\"29232376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Drosophila, Ada2a nucleates formation of the ATAC complex (distinct from SAGA which is nucleated by Ada2b). Only the Ada2b-PB isoform is in SAGA; Ada2b-PA forms the distinct CHAT complex. This establishes that Ada2a is the defining subunit of the ATAC complex.\",\n      \"method\": \"Affinity purification, mass spectrometry, genetic analysis of isoform-specific mutants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — affinity purification/MS of distinct complexes combined with genetic isoform analysis, multiple orthogonal methods\",\n      \"pmids\": [\"30559249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Alpha-synuclein A53T mutant preferentially localizes to the nucleus and binds TADA2A, identified as a novel binding partner via BioID proximity labeling. Alpha-synuclein A53T significantly reduces histone H3 acetylation in SH-SY5Y cells and in mouse striatum/substantia nigra after alpha-syn preformed fibril injection. TADA2A levels are decreased in the substantia nigra of Parkinson's disease patients, linking the alpha-syn A53T-TADA2A interaction to neurotoxicity.\",\n      \"method\": \"BioID proximity labeling, nuclear fractionation/localization, Western blot for histone H3 acetylation, mouse stereotaxic injection model, human PD tissue analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID identification plus functional acetylation readout in cells and in vivo, single lab, multiple methods\",\n      \"pmids\": [\"34065515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TAZ-CAMTA1 and YAP-TFE3 oncogenic fusion proteins interact with YEATS2 and ZZZ3, components of the ATAC complex (which contains TADA2A/ADA2A), as identified by a combined proteomic/genetic screen. The fusion proteins drive a unique transcriptome by simultaneously hyperactivating TEAD-based transcription and modulating chromatin via interaction with ATAC.\",\n      \"method\": \"Proteomic screen (affinity purification/MS), genetic validation, integrative next-generation sequencing (ChIP-seq, RNA-seq)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS for complex interaction, integrative genomics for functional consequence, single lab\",\n      \"pmids\": [\"33913810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Drosophila, the histone acetyltransferase complex Ada2a-containing (ATAC) cooperates with Msl3 (H3K36me3 reader) and Set2 to regulate germline stem cell (GSC) differentiation during oogenesis, establishing a role for ATAC in GSC fate transition.\",\n      \"method\": \"Genetic mutant analysis, epistasis, transcriptional profiling in Drosophila oogenesis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in defined developmental context, single lab\",\n      \"pmids\": [\"34878097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MSH6 stabilization in response to alkylation damage requires interactions with both MPTAC and the Ada2a-containing ATAC complex. MSH6 promotes sterol biosynthesis via the mevalonate pathway in a MPTAC- and ATAC-dependent manner, placing ATAC (and thus TADA2A) in an alkylation damage response-sterol biosynthesis pathway.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, biochemical assays for sterol biosynthesis\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional pathway assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"35189552\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TADA2A (ADA2A/hADA2) is a core structural and functional subunit of the human and metazoan ATAC (Ada Two A-containing) histone acetyltransferase complex, where it assembles with GCN5, ADA3, and SGF29 to stimulate GCN5-mediated acetylation of histone H3K14 and H4K5/K12; it is functionally and biochemically distinct from the paralogous ADA2B subunit of the SAGA complex, and beyond histone substrates, ATAC/TADA2A directly acetylates non-histone targets including Cyclin A to control mitotic progression, interacts with alpha-synuclein A53T to modulate histone H3 acetylation relevant to Parkinson's disease pathology, and is recruited by oncogenic TAZ/YAP fusion proteins to drive transcriptional reprogramming in cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TADA2A (hADA2/TADA2L) is the defining, nucleating subunit of the metazoan ATAC histone acetyltransferase complex, where it assembles with GCN5/PCAF, ADA3, and SGF29 to form the HAT module and stimulate GCN5-dependent acetylation [#9, #13, #15]. The TADA2A-GCN5 interaction is conserved from yeast and maps to a conserved GCN5 amino-terminal interface, and TADA2A itself carries a cryptic transcriptional activation domain [#0, #1]. Within ATAC, TADA2A directs a histone substrate preference distinct from its SAGA paralog ADA2B: loss of ADA2a/TADA2A in Drosophila reduces nucleosomal histone H4K5/K12 acetylation while leaving H3K9/K14 (the ADA2b/SAGA marks) intact, and reconstituted human ATAC HAT modules enhance GCN5 acetylation of H3K14 [#4, #7, #13]. ATAC functions broadly in chromatin and transcriptional control — it is recruited to chromatin in a manner dependent on NURF remodeling, cooperates with other remodelers to stimulate nucleosome sliding, and contains a YEATS2-NC2beta module that contacts TBP to negatively regulate transcription [#8, #9, #10]. Beyond histones, ATAC/TADA2A acetylates non-histone substrates: ATAC localizes to the mitotic spindle and GCN5-mediated acetylation targets Cyclin A for degradation, with depletion causing centrosome amplification, spindle defects, and delayed mitotic progression [#12]. ATAC architecture depends on ATAC2/KAT14, whose loss disassembles the complex [#10, #11]. TADA2A also participates in development and stem-cell fate, including germline functions and germline stem cell differentiation via cooperation with Set2/Msl3 [#4, #18], and is implicated in disease through binding the alpha-synuclein A53T mutant — which reduces histone H3 acetylation and correlates with reduced TADA2A in Parkinson's disease substantia nigra — and through recruitment of ATAC by TAZ/YAP oncogenic fusion proteins to reprogram transcription [#16, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the human ADA2 homolog physically partners with GCN5 and possesses intrinsic transcriptional activation capacity, defining TADA2A as a conserved coactivator-associated factor.\",\n      \"evidence\": \"Reciprocal yeast two-hybrid and transcriptional activation reporter assays in yeast and HeLa cells\",\n      \"pmids\": [\"8552087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the native complex containing the pair\", \"Substrate specificity unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapped the ADA2-GCN5 interaction to a conserved GCN5 amino terminus and showed coordinated genomic organization/expression of TADA2A and GCN5, hinting at functional pairing.\",\n      \"evidence\": \"Two-hybrid deletion mapping; FISH chromosomal mapping and Northern expression profiling\",\n      \"pmids\": [\"8552087\", \"9073520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether co-regulation reflects shared function in vivo\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Placed TADA2A in nuclear receptor coactivation by showing direct binding to thyroid hormone receptor and a requirement for hormone-dependent transcriptional activation.\",\n      \"evidence\": \"Yeast ada-mutant genetics, in vitro protein binding, and reporter assays with hTRbeta1/GRIP1/SRC-1\",\n      \"pmids\": [\"10809234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in yeast genetic context; mammalian in vivo relevance not tested\", \"No chromatin readout\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that ADA2a and ADA2b are functionally distinct paralogs by showing ADA2a loss reduces H4K5/K12 acetylation while leaving the H3K9/K14 marks of ADA2b intact, defining ADA2a's H4-specific GCN5 complex.\",\n      \"evidence\": \"Drosophila genetic null mutants with polytene chromosome immunostaining and dGcn5-dAda2a genetic interaction\",\n      \"pmids\": [\"16135810\", \"17030603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not biochemically isolate the human complex\", \"Direct enzymatic mechanism not reconstituted at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the subunit composition of the human and Drosophila ATAC complex containing TADA2A, identified it as a double-HAT complex, and showed it stimulates remodeler activity and contains a TBP-contacting repressive module.\",\n      \"evidence\": \"Biochemical purification with MS (MudPIT), co-IP, in vitro HAT and nucleosome sliding assays, transcriptional reporters\",\n      \"pmids\": [\"18838386\", \"18327268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Roles of individual ATAC subunits in substrate selection not fully dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified ATAC2/KAT14 as the architectural subunit whose loss disassembles mammalian ATAC, indicating TADA2A function depends on complex integrity.\",\n      \"evidence\": \"Immunoprecipitation, RNAi, in vitro HAT assay, and Atac2 knockout mice\",\n      \"pmids\": [\"19103755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TADA2A's own contribution to complex assembly versus ATAC2 not separated here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed a non-histone, mitotic function: ATAC localizes to the spindle and ATAC/GCN5-mediated acetylation targets Cyclin A for degradation, controlling mitotic progression.\",\n      \"evidence\": \"RNAi of Ada2a/Ada3, immunofluorescence, FACS cell-cycle analysis, in vitro acetylation of Cyclin A/Cdk2\",\n      \"pmids\": [\"20562830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct acetylation site on Cyclin A by TADA2A-containing module not pinpointed\", \"Link to SIRT2 partially characterized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Reconstituted the human HAT module to show ADA2a (TADA2A) enhances GCN5 acetylation of H3K14, while confirming ADA2b exerts a stronger effect, refining the paralog division of labor.\",\n      \"evidence\": \"In vitro HAT assays with recombinant and endogenous HAT modules on peptide and full-length histone substrates\",\n      \"pmids\": [\"26468280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for differential GCN5 stimulation not resolved\", \"Non-histone substrate specificity within module not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that Ada2a nucleates ATAC assembly, formally establishing TADA2A as the defining subunit distinguishing ATAC from the ADA2b-nucleated SAGA/CHAT complexes.\",\n      \"evidence\": \"Affinity purification/MS and isoform-specific genetic analysis in Drosophila\",\n      \"pmids\": [\"30559249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nucleation mechanism in mammalian cells not directly shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected TADA2A to disease, identifying it as an alpha-synuclein A53T binding partner whose engagement reduces histone H3 acetylation, with reduced TADA2A in Parkinson's disease tissue.\",\n      \"evidence\": \"BioID proximity labeling, nuclear fractionation, histone H3 acetylation Western blots, mouse PFF injection model, human PD tissue\",\n      \"pmids\": [\"34065515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of the interaction to neurodegeneration not established\", \"Whether ATAC complex integrity mediates the effect unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated ATAC/TADA2A in oncogenic transcriptional reprogramming, showing TAZ-CAMTA1 and YAP-TFE3 fusions recruit ATAC subunits to co-drive a unique transcriptome.\",\n      \"evidence\": \"Proteomic AP-MS screen, genetic validation, and integrative ChIP-seq/RNA-seq\",\n      \"pmids\": [\"33913810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TADA2A contribution versus other ATAC subunits not isolated\", \"Mechanism via YEATS2/ZZZ3 rather than TADA2A binding directly\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended ATAC/TADA2A function to stem-cell fate and stress responses, showing roles in germline stem cell differentiation and in MSH6-dependent alkylation damage response coupled to sterol biosynthesis.\",\n      \"evidence\": \"Drosophila genetic epistasis with Set2/Msl3 in oogenesis; co-IP, RNAi, and sterol biosynthesis assays for MSH6/MPTAC/ATAC axis\",\n      \"pmids\": [\"34878097\", \"35189552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct acetylation targets in these pathways unidentified\", \"TADA2A-specific requirement versus whole-complex requirement not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TADA2A structurally determines GCN5 substrate selection and how its non-histone acetylation and disease-associated interactions are regulated in mammalian cells remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the human ATAC HAT module bound to substrate\", \"Full repertoire of non-histone substrates of TADA2A-containing ATAC undefined\", \"Mechanism linking TADA2A loss to Parkinson's pathology not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [4, 7, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [7, 9, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"ATAC complex\",\n      \"ATAC HAT module (GCN5-ADA2A-ADA3-SGF29)\"\n    ],\n    \"partners\": [\n      \"GCN5\",\n      \"ADA3\",\n      \"SGF29\",\n      \"ATAC2\",\n      \"AATF\",\n      \"SNCA\",\n      \"TADA2B\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}