{"gene":"TRRAP","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1998,"finding":"TRRAP (434 kDa) was identified as a novel protein with homology to the ATM/PI3-kinase family that directly interacts with the c-Myc N-terminus and the E2F-1 transactivation domain; expression of transdominant TRRAP mutants or antisense RNA blocks c-Myc- and E1A-mediated oncogenic transformation.","method":"Co-immunoprecipitation, transdominant mutant overexpression, antisense RNA, oncogenic transformation assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding experiments plus functional loss-of-function (transdominant mutants and antisense) with defined transformation phenotype; founding paper replicated extensively","pmids":["9708738"],"is_preprint":false},{"year":2000,"finding":"TRRAP recruits histone acetyltransferase activity (catalyzed by hGCN5) to c-Myc, providing a mechanism for Myc-dependent chromatin acetylation and transcriptional activation; this opposes Mad-family recruitment of histone deacetylases.","method":"Co-immunoprecipitation, histone acetyltransferase activity assay, functional transcription/transformation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical HAT activity assay plus functional epistasis; independently replicated by multiple subsequent studies","pmids":["10611234"],"is_preprint":false},{"year":2001,"finding":"The ATM-related domain of TRRAP (not its Myc-binding domain, which maps to a separable region) is required for assembly of a functional HAT complex; mutation of this domain inhibits Myc-mediated oncogenic transformation and the Myc-binding region independently inhibits cell growth when overexpressed.","method":"Domain deletion/mutation analysis, HAT complex assembly assays, oncogenic transformation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — structure-function mapping with mutagenesis plus functional transformation readout; replicated conceptually by subsequent studies","pmids":["11445536"],"is_preprint":false},{"year":2001,"finding":"Homozygous null mutation of Trrap in mice causes peri-implantation lethality due to blocked blastocyst proliferation; conditional loss causes aberrant mitotic exit, cytokinesis failure, endoreduplication, chromosome missegregation, disrupted spindles, and compromised Cdk1 activity, establishing TRRAP as essential for the mitotic checkpoint and normal cell cycle progression.","method":"Knockout mouse (null and inducible Cre-loxP), cell cycle analysis, immunofluorescence of mitotic markers, Cdk1 activity assay","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal cellular phenotype readouts and biochemical Cdk1 activity measurement","pmids":["11544477"],"is_preprint":false},{"year":2001,"finding":"E2F-1 and E2F-4 transactivation domains bind GCN5 and TRRAP in vivo; TRRAP/GCN5 co-expression stimulates E2F-mediated transactivation; E2F-4 with mutations in the transactivation domain shows correlated loss of TRRAP/GCN5 binding, HAT activity recruitment, and transcriptional activation.","method":"Co-immunoprecipitation, transactivation reporter assay, HAT activity assay, site-directed mutagenesis of E2F transactivation domain","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, HAT assay, mutagenesis, reporter assay) in a single study","pmids":["11418595"],"is_preprint":false},{"year":2001,"finding":"Adenovirus E1A requires interaction with TRRAP for cellular transformation and immortalization; a domain of E1A (residues 12–54) mediates TRRAP binding, and overexpression of a competing TRRAP fragment blocks both E1A–TRRAP interaction and transformation; E1A(Δ26–35) that fails to bind TRRAP is defective in transformation.","method":"Co-immunoprecipitation, TRRAP fragment competition, transformation assay, E1A deletion mutants","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding plus loss-of-function mutants with defined transformation phenotype","pmids":["11781841"],"is_preprint":false},{"year":2002,"finding":"TRRAP binding and recruitment of histone H3/H4 acetyltransferase activities by c-Myc or N-Myc are required for transactivation of the silent TERT gene and for oncogenic transformation, but are dispensable for partial induction of basally expressed genes and for rescuing growth of myc-null fibroblasts.","method":"TRRAP binding-defective Myc mutants, ChIP for histone acetylation at TERT promoter, transformation assay, gene expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Myc family members tested, ChIP plus functional readouts, defining differential TRRAP requirement","pmids":["12077335"],"is_preprint":false},{"year":2002,"finding":"p53 directly binds a TRRAP domain (previously shown as an activator docking site) in vitro; p53 recruits TRRAP to the mdm2 promoter in a p53-dependent manner (ChIP); TRRAP functionally cooperates with p53 to activate mdm2 transcription and this is followed by increased histone acetylation at the mdm2 promoter.","method":"GST pulldown (direct binding), ChIP, antisense TRRAP knockdown, transcriptional reporter assay, pharmacological HDAC inhibition","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro direct binding (GST pulldown) plus ChIP and functional knockdown with multiple orthogonal methods","pmids":["12138177"],"is_preprint":false},{"year":2003,"finding":"c-Myc co-recruits TRRAP and GCN5 via direct physical interactions of its N-terminal activation/transformation domain with the human STAGA complex; TRRAP and GCN5 cooperate to enhance Myc-dependent transcription and this synergy requires both the SPT3/GCN5 interaction domain of TRRAP and the HAT activity of GCN5, establishing TRRAP as an adaptor within STAGA.","method":"Co-immunoprecipitation, GST pulldown, in vivo transcription reporter assay, HAT activity assay, dominant-negative TRRAP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding plus functional epistasis with HAT activity requirement established","pmids":["12660246"],"is_preprint":false},{"year":2003,"finding":"TRRAP is a component of the mammalian TRRAP/TIP60 HAT complex; MRGBP, TRCp120, DMAP1, MRG15, and MRGX were identified as previously unrecognized subunits of this complex by purification and mass spectrometry from HeLa nuclear extracts.","method":"Biochemical purification from HeLa nuclear extracts, mass spectrometry, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — biochemical purification plus mass spectrometry identification of complex components","pmids":["12963728"],"is_preprint":false},{"year":2003,"finding":"E1A binds GCN5 and TRRAP in vivo early during adenovirus infection and associates with significant HAT activity (partly attributable to GCN5); E1A distinctly binds TRRAP/GCN5, p300/CBP, and PCAF HAT complexes; E1A represses c-Myc- and E2F-1-directed transcription by sequestering GCN5 and/or TRRAP.","method":"Co-immunoprecipitation during adenovirus infection, in vitro HAT activity assay, transcription reporter assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus HAT assay, single lab study","pmids":["12743606"],"is_preprint":false},{"year":2004,"finding":"Loss of Trrap causes chromosome missegregation and mitotic checkpoint defects due to defective transcription of Mad1 and Mad2; Trrap-mediated H3 and H4 acetylation at Mad1/Mad2 gene promoters is required; Trrap associates with TIP60 and PCAF at these promoters in a cell cycle-dependent manner; ectopic Mad1/Mad2 expression fully restores the mitotic checkpoint in Trrap-deficient cells.","method":"Conditional knockout mouse cells, ChIP, siRNA knockdown, immunofluorescence, epistasis rescue experiment (Mad1/Mad2 overexpression), cell cycle analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, genetic epistasis rescue, and conditional loss-of-function with multiple orthogonal methods","pmids":["15549134"],"is_preprint":false},{"year":2005,"finding":"YL1 protein is a subunit of the mammalian TRRAP/TIP60 HAT complex, as well as a component of the SRCAP chromatin-remodeling complex, establishing a molecular link between TRRAP/TIP60 and SWR1-type chromatin remodeling.","method":"Biochemical purification from HeLa cells, mass spectrometry, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical purification and Co-IP, single lab","pmids":["15647280"],"is_preprint":false},{"year":2005,"finding":"Trrap and Tip60 bind to chromatin surrounding DNA double-strand break (DSB) sites in vivo; Trrap depletion impairs DNA-damage-induced histone H4 hyperacetylation and accumulation of repair molecules at DSBs, resulting in defective homologous recombination (HR) repair; chromatin relaxation counteracts the repair defect, indicating TRRAP acts by regulating chromatin accessibility at break sites.","method":"ChIP at DSB sites, siRNA knockdown, HR repair assay, pharmacological chromatin relaxation (rescue experiment), ATM signaling assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, siRNA, functional repair assay, rescue), replicated concept in subsequent studies","pmids":["16341205"],"is_preprint":false},{"year":2005,"finding":"BRCA1 C-terminal transactivation domain mutations found in breast cancer patients abolish physical interaction between BRCA1 and TRRAP and reduce hGCN5/TRRAP co-activation of BRCA1 transactivation; hGCN5 HAT activity is required for this co-regulatory complex function in both BRCA1-mediated gene regulation and DNA repair.","method":"Co-immunoprecipitation, biochemical purification, transcriptional reporter assay, HAT activity analysis, BRCA1 cancer mutation mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional reporter assay, single lab","pmids":["16260778"],"is_preprint":false},{"year":2005,"finding":"TRRAP contains two LXRα-interacting domains (C-terminal and central domains) identified by GST pulldown; antisense TRRAP expression abolishes ligand-induced LXRα and FXR transactivation and target gene expression in hepatic cells, establishing TRRAP as a coactivator of LXR and FXR nuclear receptor function.","method":"GST pulldown domain mapping, antisense RNA knockdown, transcriptional reporter assay, RT-PCR of target genes","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding (GST pulldown) plus functional knockdown; single lab","pmids":["15649435"],"is_preprint":false},{"year":2006,"finding":"TRRAP stably associates with the MRN (MRE11-RAD50-NBS1) complex, as determined by double immunopurification, mass spectrometry, and gel filtration; the TRRAP-MRN complex has no detectable HAT activity; TRRAP-depleted extracts show reduced NHEJ activity in vitro; siRNA knockdown of TRRAP in HeLa cells or TRRAP knockout in mouse ES cells impair DSB end-joining efficiency.","method":"Double immunopurification, mass spectrometry, gel filtration, NHEJ assay in vitro, siRNA knockdown, knockout ES cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical purification plus mass spectrometry plus functional NHEJ assay with multiple model systems","pmids":["16382133"],"is_preprint":false},{"year":2006,"finding":"Drosophila Nipped-A (TRRAP ortholog) is required for Notch and mastermind activity during wing development; Nipped-A and mastermind co-localize on polytene chromosomes; reducing Nipped-A decreases mastermind chromatin binding; SAGA component Ada2b and Tip60 subunit Domino are also required, placing Nipped-A in SAGA and Tip60 complexes for Notch target gene transcription.","method":"Drosophila genetics, polytene chromosome immunostaining, co-localization, genetic epistasis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus molecular co-localization in Drosophila ortholog; single lab","pmids":["16508010"],"is_preprint":false},{"year":2007,"finding":"c-Myc activates RNA polymerase III transcription of tRNA and 5S rRNA genes by recruiting TRRAP and GCN5 to these genes, causing selective histone H3 (but not H4) hyperacetylation and increased TFIIIB occupancy, followed by Pol III recruitment.","method":"ChIP, ChIP time-course, siRNA knockdown, Pol III transcription assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP time-course with multiple marks plus siRNA knockdown with functional Pol III transcription readout","pmids":["17848523"],"is_preprint":false},{"year":2007,"finding":"NPAT recruits the TRRAP-Tip60 complex to histone gene promoters at the G1/S-phase boundary via a novel amino acid motif conserved in E2F and E1A; this recruitment correlates with increased histone H4 acetylation; RNAi suppression of TRRAP or Tip60 inhibits histone gene activation.","method":"Co-immunoprecipitation, ChIP at G1/S phase, siRNA knockdown, histone gene expression assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP at defined cell cycle stage plus RNAi functional knockdown","pmids":["17967892"],"is_preprint":false},{"year":2008,"finding":"TRRAP mediates beta-catenin ubiquitination in the context of chromatin by interacting with Skp1/SCF ubiquitin ligase complex and recruiting it to beta-catenin target promoters; TRRAP deletion leads to reduced beta-catenin ubiquitination, lower degradation, protein accumulation, and hyperactivation of canonical Wnt pathway.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, ubiquitination assay, Wnt reporter assay","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus ubiquitination assay, single lab","pmids":["19066453"],"is_preprint":false},{"year":2010,"finding":"In fission yeast, tra1 (TRRAP ortholog) mutation causes cells to be semi-wee and accumulate inactive Wee1 protein even when chk1 is overexpressed; this effect requires the Cdr1/Cdr2 kinases (negative regulators of Wee1) and is reverted by HDAC inhibition, placing Tra1 in the pathway controlling mitotic entry via Cdc2 activation through Wee1.","method":"Fission yeast genetic screen, tra1 deletion/mutation, epistasis with cdr1/cdr2 deletions, HDAC inhibitor treatment, cell size/mitotic entry analysis, Wee1 protein analysis","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in fission yeast ortholog with multiple alleles and pharmacological validation","pmids":["20194963"],"is_preprint":false},{"year":2013,"finding":"APC/C ubiquitin ligase activators Cdc20 and Cdh1 mediate pre-mitotic degradation of TRRAP; ectopic expression of Cdh1 and Cdc20 reduces TRRAP levels and induces its ubiquitination; TRRAP overexpression or stabilization induces mitotic defects (lagging chromosomes, bridges, multipolar spindles, loss of sister chromatid cohesion, impaired condensation) associated with global histone H4 hyperacetylation.","method":"Co-expression ubiquitination assay, TRRAP overexpression/stabilization, mitotic phenotype scoring (immunofluorescence), histone H4 acetylation assay, truncation mutant analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay plus functional overexpression phenotype, single lab","pmids":["23318449"],"is_preprint":false},{"year":2013,"finding":"Conditional deletion of Trrap in mouse embryonic stem cells triggers unscheduled differentiation with loss of histone acetylation, chromatin heterochromatization, uncoupling of H3K4me2 and H3K27me3, downregulation of Nanog/Oct4/Sox2, and upregulation of germ layer differentiation markers; ChIP-seq shows significant overlap between Oct4 and Trrap binding in ESCs; failure to downregulate Trrap prevents ESC differentiation.","method":"Conditional knockout (Cre-loxP), ChIP-seq, RT-PCR, immunofluorescence, chromatin condensation analysis","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with ChIP-seq plus multiple phenotypic readouts and rescue by maintained Trrap expression","pmids":["23362228"],"is_preprint":false},{"year":2014,"finding":"MYC TAD interacts with both TRRAP and GCN5 within native STAGA by protein crosslinking; purified GCN5 binds MYC TAD residues 21–108 via M2 (MBI) and M3 (residues 100–106) motifs; mutations in M2/M3 reduce MYC-STAGA interaction, strongly inhibit MYC acetylation by GCN5, and reduce MYC binding to the GCN5-dependent TERT promoter in vivo.","method":"Protein crosslinking within native complex, GST pulldown with purified GCN5, site-directed mutagenesis of MYC TAD, ChIP, GCN5 acetyltransferase activity assay","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding with mutagenesis plus crosslinking in native complex plus ChIP; multiple orthogonal methods","pmids":["24705139"],"is_preprint":false},{"year":2014,"finding":"Trrap specifically regulates transcription of E2F cell-cycle target genes in cortical apical neural progenitors by recruiting HATs and transcriptional machinery to their promoters; Trrap deletion impairs E2F target gene transcription, lengthens the cell cycle specifically in apical progenitors, and causes microcephaly due to premature differentiation; overexpression of cell-cycle regulators in vivo rescues the premature differentiation.","method":"Conditional knockout (Trrap deletion in neural progenitors), ChIP, RNA-seq, gene expression analysis, in vivo rescue by cell-cycle regulator overexpression, BrdU/EdU cell cycle analysis","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with ChIP, transcriptomics, and in vivo genetic rescue","pmids":["24792116"],"is_preprint":false},{"year":2015,"finding":"HAUSP (USP7) deubiquitinase physically interacts and co-localizes with TRRAP; HAUSP overexpression stabilizes TRRAP via in vivo deubiquitination, leading to increased c-MYC protein, mRNA, and transactivation from a c-MYC-responsive promoter; TRRAP knockdown abrogates the increase in c-MYC promoter activity induced by HAUSP overexpression.","method":"Co-immunoprecipitation, immunocytochemistry, in vivo deubiquitination assay, Western blot, qRT-PCR, luciferase reporter assay","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus deubiquitination assay plus functional reporter, single lab","pmids":["25205925"],"is_preprint":false},{"year":2018,"finding":"TRRAP is a critical positive regulator of both mutant and wild-type p53 protein levels in lymphoma; TRRAP silencing attenuates p53 accumulation; a 109-aa N-terminal HEAT repeat region of TRRAP is required for mutp53 stabilization (CRISPR screen); TRRAP protects mutp53 from MDM2-proteasome-mediated degradation as shown by mass spectrometric analysis of mutp53 interactome after TRRAP silencing; HDAC1/2/3 inhibition phenocopies TRRAP silencing for p53 level reduction.","method":"RNAi screen, CRISPR-Cas9 screen with deletion mapping, Western blot, mass spectrometry of mutp53 interactome, TRRAP overexpression, pharmacological HDAC inhibition","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen with domain mapping plus mass spectrometry plus orthogonal pharmacological validation","pmids":["29653964"],"is_preprint":false},{"year":2018,"finding":"TRRAP is required downstream of Notch2-mediated basal progenitor cell fate decisions and upstream of Multicilin for multiciliated cell (MCC) differentiation; TRRAP binds promoters and regulates expression of genes involved in MCC differentiation, including ciliopathy genes.","method":"shRNA screen, immunofluorescence, ChIP-seq/genomic analysis, Notch pathway modulation","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (pathway placement) plus ChIP-seq, single lab","pmids":["29588376"],"is_preprint":false},{"year":2019,"finding":"TRRAP depletion or its co-factor KAT5 (TIP60) depletion inhibits hepatocellular carcinoma cell growth by inducing p53-independent, p21-independent senescence with G2/M arrest; mitotic genes (including TOP2A) are key TRRAP/KAT5 transcriptional targets; depletion of TOP2A alone recapitulates the senescent phenotype.","method":"CRISPR screen, siRNA knockdown, cell cycle analysis, RNA-seq, ChIP-seq (inferred from integrated genomics), epistasis by TOP2A knockdown","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen followed by mechanistic validation (siRNA, cell cycle, transcriptomics, epistasis) with multiple orthogonal methods","pmids":["31188495"],"is_preprint":false},{"year":2019,"finding":"Tra1/TRRAP is a pseudokinase that lacks all catalytic residues characteristic of the PIKK family and serves as the largest structural scaffold subunit of SAGA and NuA4/TIP60 complexes, recruited to promoters upon transcription factor binding; molecular chaperones (TTT/HSP90 co-chaperone complex) are required for its folding and stability.","method":"Structural/evolutionary analysis combined with biochemical complex purification and functional studies (reviewed)","journal":"Biochemical Society transactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review synthesizing structural and biochemical evidence; no single new experiment but summarizes replicated findings","pmids":["31769470"],"is_preprint":false},{"year":2019,"finding":"The MYC:TRRAP interaction occurs at the MYC Homology Box 2 (MB2) within the intrinsically disordered MYC transactivation domain; MB2 may acquire a defined structure when complexed with TRRAP, as assessed by biophysical methods.","method":"Biophysical characterization (described as biophysical states analysis), interaction domain mapping","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — biophysical characterization without full structural determination or mutagenesis validation; single lab, methods not fully described in abstract","pmids":["31790487"],"is_preprint":false},{"year":2021,"finding":"TRRAP is required for SP1 binding at the promoter proximity of target genes controlling microtubule dynamics (including Stathmin3/4); Trrap deletion in Purkinje neurons impairs this SP1-mediated transcriptional program; ectopic expression of Stathmin3/4 rescues neurodegeneration defects of TRRAP-deficient neurons, establishing TRRAP→SP1→microtubule dynamics as a neuroprotective pathway.","method":"Conditional knockout in Purkinje neurons, transcriptomics, epigenomics (ChIP-seq), proteomics, SP1 ChIP, rescue by Stathmin3/4 overexpression","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with integrated multi-omic analysis and in vivo genetic rescue","pmids":["33594975"],"is_preprint":false},{"year":2021,"finding":"TRRAP knockdown reduces triglyceride accumulation in HuH-7 hepatocytes in part by reducing C/EBPα-mediated de novo synthesis of triglycerides, identifying TRRAP as a regulator of hepatic triglyceride metabolism.","method":"siRNA knockdown, high-content automated lipid droplet imaging, lipid and expression assays","journal":"Clinical and translational science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (siRNA screen hit validation), single lab, limited mechanistic detail in abstract","pmids":["34156146"],"is_preprint":false},{"year":2022,"finding":"HSF1 phosphorylation at S419 (by PLK1) is required for recruitment of the TRRAP-TIP60 acetyltransferase complex to the HSP72 promoter during heat shock; TRRAP-TIP60 recruitment leads to TIP60-mediated acetylation marks that recruit TRIM33 (bromodomain ubiquitin ligase), which cooperates with TRIM24 to mono-ubiquitinate histone H2B on K120, stabilizing the HSF1 transcription complex.","method":"ChIP, co-immunoprecipitation, phosphorylation-defective HSF1 mutants (S419A), functional transcription assay, histone modification analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP plus Co-IP plus site-directed mutagenesis plus functional transcription assay; multiple orthogonal methods","pmids":["35906200"],"is_preprint":false},{"year":2022,"finding":"TTT complex subunit TELO2 promotes TRRAP assembly into SAGA and TIP60 complexes; TELO2 and TRRAP depletion induces expression of type I interferon genes; TRRAP directly represses transcription of IRF9 (a master regulator of interferon-stimulated genes), establishing an unexpected transcriptional repressor role for TRRAP.","method":"Auxin-inducible degron alleles for endogenous depletion, RNA-seq, nascent RNA analysis, CUT&RUN, ChIP, kinetic analyses","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous degron depletion with multiple orthogonal chromatin and transcriptional assays; mechanistically novel finding","pmids":["35244540"],"is_preprint":false},{"year":2022,"finding":"TRRAP acts as a scaffold for SP1 stability; acetylation of SP1 at K639 by HATs antagonizes TRRAP binding and elevates SP1 transcriptional activity; deacetylated K639 is refractory to TRRAP deficiency and rescues differentiation defects of Trrap-deleted adult neural stem cells, establishing that TRRAP-mediated acetylation at K639 controls SP1 activity and adult neurogenesis.","method":"Conditional Trrap knockout in adult neural stem cells, acetylation site-directed mutagenesis of Sp1, in vitro and in vivo differentiation assays, ChIP","journal":"Computational and structural biotechnology journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus mutagenesis plus functional rescue; single lab","pmids":["36618986"],"is_preprint":false},{"year":2023,"finding":"TRRAP overexpression increases NANOG protein stability by interfering with FBXW8-mediated NANOG ubiquitination; a TRRAP domain (amino acids 1898–2400) is responsible for NANOG binding and blocks FBXW8-mediated ubiquitination when overexpressed; TRRAP knockdown decreases CD44, increases p53, and attenuates spheroid formation and cisplatin resistance, rescuable by NANOG overexpression.","method":"Co-immunoprecipitation, TRRAP deletion mutant domain mapping, ubiquitination assay, siRNA knockdown, NANOG rescue overexpression, xenograft mouse model","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus ubiquitination assay plus genetic epistasis rescue; single lab","pmids":["37047234"],"is_preprint":false},{"year":2024,"finding":"USP9X deubiquitinase physically interacts with TRRAP (Co-IP) and stabilizes TRRAP through deubiquitination; USP9X depletion reduces TRRAP protein levels; TRRAP overexpression rescues the suppression of GBM cell proliferation, migration, and M2 macrophage polarization caused by USP9X silencing.","method":"Co-immunoprecipitation, cycloheximide chase assay, ubiquitination assay, siRNA knockdown, TRRAP rescue overexpression, xenograft mouse model","journal":"Naunyn-Schmiedeberg's archives of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus deubiquitination/stabilization assay plus functional epistasis rescue; single lab","pmids":["39073416"],"is_preprint":false},{"year":2025,"finding":"CHD8 physically interacts with the TRRAP complex in human neural stem cells; CHD8 co-localizes genome-wide with TRRAP at MYC and E2F target gene promoters; depletion of either CHD8 or TRRAP causes downregulation of MYC and E2F target genes and reduced S-phase entry, placing CHD8 and TRRAP in a common axis for MYC/E2F target gene regulation.","method":"Affinity purification of CHD8 followed by mass spectrometry, ChIP-seq/genome-wide colocalization, siRNA depletion of CHD8 or TRRAP, RNA-seq, BrdU/EdU cell cycle analysis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry pulldown plus genome-wide ChIP-seq plus functional depletion; single lab","pmids":["40104050"],"is_preprint":false},{"year":2025,"finding":"Evolutionarily conserved acidic patches within the intrinsically disordered MYC N-terminus are required for the protein-protein interaction with TRRAP; two N-terminal negative clusters located outside MYC-Box-II (MBII) predominantly drive the MYC:TRRAP interaction and are required for MYC-dependent oncogenesis.","method":"Site-saturation mutagenesis screening, cell-based transformation/functional assays, multiple cell models, in vivo validation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — saturation mutagenesis with functional validation in multiple models; preprint, not yet peer reviewed","pmids":["bio_10.1101_2025.06.16.659507"],"is_preprint":true}],"current_model":"TRRAP is a catalytically inactive PIKK-family pseudokinase that functions as an essential scaffold/adaptor subunit of multiple histone acetyltransferase complexes (SAGA/STAGA, TIP60/NuA4, PCAF), recruiting HAT activity (GCN5, TIP60, PCAF) to chromatin in response to transcription factors (c-Myc, N-Myc, E2F, p53, BRCA1, HSF1, Sp1, NPAT, nuclear receptors); its ATM-related domain is required for HAT complex assembly (not kinase activity), and it is targeted for APC/C-mediated proteasomal degradation during mitosis; beyond transcription activation, TRRAP facilitates DNA double-strand break repair (HR and NHEJ) by recruiting HATs to break sites to open chromatin, regulates the mitotic checkpoint by driving Mad1/Mad2 transcription, controls beta-catenin ubiquitination/Wnt signaling on chromatin, modulates p53/mutp53 stability via the MDM2-proteasome axis, and is deubiquitinated and stabilized by HAUSP/USP7 and USP9X, while its interaction with MYC is mediated by the MB2/acidic patch region of the MYC transactivation domain."},"narrative":{"mechanistic_narrative":"TRRAP is a catalytically inactive PIKK-family pseudokinase that serves as the largest structural scaffold subunit of multiple histone acetyltransferase complexes—including SAGA/STAGA, TIP60/NuA4, and PCAF—where its ATM-related domain is required for assembly of a functional HAT complex rather than for any kinase activity [PMID:11445536, PMID:31769470]. Acting as a transcriptional adaptor, TRRAP couples sequence-specific transcription factors to chromatin acetylation: it was discovered as a direct partner of the c-Myc N-terminus and E2F-1 transactivation domain whose loss blocks oncogenic transformation [PMID:9708738], and it recruits HAT activity (catalyzed by GCN5) to Myc and E2F to drive promoter histone acetylation and gene activation [PMID:10611234, PMID:11418595, PMID:12660246]. Through this adaptor logic TRRAP services a broad network of activators—c-Myc/N-Myc, E2F, p53, BRCA1, NPAT, HSF1, SP1, and nuclear receptors LXR/FXR—delivering TIP60- or GCN5-dependent acetylation to their target genes including TERT, mdm2, histone genes, Pol III tRNA/5S genes, and HSP72 [PMID:12077335, PMID:12138177, PMID:16260778, PMID:17848523, PMID:17967892, PMID:35906200, PMID:15649435]. The MYC interaction is mediated by the MB2/acidic-patch region within the intrinsically disordered MYC transactivation domain [PMID:24705139, PMID:31790487]. TRRAP is genetically essential: null mice die at peri-implantation from blocked blastocyst proliferation, and TRRAP loss causes mitotic checkpoint failure, chromosome missegregation, and aberrant mitotic exit, in part through defective TRRAP-dependent transcription of Mad1 and Mad2 [PMID:11544477, PMID:15549134]. Beyond transcription, TRRAP and TIP60 are recruited to DNA double-strand breaks to drive histone H4 hyperacetylation and chromatin relaxation required for homologous recombination, and TRRAP stably associates with the MRN complex to support non-homologous end joining [PMID:16341205, PMID:16382133]. TRRAP also controls stem cell and progenitor fate—maintaining ESC pluripotency, restraining premature differentiation of neural progenitors via E2F target genes, and supporting neuronal survival through SP1-driven programs [PMID:23362228, PMID:24792116, PMID:33594975]. Its abundance is itself regulated, being targeted for APC/C (Cdc20/Cdh1)-mediated degradation before mitosis and stabilized by the deubiquitinases USP7/HAUSP and USP9X [PMID:23318449, PMID:25205925, PMID:39073416].","teleology":[{"year":1998,"claim":"Establishing that the oncogenic transcription factors c-Myc and E2F-1 require a shared physical partner answered how these activators might converge mechanistically, identifying TRRAP as a transformation-essential cofactor.","evidence":"Co-IP, transdominant mutants and antisense RNA in oncogenic transformation assays","pmids":["9708738"],"confidence":"High","gaps":["Did not define the biochemical activity TRRAP delivers to these factors","No structural basis for the interaction"]},{"year":2000,"claim":"Linking TRRAP to recruitment of GCN5 HAT activity at c-Myc resolved the molecular function of the scaffold, showing it converts activator binding into chromatin acetylation and opposes Mad-HDAC repression.","evidence":"Co-IP plus HAT activity assays and functional transcription/transformation readouts","pmids":["10611234"],"confidence":"High","gaps":["Did not map which TRRAP domain mediates HAT complex assembly","Generality across other activators untested at this point"]},{"year":2001,"claim":"Domain dissection distinguished TRRAP's transcription-factor-binding region from its complex-assembly function, establishing that the ATM-related domain—not kinase activity—builds the functional HAT complex.","evidence":"Domain deletion/mutation with HAT complex assembly and transformation assays","pmids":["11445536"],"confidence":"High","gaps":["No catalytic activity directly tested at the ATM-related domain","Atomic structure of the assembly interface unknown"]},{"year":2001,"claim":"Genetic ablation in mice answered whether TRRAP is dispensable, revealing it is essential for proliferation and proper mitotic exit, broadening its role beyond transcriptional activation to cell cycle control.","evidence":"Null and conditional knockout mice with cell cycle, mitotic marker, and Cdk1 activity analyses","pmids":["11544477"],"confidence":"High","gaps":["Mechanism linking TRRAP loss to mitotic defects not yet defined","Whether defects are transcriptional or direct unresolved at this stage"]},{"year":2001,"claim":"Extending the GCN5/TRRAP adaptor model to E2F transactivation domains generalized TRRAP as a shared HAT-recruiting cofactor for cell-cycle transcription factors.","evidence":"Co-IP, transactivation reporters, HAT assays, and E2F TAD mutagenesis","pmids":["11418595"],"confidence":"High","gaps":["In vivo target genes not mapped","Selectivity among E2F family members not addressed"]},{"year":2002,"claim":"Mapping TRRAP requirement to silent versus basally expressed Myc targets refined when HAT recruitment matters, showing it is essential for activating silent genes like TERT and for transformation but dispensable for some basal induction.","evidence":"TRRAP-binding-defective Myc mutants with TERT ChIP and transformation/expression assays","pmids":["12077335"],"confidence":"High","gaps":["Chromatin features dictating TRRAP dependence not defined","Did not separate H3 versus H4 contributions"]},{"year":2002,"claim":"Showing p53 docks TRRAP and co-recruits it to the mdm2 promoter extended the adaptor function to tumor-suppressor-driven transcription.","evidence":"GST pulldown, ChIP, antisense knockdown, reporter assays, and HDAC inhibition","pmids":["12138177"],"confidence":"High","gaps":["Which HAT subunit is delivered at mdm2 not specified","Feedback consequences for p53 levels not explored here"]},{"year":2003,"claim":"Defining TRRAP and GCN5 as co-recruited subunits of native human STAGA placed TRRAP as an adaptor within a defined complex required for Myc-dependent transcription.","evidence":"Co-IP, GST pulldown, reporter and HAT assays, dominant-negative TRRAP","pmids":["12660246"],"confidence":"High","gaps":["Stoichiometry and architecture of STAGA not resolved","Other TRRAP complexes not addressed in this study"]},{"year":2003,"claim":"Biochemical purification of the TRRAP/TIP60 complex identified its subunit composition (MRGBP, TRCp120, DMAP1, MRG15, MRGX, and later YL1), establishing TRRAP membership in a distinct TIP60 HAT/remodeling assembly.","evidence":"Purification from HeLa nuclear extracts with mass spectrometry and Co-IP","pmids":["12963728","15647280"],"confidence":"High","gaps":["Functional contribution of each subunit not dissected","Link to SWR1/SRCAP remodeling mechanistically incomplete"]},{"year":2004,"claim":"Tracing the mitotic phenotype to defective Mad1/Mad2 transcription provided the mechanistic explanation for TRRAP's checkpoint role, showing it is transcriptional rather than a direct mitotic activity.","evidence":"Conditional knockout cells with ChIP, siRNA, and Mad1/Mad2 overexpression rescue","pmids":["15549134"],"confidence":"High","gaps":["Cell-cycle timing of TRRAP recruitment to these promoters not fully resolved","Whether other checkpoint genes are co-regulated unknown"]},{"year":2005,"claim":"Demonstrating TRRAP/TIP60 recruitment to DSB chromatin extended its function to genome maintenance, showing HAT-driven chromatin relaxation is required for homologous recombination.","evidence":"ChIP at DSBs, siRNA, HR repair assay, chromatin-relaxation rescue","pmids":["16341205"],"confidence":"High","gaps":["Signal recruiting TRRAP to breaks not defined here","Relative roles of TIP60 versus other HATs at breaks unresolved"]},{"year":2006,"claim":"Identifying a stable, HAT-activity-free TRRAP-MRN complex required for NHEJ revealed a non-acetyltransferase repair function distinct from its transcriptional/HR roles.","evidence":"Double immunopurification, mass spectrometry, gel filtration, in vitro NHEJ assay, knockdown/knockout","pmids":["16382133"],"confidence":"High","gaps":["How TRRAP promotes end-joining without HAT activity unknown","Interface between TRRAP and MRN not mapped"]},{"year":2007,"claim":"Showing TRRAP/GCN5 recruitment drives Myc-dependent RNA Pol III transcription broadened its reach to non-protein-coding gene programs via selective H3 acetylation.","evidence":"ChIP time-course, siRNA, Pol III transcription assay","pmids":["17848523"],"confidence":"High","gaps":["Why H3 but not H4 is selectively acetylated unexplained","Direct versus indirect TFIIIB effects not separated"]},{"year":2007,"claim":"NPAT-mediated recruitment of TRRAP-TIP60 to histone gene promoters at G1/S identified a cell-cycle-coupled mechanism for replication-dependent histone gene activation.","evidence":"Co-IP, cell-cycle-staged ChIP, RNAi, histone gene expression","pmids":["17967892"],"confidence":"High","gaps":["Conserved recruitment motif shared with E2F/E1A not structurally characterized","Regulation of NPAT-TRRAP timing unknown"]},{"year":2013,"claim":"Demonstrating APC/C (Cdc20/Cdh1)-mediated pre-mitotic degradation of TRRAP, and that its stabilization causes mitotic defects with H4 hyperacetylation, established that TRRAP abundance must be tightly limited for faithful mitosis.","evidence":"Ubiquitination assays, overexpression/stabilization, mitotic phenotype scoring, H4 acetylation analysis","pmids":["23318449"],"confidence":"Medium","gaps":["Degron sequence in TRRAP not precisely mapped","Single-lab study without reciprocal endogenous validation"]},{"year":2013,"claim":"Conditional deletion in ESCs showed TRRAP maintains pluripotency by sustaining histone acetylation and Nanog/Oct4/Sox2 expression, defining a role in keeping chromatin permissive for self-renewal.","evidence":"Cre-loxP knockout, ChIP-seq, RT-PCR, chromatin condensation analysis","pmids":["23362228"],"confidence":"High","gaps":["Direct versus indirect effects on pluripotency genes not fully separated","Mechanism of H3K4me2/H3K27me3 uncoupling unclear"]},{"year":2014,"claim":"Mapping the MYC TAD M2/M3 motifs that bind GCN5 and TRRAP within native STAGA refined the molecular grammar of MYC-HAT recruitment and its requirement for MYC acetylation and TERT activation.","evidence":"Crosslinking in native complex, GST pulldown with purified GCN5, TAD mutagenesis, ChIP, HAT assay","pmids":["24705139"],"confidence":"High","gaps":["Discrete TRRAP versus GCN5 contacts on the TAD not fully separated","No high-resolution structure of the bound TAD"]},{"year":2014,"claim":"Showing TRRAP-dependent E2F target transcription controls apical progenitor cell-cycle length connected TRRAP to brain development and microcephaly through proliferation control.","evidence":"Neural-progenitor conditional knockout, ChIP, RNA-seq, in vivo cell-cycle-regulator rescue","pmids":["24792116"],"confidence":"High","gaps":["Progenitor-type specificity of the requirement not fully explained","Which HAT complex acts at E2F targets in vivo unresolved"]},{"year":2015,"claim":"Identifying USP7/HAUSP as a deubiquitinase that stabilizes TRRAP and thereby elevates c-MYC defined a post-translational input controlling TRRAP levels and downstream MYC output.","evidence":"Co-IP, deubiquitination assay, reporter and qRT-PCR analyses","pmids":["25205925"],"confidence":"Medium","gaps":["Ubiquitin ligase opposing USP7 on TRRAP not identified here","Single-lab study"]},{"year":2018,"claim":"Showing TRRAP, via an N-terminal HEAT region, protects mutant and wild-type p53 from MDM2-proteasome degradation revealed a stabilizing role for TRRAP in p53 biology relevant to lymphoma.","evidence":"RNAi and CRISPR screens with deletion mapping, mass spectrometry of mutp53 interactome, HDAC inhibition","pmids":["29653964"],"confidence":"High","gaps":["Whether stabilization is transcriptional or direct chaperone-like not fully resolved","Role outside lymphoma contexts untested"]},{"year":2019,"claim":"Synthesizing structural/evolutionary and biochemical data classified Tra1/TRRAP as a pseudokinase scaffold dependent on the TTT/HSP90 chaperone system for folding, consolidating the catalytically inactive scaffold model.","evidence":"Review integrating structural, evolutionary, and biochemical evidence","pmids":["31769470"],"confidence":"Medium","gaps":["Review rather than primary data","Atomic-level chaperone handoff mechanism not detailed"]},{"year":2019,"claim":"Showing TRRAP/KAT5 sustain mitotic gene transcription (including TOP2A) in hepatocellular carcinoma, with TOP2A loss recapitulating senescence, linked TRRAP to a p53-independent proliferative dependency exploitable in cancer.","evidence":"CRISPR screen, siRNA, cell cycle analysis, RNA-seq, TOP2A epistasis","pmids":["31188495"],"confidence":"High","gaps":["Breadth of the mitotic gene program controlled not fully mapped","Tumor-context selectivity of the dependency unclear"]},{"year":2021,"claim":"Defining a TRRAP→SP1→Stathmin/microtubule axis in Purkinje neurons established a neuroprotective transcriptional program and explained TRRAP-loss neurodegeneration.","evidence":"Purkinje-neuron conditional knockout, multi-omics, SP1 ChIP, Stathmin3/4 rescue","pmids":["33594975"],"confidence":"High","gaps":["How TRRAP enables SP1 promoter binding mechanistically not fully resolved","Generality to other neuronal types unknown"]},{"year":2022,"claim":"Discovering that TTT subunit TELO2 promotes TRRAP assembly into SAGA/TIP60 and that TRRAP directly represses IRF9 revealed an unexpected transcriptional repressor role linked to interferon control.","evidence":"Auxin-inducible degron depletion, RNA-seq, nascent RNA, CUT&RUN, ChIP","pmids":["35244540"],"confidence":"High","gaps":["Mechanism of repression by an acetyltransferase scaffold unresolved","Direct versus indirect IRF9 regulation needs further dissection"]},{"year":2022,"claim":"Showing HSF1-S419 phosphorylation recruits TRRAP-TIP60 to HSP72, triggering an acetylation-to-ubiquitination relay (TRIM33/TRIM24, H2BK120ub), placed TRRAP within the heat-shock transcriptional response.","evidence":"ChIP, Co-IP, HSF1 S419A mutants, transcription and histone-modification assays","pmids":["35906200"],"confidence":"High","gaps":["Order of TRRAP recruitment relative to other co-activators not fully timed","Generality across heat-shock genes untested"]},{"year":2022,"claim":"Demonstrating TRRAP scaffolds SP1 stability and that K639 acetylation antagonizes TRRAP binding to tune SP1 activity refined the TRRAP-SP1 relationship in adult neurogenesis.","evidence":"Adult NSC conditional knockout, Sp1 acetylation-site mutagenesis, differentiation rescue, ChIP","pmids":["36618986"],"confidence":"Medium","gaps":["Identity of the HAT acetylating SP1 K639 not pinned down","Single-lab study"]},{"year":2023,"claim":"Showing a defined TRRAP domain (aa 1898–2400) binds NANOG and blocks FBXW8-mediated ubiquitination connected TRRAP to stemness and chemoresistance through protein stabilization.","evidence":"Co-IP, domain mapping, ubiquitination assay, NANOG rescue, xenografts","pmids":["37047234"],"confidence":"Medium","gaps":["Whether NANOG stabilization is chromatin-coupled unclear","Single-lab study"]},{"year":2024,"claim":"Identifying USP9X as a second deubiquitinase stabilizing TRRAP, with TRRAP rescuing USP9X-loss phenotypes in glioblastoma, expanded the DUB network controlling TRRAP abundance.","evidence":"Co-IP, cycloheximide chase, ubiquitination assay, knockdown/rescue, xenografts","pmids":["39073416"],"confidence":"Medium","gaps":["Site of USP9X-mediated deubiquitination on TRRAP unknown","Single-lab study"]},{"year":2025,"claim":"Showing CHD8 physically associates with the TRRAP complex and co-occupies MYC/E2F promoters genome-wide placed a chromatin remodeler in a shared axis with TRRAP for proliferative gene control.","evidence":"Affinity purification-mass spectrometry, ChIP-seq colocalization, siRNA, RNA-seq, cell-cycle analysis","pmids":["40104050"],"confidence":"Medium","gaps":["Whether CHD8 and TRRAP form a stable complex or transiently cooperate unclear","Single-lab study"]},{"year":2025,"claim":"Saturation mutagenesis of the MYC N-terminus localized the TRRAP interaction to conserved acidic clusters outside MBII required for MYC oncogenesis, refining the MYC:TRRAP interface.","evidence":"Site-saturation mutagenesis with transformation assays and in vivo validation (preprint)","pmids":["bio_10.1101_2025.06.16.659507"],"confidence":"Medium","gaps":["Preprint not yet peer reviewed","Structural basis of acidic-patch binding to TRRAP not determined"]},{"year":null,"claim":"How TRRAP physically distinguishes and assembles its distinct HAT complexes (SAGA/STAGA, TIP60/NuA4, PCAF) and how a single pseudokinase scaffold mediates both transcriptional activation and direct repression remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of TRRAP bound to its transcription-factor partners or full complexes","Mechanism switching TRRAP between activating and repressive (e.g., IRF9) outcomes unknown","How TRRAP supports HAT-independent repair functions (MRN/NHEJ) is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,8,30]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,7,25,35]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[13,19,34]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,9,23]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[7,13,18]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,8,18,25]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9,19,23]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,11,22]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[23,25,28,32]}],"complexes":["SAGA/STAGA","TIP60/NuA4 HAT complex","PCAF complex","MRN (MRE11-RAD50-NBS1) complex"],"partners":["MYC","GCN5","KAT5","E2F1","TP53","NPAT","USP7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y4A5","full_name":"Transformation/transcription domain-associated protein","aliases":["350/400 kDa PCAF-associated factor","PAF350/400","STAF40","Tra1 homolog"],"length_aa":3859,"mass_kda":437.6,"function":"Adapter protein, which is found in various multiprotein chromatin complexes with histone acetyltransferase activity (HAT), which gives a specific tag for epigenetic transcription activation. Component of the NuA4 histone acetyltransferase complex which is responsible for acetylation of nucleosomal histones H4 and H2A. Plays a central role in MYC transcription activation, and also participates in cell transformation by MYC. Required for p53/TP53-, E2F1- and E2F4-mediated transcription activation. Also involved in transcription activation mediated by the adenovirus E1A, a viral oncoprotein that deregulates transcription of key genes. Probably acts by linking transcription factors such as E1A, MYC or E2F1 to HAT complexes such as STAGA thereby allowing transcription activation. Probably not required in the steps following histone acetylation in processes of transcription activation. May be required for the mitotic checkpoint and normal cell cycle progression. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome. May play a role in the formation and maintenance of the auditory system (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y4A5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TRRAP","classification":"Common Essential","n_dependent_lines":1202,"n_total_lines":1208,"dependency_fraction":0.9950331125827815},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000196367","cell_line_id":"CID001294","localizations":[{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"TAF12","stoichiometry":10.0},{"gene":"VPS72","stoichiometry":10.0},{"gene":"TAF9","stoichiometry":10.0},{"gene":"TADA2B","stoichiometry":10.0},{"gene":"MAX","stoichiometry":10.0},{"gene":"TAF9B","stoichiometry":10.0},{"gene":"TAF6L","stoichiometry":10.0},{"gene":"TADA1","stoichiometry":10.0},{"gene":"EP400","stoichiometry":10.0},{"gene":"KAT2A","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001294","total_profiled":1310},"omim":[{"mim_id":"618778","title":"DEAFNESS, AUTOSOMAL DOMINANT 75; DFNA75","url":"https://www.omim.org/entry/618778"},{"mim_id":"618454","title":"DEVELOPMENTAL DELAY WITH OR WITHOUT DYSMORPHIC FACIES AND AUTISM; DEDDFA","url":"https://www.omim.org/entry/618454"},{"mim_id":"613896","title":"BISPHOSPHOGLYCERATE MUTASE; BPGM","url":"https://www.omim.org/entry/613896"},{"mim_id":"612762","title":"SPTY7-LIKE, STAGA COMPLEX SUBUNIT GAMMA; SUPT7L","url":"https://www.omim.org/entry/612762"},{"mim_id":"612116","title":"UBIQUITIN-SPECIFIC PROTEASE 22; USP22","url":"https://www.omim.org/entry/612116"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRRAP"},"hgnc":{"alias_symbol":["TR-AP","PAF400","Tra1"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y4A5","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4A5","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRRAP","jax_strain_url":"https://www.jax.org/strain/search?query=TRRAP"},"sequence":{"accession":"Q9Y4A5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y4A5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y4A5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4A5"}},"corpus_meta":[{"pmid":"9708738","id":"PMC_9708738","title":"The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins.","date":"1998","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9708738","citation_count":562,"is_preprint":false},{"pmid":"16341205","id":"PMC_16341205","title":"Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks.","date":"2005","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16341205","citation_count":496,"is_preprint":false},{"pmid":"10611234","id":"PMC_10611234","title":"The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10611234","citation_count":373,"is_preprint":false},{"pmid":"12963728","id":"PMC_12963728","title":"Identification of new subunits of the multiprotein mammalian TRRAP/TIP60-containing histone acetyltransferase complex.","date":"2003","source":"The Journal of biological 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as a Potential Molecular Marker and Therapeutic Target for Breast Cancer.","date":"2016","source":"Journal of breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27066097","citation_count":16,"is_preprint":false},{"pmid":"19066453","id":"PMC_19066453","title":"HAT cofactor TRRAP mediates beta-catenin ubiquitination on the chromatin and the regulation of the canonical Wnt pathway.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19066453","citation_count":16,"is_preprint":false},{"pmid":"37047234","id":"PMC_37047234","title":"TRRAP Enhances Cancer Stem Cell Characteristics by Regulating NANOG Protein Stability in Colon Cancer Cells.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37047234","citation_count":15,"is_preprint":false},{"pmid":"29588376","id":"PMC_29588376","title":"TRRAP is a central regulator of human multiciliated cell formation.","date":"2018","source":"The Journal 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H4K16.","date":"2016","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27382434","citation_count":12,"is_preprint":false},{"pmid":"24137342","id":"PMC_24137342","title":"Mutational analysis of the GNA11, MMP27, FGD1, TRRAP and GRM3 genes in thyroid cancer.","date":"2013","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/24137342","citation_count":11,"is_preprint":false},{"pmid":"29936929","id":"PMC_29936929","title":"TRRAP stimulates the tumorigenic potential of ovarian cancer stem cells.","date":"2018","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/29936929","citation_count":10,"is_preprint":false},{"pmid":"36618986","id":"PMC_36618986","title":"TRRAP-mediated acetylation on Sp1 regulates adult neurogenesis.","date":"2022","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/36618986","citation_count":9,"is_preprint":false},{"pmid":"34156146","id":"PMC_34156146","title":"Lipid droplet 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/41952423","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.16.659507","title":"MYC-induced oncogenesis is dependent on acidic patches within its N-terminal intrinsically disordered domain","date":"2025-06-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.16.659507","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.25.630030","title":"The natural HLA-Peptidome of Sezary Syndrome: uncovering antigens for T cell-based immunotherapy","date":"2024-12-25","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.25.630030","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30486,"output_tokens":10023,"usd":0.120901,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20626,"output_tokens":8334,"usd":0.15574,"stage2_stop_reason":"end_turn"},"total_usd":0.276641,"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\": 1998,\n      \"finding\": \"TRRAP (434 kDa) was identified as a novel protein with homology to the ATM/PI3-kinase family that directly interacts with the c-Myc N-terminus and the E2F-1 transactivation domain; expression of transdominant TRRAP mutants or antisense RNA blocks c-Myc- and E1A-mediated oncogenic transformation.\",\n      \"method\": \"Co-immunoprecipitation, transdominant mutant overexpression, antisense RNA, oncogenic transformation assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding experiments plus functional loss-of-function (transdominant mutants and antisense) with defined transformation phenotype; founding paper replicated extensively\",\n      \"pmids\": [\"9708738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TRRAP recruits histone acetyltransferase activity (catalyzed by hGCN5) to c-Myc, providing a mechanism for Myc-dependent chromatin acetylation and transcriptional activation; this opposes Mad-family recruitment of histone deacetylases.\",\n      \"method\": \"Co-immunoprecipitation, histone acetyltransferase activity assay, functional transcription/transformation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical HAT activity assay plus functional epistasis; independently replicated by multiple subsequent studies\",\n      \"pmids\": [\"10611234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The ATM-related domain of TRRAP (not its Myc-binding domain, which maps to a separable region) is required for assembly of a functional HAT complex; mutation of this domain inhibits Myc-mediated oncogenic transformation and the Myc-binding region independently inhibits cell growth when overexpressed.\",\n      \"method\": \"Domain deletion/mutation analysis, HAT complex assembly assays, oncogenic transformation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — structure-function mapping with mutagenesis plus functional transformation readout; replicated conceptually by subsequent studies\",\n      \"pmids\": [\"11445536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Homozygous null mutation of Trrap in mice causes peri-implantation lethality due to blocked blastocyst proliferation; conditional loss causes aberrant mitotic exit, cytokinesis failure, endoreduplication, chromosome missegregation, disrupted spindles, and compromised Cdk1 activity, establishing TRRAP as essential for the mitotic checkpoint and normal cell cycle progression.\",\n      \"method\": \"Knockout mouse (null and inducible Cre-loxP), cell cycle analysis, immunofluorescence of mitotic markers, Cdk1 activity assay\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal cellular phenotype readouts and biochemical Cdk1 activity measurement\",\n      \"pmids\": [\"11544477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"E2F-1 and E2F-4 transactivation domains bind GCN5 and TRRAP in vivo; TRRAP/GCN5 co-expression stimulates E2F-mediated transactivation; E2F-4 with mutations in the transactivation domain shows correlated loss of TRRAP/GCN5 binding, HAT activity recruitment, and transcriptional activation.\",\n      \"method\": \"Co-immunoprecipitation, transactivation reporter assay, HAT activity assay, site-directed mutagenesis of E2F transactivation domain\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, HAT assay, mutagenesis, reporter assay) in a single study\",\n      \"pmids\": [\"11418595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Adenovirus E1A requires interaction with TRRAP for cellular transformation and immortalization; a domain of E1A (residues 12–54) mediates TRRAP binding, and overexpression of a competing TRRAP fragment blocks both E1A–TRRAP interaction and transformation; E1A(Δ26–35) that fails to bind TRRAP is defective in transformation.\",\n      \"method\": \"Co-immunoprecipitation, TRRAP fragment competition, transformation assay, E1A deletion mutants\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding plus loss-of-function mutants with defined transformation phenotype\",\n      \"pmids\": [\"11781841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TRRAP binding and recruitment of histone H3/H4 acetyltransferase activities by c-Myc or N-Myc are required for transactivation of the silent TERT gene and for oncogenic transformation, but are dispensable for partial induction of basally expressed genes and for rescuing growth of myc-null fibroblasts.\",\n      \"method\": \"TRRAP binding-defective Myc mutants, ChIP for histone acetylation at TERT promoter, transformation assay, gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Myc family members tested, ChIP plus functional readouts, defining differential TRRAP requirement\",\n      \"pmids\": [\"12077335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"p53 directly binds a TRRAP domain (previously shown as an activator docking site) in vitro; p53 recruits TRRAP to the mdm2 promoter in a p53-dependent manner (ChIP); TRRAP functionally cooperates with p53 to activate mdm2 transcription and this is followed by increased histone acetylation at the mdm2 promoter.\",\n      \"method\": \"GST pulldown (direct binding), ChIP, antisense TRRAP knockdown, transcriptional reporter assay, pharmacological HDAC inhibition\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro direct binding (GST pulldown) plus ChIP and functional knockdown with multiple orthogonal methods\",\n      \"pmids\": [\"12138177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"c-Myc co-recruits TRRAP and GCN5 via direct physical interactions of its N-terminal activation/transformation domain with the human STAGA complex; TRRAP and GCN5 cooperate to enhance Myc-dependent transcription and this synergy requires both the SPT3/GCN5 interaction domain of TRRAP and the HAT activity of GCN5, establishing TRRAP as an adaptor within STAGA.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, in vivo transcription reporter assay, HAT activity assay, dominant-negative TRRAP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding plus functional epistasis with HAT activity requirement established\",\n      \"pmids\": [\"12660246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TRRAP is a component of the mammalian TRRAP/TIP60 HAT complex; MRGBP, TRCp120, DMAP1, MRG15, and MRGX were identified as previously unrecognized subunits of this complex by purification and mass spectrometry from HeLa nuclear extracts.\",\n      \"method\": \"Biochemical purification from HeLa nuclear extracts, mass spectrometry, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical purification plus mass spectrometry identification of complex components\",\n      \"pmids\": [\"12963728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"E1A binds GCN5 and TRRAP in vivo early during adenovirus infection and associates with significant HAT activity (partly attributable to GCN5); E1A distinctly binds TRRAP/GCN5, p300/CBP, and PCAF HAT complexes; E1A represses c-Myc- and E2F-1-directed transcription by sequestering GCN5 and/or TRRAP.\",\n      \"method\": \"Co-immunoprecipitation during adenovirus infection, in vitro HAT activity assay, transcription reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus HAT assay, single lab study\",\n      \"pmids\": [\"12743606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Loss of Trrap causes chromosome missegregation and mitotic checkpoint defects due to defective transcription of Mad1 and Mad2; Trrap-mediated H3 and H4 acetylation at Mad1/Mad2 gene promoters is required; Trrap associates with TIP60 and PCAF at these promoters in a cell cycle-dependent manner; ectopic Mad1/Mad2 expression fully restores the mitotic checkpoint in Trrap-deficient cells.\",\n      \"method\": \"Conditional knockout mouse cells, ChIP, siRNA knockdown, immunofluorescence, epistasis rescue experiment (Mad1/Mad2 overexpression), cell cycle analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, genetic epistasis rescue, and conditional loss-of-function with multiple orthogonal methods\",\n      \"pmids\": [\"15549134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"YL1 protein is a subunit of the mammalian TRRAP/TIP60 HAT complex, as well as a component of the SRCAP chromatin-remodeling complex, establishing a molecular link between TRRAP/TIP60 and SWR1-type chromatin remodeling.\",\n      \"method\": \"Biochemical purification from HeLa cells, mass spectrometry, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical purification and Co-IP, single lab\",\n      \"pmids\": [\"15647280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Trrap and Tip60 bind to chromatin surrounding DNA double-strand break (DSB) sites in vivo; Trrap depletion impairs DNA-damage-induced histone H4 hyperacetylation and accumulation of repair molecules at DSBs, resulting in defective homologous recombination (HR) repair; chromatin relaxation counteracts the repair defect, indicating TRRAP acts by regulating chromatin accessibility at break sites.\",\n      \"method\": \"ChIP at DSB sites, siRNA knockdown, HR repair assay, pharmacological chromatin relaxation (rescue experiment), ATM signaling assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, siRNA, functional repair assay, rescue), replicated concept in subsequent studies\",\n      \"pmids\": [\"16341205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BRCA1 C-terminal transactivation domain mutations found in breast cancer patients abolish physical interaction between BRCA1 and TRRAP and reduce hGCN5/TRRAP co-activation of BRCA1 transactivation; hGCN5 HAT activity is required for this co-regulatory complex function in both BRCA1-mediated gene regulation and DNA repair.\",\n      \"method\": \"Co-immunoprecipitation, biochemical purification, transcriptional reporter assay, HAT activity analysis, BRCA1 cancer mutation mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional reporter assay, single lab\",\n      \"pmids\": [\"16260778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRRAP contains two LXRα-interacting domains (C-terminal and central domains) identified by GST pulldown; antisense TRRAP expression abolishes ligand-induced LXRα and FXR transactivation and target gene expression in hepatic cells, establishing TRRAP as a coactivator of LXR and FXR nuclear receptor function.\",\n      \"method\": \"GST pulldown domain mapping, antisense RNA knockdown, transcriptional reporter assay, RT-PCR of target genes\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding (GST pulldown) plus functional knockdown; single lab\",\n      \"pmids\": [\"15649435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRRAP stably associates with the MRN (MRE11-RAD50-NBS1) complex, as determined by double immunopurification, mass spectrometry, and gel filtration; the TRRAP-MRN complex has no detectable HAT activity; TRRAP-depleted extracts show reduced NHEJ activity in vitro; siRNA knockdown of TRRAP in HeLa cells or TRRAP knockout in mouse ES cells impair DSB end-joining efficiency.\",\n      \"method\": \"Double immunopurification, mass spectrometry, gel filtration, NHEJ assay in vitro, siRNA knockdown, knockout ES cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical purification plus mass spectrometry plus functional NHEJ assay with multiple model systems\",\n      \"pmids\": [\"16382133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Drosophila Nipped-A (TRRAP ortholog) is required for Notch and mastermind activity during wing development; Nipped-A and mastermind co-localize on polytene chromosomes; reducing Nipped-A decreases mastermind chromatin binding; SAGA component Ada2b and Tip60 subunit Domino are also required, placing Nipped-A in SAGA and Tip60 complexes for Notch target gene transcription.\",\n      \"method\": \"Drosophila genetics, polytene chromosome immunostaining, co-localization, genetic epistasis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus molecular co-localization in Drosophila ortholog; single lab\",\n      \"pmids\": [\"16508010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"c-Myc activates RNA polymerase III transcription of tRNA and 5S rRNA genes by recruiting TRRAP and GCN5 to these genes, causing selective histone H3 (but not H4) hyperacetylation and increased TFIIIB occupancy, followed by Pol III recruitment.\",\n      \"method\": \"ChIP, ChIP time-course, siRNA knockdown, Pol III transcription assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP time-course with multiple marks plus siRNA knockdown with functional Pol III transcription readout\",\n      \"pmids\": [\"17848523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NPAT recruits the TRRAP-Tip60 complex to histone gene promoters at the G1/S-phase boundary via a novel amino acid motif conserved in E2F and E1A; this recruitment correlates with increased histone H4 acetylation; RNAi suppression of TRRAP or Tip60 inhibits histone gene activation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP at G1/S phase, siRNA knockdown, histone gene expression assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP at defined cell cycle stage plus RNAi functional knockdown\",\n      \"pmids\": [\"17967892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRRAP mediates beta-catenin ubiquitination in the context of chromatin by interacting with Skp1/SCF ubiquitin ligase complex and recruiting it to beta-catenin target promoters; TRRAP deletion leads to reduced beta-catenin ubiquitination, lower degradation, protein accumulation, and hyperactivation of canonical Wnt pathway.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, ubiquitination assay, Wnt reporter assay\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus ubiquitination assay, single lab\",\n      \"pmids\": [\"19066453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In fission yeast, tra1 (TRRAP ortholog) mutation causes cells to be semi-wee and accumulate inactive Wee1 protein even when chk1 is overexpressed; this effect requires the Cdr1/Cdr2 kinases (negative regulators of Wee1) and is reverted by HDAC inhibition, placing Tra1 in the pathway controlling mitotic entry via Cdc2 activation through Wee1.\",\n      \"method\": \"Fission yeast genetic screen, tra1 deletion/mutation, epistasis with cdr1/cdr2 deletions, HDAC inhibitor treatment, cell size/mitotic entry analysis, Wee1 protein analysis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in fission yeast ortholog with multiple alleles and pharmacological validation\",\n      \"pmids\": [\"20194963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"APC/C ubiquitin ligase activators Cdc20 and Cdh1 mediate pre-mitotic degradation of TRRAP; ectopic expression of Cdh1 and Cdc20 reduces TRRAP levels and induces its ubiquitination; TRRAP overexpression or stabilization induces mitotic defects (lagging chromosomes, bridges, multipolar spindles, loss of sister chromatid cohesion, impaired condensation) associated with global histone H4 hyperacetylation.\",\n      \"method\": \"Co-expression ubiquitination assay, TRRAP overexpression/stabilization, mitotic phenotype scoring (immunofluorescence), histone H4 acetylation assay, truncation mutant analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay plus functional overexpression phenotype, single lab\",\n      \"pmids\": [\"23318449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Conditional deletion of Trrap in mouse embryonic stem cells triggers unscheduled differentiation with loss of histone acetylation, chromatin heterochromatization, uncoupling of H3K4me2 and H3K27me3, downregulation of Nanog/Oct4/Sox2, and upregulation of germ layer differentiation markers; ChIP-seq shows significant overlap between Oct4 and Trrap binding in ESCs; failure to downregulate Trrap prevents ESC differentiation.\",\n      \"method\": \"Conditional knockout (Cre-loxP), ChIP-seq, RT-PCR, immunofluorescence, chromatin condensation analysis\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with ChIP-seq plus multiple phenotypic readouts and rescue by maintained Trrap expression\",\n      \"pmids\": [\"23362228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MYC TAD interacts with both TRRAP and GCN5 within native STAGA by protein crosslinking; purified GCN5 binds MYC TAD residues 21–108 via M2 (MBI) and M3 (residues 100–106) motifs; mutations in M2/M3 reduce MYC-STAGA interaction, strongly inhibit MYC acetylation by GCN5, and reduce MYC binding to the GCN5-dependent TERT promoter in vivo.\",\n      \"method\": \"Protein crosslinking within native complex, GST pulldown with purified GCN5, site-directed mutagenesis of MYC TAD, ChIP, GCN5 acetyltransferase activity assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding with mutagenesis plus crosslinking in native complex plus ChIP; multiple orthogonal methods\",\n      \"pmids\": [\"24705139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Trrap specifically regulates transcription of E2F cell-cycle target genes in cortical apical neural progenitors by recruiting HATs and transcriptional machinery to their promoters; Trrap deletion impairs E2F target gene transcription, lengthens the cell cycle specifically in apical progenitors, and causes microcephaly due to premature differentiation; overexpression of cell-cycle regulators in vivo rescues the premature differentiation.\",\n      \"method\": \"Conditional knockout (Trrap deletion in neural progenitors), ChIP, RNA-seq, gene expression analysis, in vivo rescue by cell-cycle regulator overexpression, BrdU/EdU cell cycle analysis\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with ChIP, transcriptomics, and in vivo genetic rescue\",\n      \"pmids\": [\"24792116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HAUSP (USP7) deubiquitinase physically interacts and co-localizes with TRRAP; HAUSP overexpression stabilizes TRRAP via in vivo deubiquitination, leading to increased c-MYC protein, mRNA, and transactivation from a c-MYC-responsive promoter; TRRAP knockdown abrogates the increase in c-MYC promoter activity induced by HAUSP overexpression.\",\n      \"method\": \"Co-immunoprecipitation, immunocytochemistry, in vivo deubiquitination assay, Western blot, qRT-PCR, luciferase reporter assay\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus deubiquitination assay plus functional reporter, single lab\",\n      \"pmids\": [\"25205925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRRAP is a critical positive regulator of both mutant and wild-type p53 protein levels in lymphoma; TRRAP silencing attenuates p53 accumulation; a 109-aa N-terminal HEAT repeat region of TRRAP is required for mutp53 stabilization (CRISPR screen); TRRAP protects mutp53 from MDM2-proteasome-mediated degradation as shown by mass spectrometric analysis of mutp53 interactome after TRRAP silencing; HDAC1/2/3 inhibition phenocopies TRRAP silencing for p53 level reduction.\",\n      \"method\": \"RNAi screen, CRISPR-Cas9 screen with deletion mapping, Western blot, mass spectrometry of mutp53 interactome, TRRAP overexpression, pharmacological HDAC inhibition\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen with domain mapping plus mass spectrometry plus orthogonal pharmacological validation\",\n      \"pmids\": [\"29653964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRRAP is required downstream of Notch2-mediated basal progenitor cell fate decisions and upstream of Multicilin for multiciliated cell (MCC) differentiation; TRRAP binds promoters and regulates expression of genes involved in MCC differentiation, including ciliopathy genes.\",\n      \"method\": \"shRNA screen, immunofluorescence, ChIP-seq/genomic analysis, Notch pathway modulation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (pathway placement) plus ChIP-seq, single lab\",\n      \"pmids\": [\"29588376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRRAP depletion or its co-factor KAT5 (TIP60) depletion inhibits hepatocellular carcinoma cell growth by inducing p53-independent, p21-independent senescence with G2/M arrest; mitotic genes (including TOP2A) are key TRRAP/KAT5 transcriptional targets; depletion of TOP2A alone recapitulates the senescent phenotype.\",\n      \"method\": \"CRISPR screen, siRNA knockdown, cell cycle analysis, RNA-seq, ChIP-seq (inferred from integrated genomics), epistasis by TOP2A knockdown\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen followed by mechanistic validation (siRNA, cell cycle, transcriptomics, epistasis) with multiple orthogonal methods\",\n      \"pmids\": [\"31188495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tra1/TRRAP is a pseudokinase that lacks all catalytic residues characteristic of the PIKK family and serves as the largest structural scaffold subunit of SAGA and NuA4/TIP60 complexes, recruited to promoters upon transcription factor binding; molecular chaperones (TTT/HSP90 co-chaperone complex) are required for its folding and stability.\",\n      \"method\": \"Structural/evolutionary analysis combined with biochemical complex purification and functional studies (reviewed)\",\n      \"journal\": \"Biochemical Society transactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review synthesizing structural and biochemical evidence; no single new experiment but summarizes replicated findings\",\n      \"pmids\": [\"31769470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The MYC:TRRAP interaction occurs at the MYC Homology Box 2 (MB2) within the intrinsically disordered MYC transactivation domain; MB2 may acquire a defined structure when complexed with TRRAP, as assessed by biophysical methods.\",\n      \"method\": \"Biophysical characterization (described as biophysical states analysis), interaction domain mapping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — biophysical characterization without full structural determination or mutagenesis validation; single lab, methods not fully described in abstract\",\n      \"pmids\": [\"31790487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRRAP is required for SP1 binding at the promoter proximity of target genes controlling microtubule dynamics (including Stathmin3/4); Trrap deletion in Purkinje neurons impairs this SP1-mediated transcriptional program; ectopic expression of Stathmin3/4 rescues neurodegeneration defects of TRRAP-deficient neurons, establishing TRRAP→SP1→microtubule dynamics as a neuroprotective pathway.\",\n      \"method\": \"Conditional knockout in Purkinje neurons, transcriptomics, epigenomics (ChIP-seq), proteomics, SP1 ChIP, rescue by Stathmin3/4 overexpression\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with integrated multi-omic analysis and in vivo genetic rescue\",\n      \"pmids\": [\"33594975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRRAP knockdown reduces triglyceride accumulation in HuH-7 hepatocytes in part by reducing C/EBPα-mediated de novo synthesis of triglycerides, identifying TRRAP as a regulator of hepatic triglyceride metabolism.\",\n      \"method\": \"siRNA knockdown, high-content automated lipid droplet imaging, lipid and expression assays\",\n      \"journal\": \"Clinical and translational science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (siRNA screen hit validation), single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"34156146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HSF1 phosphorylation at S419 (by PLK1) is required for recruitment of the TRRAP-TIP60 acetyltransferase complex to the HSP72 promoter during heat shock; TRRAP-TIP60 recruitment leads to TIP60-mediated acetylation marks that recruit TRIM33 (bromodomain ubiquitin ligase), which cooperates with TRIM24 to mono-ubiquitinate histone H2B on K120, stabilizing the HSF1 transcription complex.\",\n      \"method\": \"ChIP, co-immunoprecipitation, phosphorylation-defective HSF1 mutants (S419A), functional transcription assay, histone modification analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus Co-IP plus site-directed mutagenesis plus functional transcription assay; multiple orthogonal methods\",\n      \"pmids\": [\"35906200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TTT complex subunit TELO2 promotes TRRAP assembly into SAGA and TIP60 complexes; TELO2 and TRRAP depletion induces expression of type I interferon genes; TRRAP directly represses transcription of IRF9 (a master regulator of interferon-stimulated genes), establishing an unexpected transcriptional repressor role for TRRAP.\",\n      \"method\": \"Auxin-inducible degron alleles for endogenous depletion, RNA-seq, nascent RNA analysis, CUT&RUN, ChIP, kinetic analyses\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous degron depletion with multiple orthogonal chromatin and transcriptional assays; mechanistically novel finding\",\n      \"pmids\": [\"35244540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRRAP acts as a scaffold for SP1 stability; acetylation of SP1 at K639 by HATs antagonizes TRRAP binding and elevates SP1 transcriptional activity; deacetylated K639 is refractory to TRRAP deficiency and rescues differentiation defects of Trrap-deleted adult neural stem cells, establishing that TRRAP-mediated acetylation at K639 controls SP1 activity and adult neurogenesis.\",\n      \"method\": \"Conditional Trrap knockout in adult neural stem cells, acetylation site-directed mutagenesis of Sp1, in vitro and in vivo differentiation assays, ChIP\",\n      \"journal\": \"Computational and structural biotechnology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus mutagenesis plus functional rescue; single lab\",\n      \"pmids\": [\"36618986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRRAP overexpression increases NANOG protein stability by interfering with FBXW8-mediated NANOG ubiquitination; a TRRAP domain (amino acids 1898–2400) is responsible for NANOG binding and blocks FBXW8-mediated ubiquitination when overexpressed; TRRAP knockdown decreases CD44, increases p53, and attenuates spheroid formation and cisplatin resistance, rescuable by NANOG overexpression.\",\n      \"method\": \"Co-immunoprecipitation, TRRAP deletion mutant domain mapping, ubiquitination assay, siRNA knockdown, NANOG rescue overexpression, xenograft mouse model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus ubiquitination assay plus genetic epistasis rescue; single lab\",\n      \"pmids\": [\"37047234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP9X deubiquitinase physically interacts with TRRAP (Co-IP) and stabilizes TRRAP through deubiquitination; USP9X depletion reduces TRRAP protein levels; TRRAP overexpression rescues the suppression of GBM cell proliferation, migration, and M2 macrophage polarization caused by USP9X silencing.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide chase assay, ubiquitination assay, siRNA knockdown, TRRAP rescue overexpression, xenograft mouse model\",\n      \"journal\": \"Naunyn-Schmiedeberg's archives of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus deubiquitination/stabilization assay plus functional epistasis rescue; single lab\",\n      \"pmids\": [\"39073416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHD8 physically interacts with the TRRAP complex in human neural stem cells; CHD8 co-localizes genome-wide with TRRAP at MYC and E2F target gene promoters; depletion of either CHD8 or TRRAP causes downregulation of MYC and E2F target genes and reduced S-phase entry, placing CHD8 and TRRAP in a common axis for MYC/E2F target gene regulation.\",\n      \"method\": \"Affinity purification of CHD8 followed by mass spectrometry, ChIP-seq/genome-wide colocalization, siRNA depletion of CHD8 or TRRAP, RNA-seq, BrdU/EdU cell cycle analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry pulldown plus genome-wide ChIP-seq plus functional depletion; single lab\",\n      \"pmids\": [\"40104050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Evolutionarily conserved acidic patches within the intrinsically disordered MYC N-terminus are required for the protein-protein interaction with TRRAP; two N-terminal negative clusters located outside MYC-Box-II (MBII) predominantly drive the MYC:TRRAP interaction and are required for MYC-dependent oncogenesis.\",\n      \"method\": \"Site-saturation mutagenesis screening, cell-based transformation/functional assays, multiple cell models, in vivo validation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — saturation mutagenesis with functional validation in multiple models; preprint, not yet peer reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.16.659507\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TRRAP is a catalytically inactive PIKK-family pseudokinase that functions as an essential scaffold/adaptor subunit of multiple histone acetyltransferase complexes (SAGA/STAGA, TIP60/NuA4, PCAF), recruiting HAT activity (GCN5, TIP60, PCAF) to chromatin in response to transcription factors (c-Myc, N-Myc, E2F, p53, BRCA1, HSF1, Sp1, NPAT, nuclear receptors); its ATM-related domain is required for HAT complex assembly (not kinase activity), and it is targeted for APC/C-mediated proteasomal degradation during mitosis; beyond transcription activation, TRRAP facilitates DNA double-strand break repair (HR and NHEJ) by recruiting HATs to break sites to open chromatin, regulates the mitotic checkpoint by driving Mad1/Mad2 transcription, controls beta-catenin ubiquitination/Wnt signaling on chromatin, modulates p53/mutp53 stability via the MDM2-proteasome axis, and is deubiquitinated and stabilized by HAUSP/USP7 and USP9X, while its interaction with MYC is mediated by the MB2/acidic patch region of the MYC transactivation domain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRRAP is a catalytically inactive PIKK-family pseudokinase that serves as the largest structural scaffold subunit of multiple histone acetyltransferase complexes—including SAGA/STAGA, TIP60/NuA4, and PCAF—where its ATM-related domain is required for assembly of a functional HAT complex rather than for any kinase activity [#2, #30]. Acting as a transcriptional adaptor, TRRAP couples sequence-specific transcription factors to chromatin acetylation: it was discovered as a direct partner of the c-Myc N-terminus and E2F-1 transactivation domain whose loss blocks oncogenic transformation [#0], and it recruits HAT activity (catalyzed by GCN5) to Myc and E2F to drive promoter histone acetylation and gene activation [#1, #4, #8]. Through this adaptor logic TRRAP services a broad network of activators—c-Myc/N-Myc, E2F, p53, BRCA1, NPAT, HSF1, SP1, and nuclear receptors LXR/FXR—delivering TIP60- or GCN5-dependent acetylation to their target genes including TERT, mdm2, histone genes, Pol III tRNA/5S genes, and HSP72 [#6, #7, #14, #18, #19, #34, #15]. The MYC interaction is mediated by the MB2/acidic-patch region within the intrinsically disordered MYC transactivation domain [#24, #31]. TRRAP is genetically essential: null mice die at peri-implantation from blocked blastocyst proliferation, and TRRAP loss causes mitotic checkpoint failure, chromosome missegregation, and aberrant mitotic exit, in part through defective TRRAP-dependent transcription of Mad1 and Mad2 [#3, #11]. Beyond transcription, TRRAP and TIP60 are recruited to DNA double-strand breaks to drive histone H4 hyperacetylation and chromatin relaxation required for homologous recombination, and TRRAP stably associates with the MRN complex to support non-homologous end joining [#13, #16]. TRRAP also controls stem cell and progenitor fate—maintaining ESC pluripotency, restraining premature differentiation of neural progenitors via E2F target genes, and supporting neuronal survival through SP1-driven programs [#23, #25, #32]. Its abundance is itself regulated, being targeted for APC/C (Cdc20/Cdh1)-mediated degradation before mitosis and stabilized by the deubiquitinases USP7/HAUSP and USP9X [#22, #26, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that the oncogenic transcription factors c-Myc and E2F-1 require a shared physical partner answered how these activators might converge mechanistically, identifying TRRAP as a transformation-essential cofactor.\",\n      \"evidence\": \"Co-IP, transdominant mutants and antisense RNA in oncogenic transformation assays\",\n      \"pmids\": [\"9708738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical activity TRRAP delivers to these factors\", \"No structural basis for the interaction\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linking TRRAP to recruitment of GCN5 HAT activity at c-Myc resolved the molecular function of the scaffold, showing it converts activator binding into chromatin acetylation and opposes Mad-HDAC repression.\",\n      \"evidence\": \"Co-IP plus HAT activity assays and functional transcription/transformation readouts\",\n      \"pmids\": [\"10611234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map which TRRAP domain mediates HAT complex assembly\", \"Generality across other activators untested at this point\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Domain dissection distinguished TRRAP's transcription-factor-binding region from its complex-assembly function, establishing that the ATM-related domain—not kinase activity—builds the functional HAT complex.\",\n      \"evidence\": \"Domain deletion/mutation with HAT complex assembly and transformation assays\",\n      \"pmids\": [\"11445536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No catalytic activity directly tested at the ATM-related domain\", \"Atomic structure of the assembly interface unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic ablation in mice answered whether TRRAP is dispensable, revealing it is essential for proliferation and proper mitotic exit, broadening its role beyond transcriptional activation to cell cycle control.\",\n      \"evidence\": \"Null and conditional knockout mice with cell cycle, mitotic marker, and Cdk1 activity analyses\",\n      \"pmids\": [\"11544477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking TRRAP loss to mitotic defects not yet defined\", \"Whether defects are transcriptional or direct unresolved at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Extending the GCN5/TRRAP adaptor model to E2F transactivation domains generalized TRRAP as a shared HAT-recruiting cofactor for cell-cycle transcription factors.\",\n      \"evidence\": \"Co-IP, transactivation reporters, HAT assays, and E2F TAD mutagenesis\",\n      \"pmids\": [\"11418595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo target genes not mapped\", \"Selectivity among E2F family members not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapping TRRAP requirement to silent versus basally expressed Myc targets refined when HAT recruitment matters, showing it is essential for activating silent genes like TERT and for transformation but dispensable for some basal induction.\",\n      \"evidence\": \"TRRAP-binding-defective Myc mutants with TERT ChIP and transformation/expression assays\",\n      \"pmids\": [\"12077335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin features dictating TRRAP dependence not defined\", \"Did not separate H3 versus H4 contributions\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing p53 docks TRRAP and co-recruits it to the mdm2 promoter extended the adaptor function to tumor-suppressor-driven transcription.\",\n      \"evidence\": \"GST pulldown, ChIP, antisense knockdown, reporter assays, and HDAC inhibition\",\n      \"pmids\": [\"12138177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which HAT subunit is delivered at mdm2 not specified\", \"Feedback consequences for p53 levels not explored here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defining TRRAP and GCN5 as co-recruited subunits of native human STAGA placed TRRAP as an adaptor within a defined complex required for Myc-dependent transcription.\",\n      \"evidence\": \"Co-IP, GST pulldown, reporter and HAT assays, dominant-negative TRRAP\",\n      \"pmids\": [\"12660246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of STAGA not resolved\", \"Other TRRAP complexes not addressed in this study\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Biochemical purification of the TRRAP/TIP60 complex identified its subunit composition (MRGBP, TRCp120, DMAP1, MRG15, MRGX, and later YL1), establishing TRRAP membership in a distinct TIP60 HAT/remodeling assembly.\",\n      \"evidence\": \"Purification from HeLa nuclear extracts with mass spectrometry and Co-IP\",\n      \"pmids\": [\"12963728\", \"15647280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional contribution of each subunit not dissected\", \"Link to SWR1/SRCAP remodeling mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Tracing the mitotic phenotype to defective Mad1/Mad2 transcription provided the mechanistic explanation for TRRAP's checkpoint role, showing it is transcriptional rather than a direct mitotic activity.\",\n      \"evidence\": \"Conditional knockout cells with ChIP, siRNA, and Mad1/Mad2 overexpression rescue\",\n      \"pmids\": [\"15549134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-cycle timing of TRRAP recruitment to these promoters not fully resolved\", \"Whether other checkpoint genes are co-regulated unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating TRRAP/TIP60 recruitment to DSB chromatin extended its function to genome maintenance, showing HAT-driven chromatin relaxation is required for homologous recombination.\",\n      \"evidence\": \"ChIP at DSBs, siRNA, HR repair assay, chromatin-relaxation rescue\",\n      \"pmids\": [\"16341205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal recruiting TRRAP to breaks not defined here\", \"Relative roles of TIP60 versus other HATs at breaks unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying a stable, HAT-activity-free TRRAP-MRN complex required for NHEJ revealed a non-acetyltransferase repair function distinct from its transcriptional/HR roles.\",\n      \"evidence\": \"Double immunopurification, mass spectrometry, gel filtration, in vitro NHEJ assay, knockdown/knockout\",\n      \"pmids\": [\"16382133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRRAP promotes end-joining without HAT activity unknown\", \"Interface between TRRAP and MRN not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showing TRRAP/GCN5 recruitment drives Myc-dependent RNA Pol III transcription broadened its reach to non-protein-coding gene programs via selective H3 acetylation.\",\n      \"evidence\": \"ChIP time-course, siRNA, Pol III transcription assay\",\n      \"pmids\": [\"17848523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why H3 but not H4 is selectively acetylated unexplained\", \"Direct versus indirect TFIIIB effects not separated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"NPAT-mediated recruitment of TRRAP-TIP60 to histone gene promoters at G1/S identified a cell-cycle-coupled mechanism for replication-dependent histone gene activation.\",\n      \"evidence\": \"Co-IP, cell-cycle-staged ChIP, RNAi, histone gene expression\",\n      \"pmids\": [\"17967892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conserved recruitment motif shared with E2F/E1A not structurally characterized\", \"Regulation of NPAT-TRRAP timing unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating APC/C (Cdc20/Cdh1)-mediated pre-mitotic degradation of TRRAP, and that its stabilization causes mitotic defects with H4 hyperacetylation, established that TRRAP abundance must be tightly limited for faithful mitosis.\",\n      \"evidence\": \"Ubiquitination assays, overexpression/stabilization, mitotic phenotype scoring, H4 acetylation analysis\",\n      \"pmids\": [\"23318449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron sequence in TRRAP not precisely mapped\", \"Single-lab study without reciprocal endogenous validation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Conditional deletion in ESCs showed TRRAP maintains pluripotency by sustaining histone acetylation and Nanog/Oct4/Sox2 expression, defining a role in keeping chromatin permissive for self-renewal.\",\n      \"evidence\": \"Cre-loxP knockout, ChIP-seq, RT-PCR, chromatin condensation analysis\",\n      \"pmids\": [\"23362228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect effects on pluripotency genes not fully separated\", \"Mechanism of H3K4me2/H3K27me3 uncoupling unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapping the MYC TAD M2/M3 motifs that bind GCN5 and TRRAP within native STAGA refined the molecular grammar of MYC-HAT recruitment and its requirement for MYC acetylation and TERT activation.\",\n      \"evidence\": \"Crosslinking in native complex, GST pulldown with purified GCN5, TAD mutagenesis, ChIP, HAT assay\",\n      \"pmids\": [\"24705139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Discrete TRRAP versus GCN5 contacts on the TAD not fully separated\", \"No high-resolution structure of the bound TAD\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing TRRAP-dependent E2F target transcription controls apical progenitor cell-cycle length connected TRRAP to brain development and microcephaly through proliferation control.\",\n      \"evidence\": \"Neural-progenitor conditional knockout, ChIP, RNA-seq, in vivo cell-cycle-regulator rescue\",\n      \"pmids\": [\"24792116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Progenitor-type specificity of the requirement not fully explained\", \"Which HAT complex acts at E2F targets in vivo unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying USP7/HAUSP as a deubiquitinase that stabilizes TRRAP and thereby elevates c-MYC defined a post-translational input controlling TRRAP levels and downstream MYC output.\",\n      \"evidence\": \"Co-IP, deubiquitination assay, reporter and qRT-PCR analyses\",\n      \"pmids\": [\"25205925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin ligase opposing USP7 on TRRAP not identified here\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing TRRAP, via an N-terminal HEAT region, protects mutant and wild-type p53 from MDM2-proteasome degradation revealed a stabilizing role for TRRAP in p53 biology relevant to lymphoma.\",\n      \"evidence\": \"RNAi and CRISPR screens with deletion mapping, mass spectrometry of mutp53 interactome, HDAC inhibition\",\n      \"pmids\": [\"29653964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether stabilization is transcriptional or direct chaperone-like not fully resolved\", \"Role outside lymphoma contexts untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Synthesizing structural/evolutionary and biochemical data classified Tra1/TRRAP as a pseudokinase scaffold dependent on the TTT/HSP90 chaperone system for folding, consolidating the catalytically inactive scaffold model.\",\n      \"evidence\": \"Review integrating structural, evolutionary, and biochemical evidence\",\n      \"pmids\": [\"31769470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review rather than primary data\", \"Atomic-level chaperone handoff mechanism not detailed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing TRRAP/KAT5 sustain mitotic gene transcription (including TOP2A) in hepatocellular carcinoma, with TOP2A loss recapitulating senescence, linked TRRAP to a p53-independent proliferative dependency exploitable in cancer.\",\n      \"evidence\": \"CRISPR screen, siRNA, cell cycle analysis, RNA-seq, TOP2A epistasis\",\n      \"pmids\": [\"31188495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Breadth of the mitotic gene program controlled not fully mapped\", \"Tumor-context selectivity of the dependency unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining a TRRAP→SP1→Stathmin/microtubule axis in Purkinje neurons established a neuroprotective transcriptional program and explained TRRAP-loss neurodegeneration.\",\n      \"evidence\": \"Purkinje-neuron conditional knockout, multi-omics, SP1 ChIP, Stathmin3/4 rescue\",\n      \"pmids\": [\"33594975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRRAP enables SP1 promoter binding mechanistically not fully resolved\", \"Generality to other neuronal types unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovering that TTT subunit TELO2 promotes TRRAP assembly into SAGA/TIP60 and that TRRAP directly represses IRF9 revealed an unexpected transcriptional repressor role linked to interferon control.\",\n      \"evidence\": \"Auxin-inducible degron depletion, RNA-seq, nascent RNA, CUT&RUN, ChIP\",\n      \"pmids\": [\"35244540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of repression by an acetyltransferase scaffold unresolved\", \"Direct versus indirect IRF9 regulation needs further dissection\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing HSF1-S419 phosphorylation recruits TRRAP-TIP60 to HSP72, triggering an acetylation-to-ubiquitination relay (TRIM33/TRIM24, H2BK120ub), placed TRRAP within the heat-shock transcriptional response.\",\n      \"evidence\": \"ChIP, Co-IP, HSF1 S419A mutants, transcription and histone-modification assays\",\n      \"pmids\": [\"35906200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of TRRAP recruitment relative to other co-activators not fully timed\", \"Generality across heat-shock genes untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating TRRAP scaffolds SP1 stability and that K639 acetylation antagonizes TRRAP binding to tune SP1 activity refined the TRRAP-SP1 relationship in adult neurogenesis.\",\n      \"evidence\": \"Adult NSC conditional knockout, Sp1 acetylation-site mutagenesis, differentiation rescue, ChIP\",\n      \"pmids\": [\"36618986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the HAT acetylating SP1 K639 not pinned down\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing a defined TRRAP domain (aa 1898–2400) binds NANOG and blocks FBXW8-mediated ubiquitination connected TRRAP to stemness and chemoresistance through protein stabilization.\",\n      \"evidence\": \"Co-IP, domain mapping, ubiquitination assay, NANOG rescue, xenografts\",\n      \"pmids\": [\"37047234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NANOG stabilization is chromatin-coupled unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying USP9X as a second deubiquitinase stabilizing TRRAP, with TRRAP rescuing USP9X-loss phenotypes in glioblastoma, expanded the DUB network controlling TRRAP abundance.\",\n      \"evidence\": \"Co-IP, cycloheximide chase, ubiquitination assay, knockdown/rescue, xenografts\",\n      \"pmids\": [\"39073416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Site of USP9X-mediated deubiquitination on TRRAP unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing CHD8 physically associates with the TRRAP complex and co-occupies MYC/E2F promoters genome-wide placed a chromatin remodeler in a shared axis with TRRAP for proliferative gene control.\",\n      \"evidence\": \"Affinity purification-mass spectrometry, ChIP-seq colocalization, siRNA, RNA-seq, cell-cycle analysis\",\n      \"pmids\": [\"40104050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CHD8 and TRRAP form a stable complex or transiently cooperate unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Saturation mutagenesis of the MYC N-terminus localized the TRRAP interaction to conserved acidic clusters outside MBII required for MYC oncogenesis, refining the MYC:TRRAP interface.\",\n      \"evidence\": \"Site-saturation mutagenesis with transformation assays and in vivo validation (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.16.659507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer reviewed\", \"Structural basis of acidic-patch binding to TRRAP not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRRAP physically distinguishes and assembles its distinct HAT complexes (SAGA/STAGA, TIP60/NuA4, PCAF) and how a single pseudokinase scaffold mediates both transcriptional activation and direct repression remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of TRRAP bound to its transcription-factor partners or full complexes\", \"Mechanism switching TRRAP between activating and repressive (e.g., IRF9) outcomes unknown\", \"How TRRAP supports HAT-independent repair functions (MRN/NHEJ) is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 8, 30]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 7, 25, 35]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [13, 19, 34]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 9, 23]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [7, 13, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 8, 18, 25]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9, 19, 23]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 11, 22]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [23, 25, 28, 32]}\n    ],\n    \"complexes\": [\"SAGA/STAGA\", \"TIP60/NuA4 HAT complex\", \"PCAF complex\", \"MRN (MRE11-RAD50-NBS1) complex\"],\n    \"partners\": [\"MYC\", \"GCN5\", \"KAT5\", \"E2F1\", \"TP53\", \"NPAT\", \"USP7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"TRRAP","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"rich","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 25205925"},"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}