Affinage

TRRAP

Transformation/transcription domain-associated protein · UniProt Q9Y4A5

Audit flag: ungrounded claim
Length
3859 aa
Mass
437.6 kDa
Annotated
2026-06-10
63 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 30 steps
  1. 1998 High

    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

    PMID:9708738

    Open questions at the time
    • Did not define the biochemical activity TRRAP delivers to these factors
    • No structural basis for the interaction
  2. 2000 High

    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

    PMID:10611234

    Open questions at the time
    • Did not map which TRRAP domain mediates HAT complex assembly
    • Generality across other activators untested at this point
  3. 2001 High

    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

    PMID:11445536

    Open questions at the time
    • No catalytic activity directly tested at the ATM-related domain
    • Atomic structure of the assembly interface unknown
  4. 2001 High

    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

    PMID:11544477

    Open questions at the time
    • Mechanism linking TRRAP loss to mitotic defects not yet defined
    • Whether defects are transcriptional or direct unresolved at this stage
  5. 2001 High

    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

    PMID:11418595

    Open questions at the time
    • In vivo target genes not mapped
    • Selectivity among E2F family members not addressed
  6. 2002 High

    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

    PMID:12077335

    Open questions at the time
    • Chromatin features dictating TRRAP dependence not defined
    • Did not separate H3 versus H4 contributions
  7. 2002 High

    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

    PMID:12138177

    Open questions at the time
    • Which HAT subunit is delivered at mdm2 not specified
    • Feedback consequences for p53 levels not explored here
  8. 2003 High

    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

    PMID:12660246

    Open questions at the time
    • Stoichiometry and architecture of STAGA not resolved
    • Other TRRAP complexes not addressed in this study
  9. 2003 High

    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

    PMID:12963728 PMID:15647280

    Open questions at the time
    • Functional contribution of each subunit not dissected
    • Link to SWR1/SRCAP remodeling mechanistically incomplete
  10. 2004 High

    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

    PMID:15549134

    Open questions at the time
    • Cell-cycle timing of TRRAP recruitment to these promoters not fully resolved
    • Whether other checkpoint genes are co-regulated unknown
  11. 2005 High

    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

    PMID:16341205

    Open questions at the time
    • Signal recruiting TRRAP to breaks not defined here
    • Relative roles of TIP60 versus other HATs at breaks unresolved
  12. 2006 High

    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

    PMID:16382133

    Open questions at the time
    • How TRRAP promotes end-joining without HAT activity unknown
    • Interface between TRRAP and MRN not mapped
  13. 2007 High

    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

    PMID:17848523

    Open questions at the time
    • Why H3 but not H4 is selectively acetylated unexplained
    • Direct versus indirect TFIIIB effects not separated
  14. 2007 High

    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

    PMID:17967892

    Open questions at the time
    • Conserved recruitment motif shared with E2F/E1A not structurally characterized
    • Regulation of NPAT-TRRAP timing unknown
  15. 2013 Medium

    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

    PMID:23318449

    Open questions at the time
    • Degron sequence in TRRAP not precisely mapped
    • Single-lab study without reciprocal endogenous validation
  16. 2013 High

    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

    PMID:23362228

    Open questions at the time
    • Direct versus indirect effects on pluripotency genes not fully separated
    • Mechanism of H3K4me2/H3K27me3 uncoupling unclear
  17. 2014 High

    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

    PMID:24705139

    Open questions at the time
    • Discrete TRRAP versus GCN5 contacts on the TAD not fully separated
    • No high-resolution structure of the bound TAD
  18. 2014 High

    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

    PMID:24792116

    Open questions at the time
    • Progenitor-type specificity of the requirement not fully explained
    • Which HAT complex acts at E2F targets in vivo unresolved
  19. 2015 Medium

    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

    PMID:25205925

    Open questions at the time
    • Ubiquitin ligase opposing USP7 on TRRAP not identified here
    • Single-lab study
  20. 2018 High

    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

    PMID:29653964

    Open questions at the time
    • Whether stabilization is transcriptional or direct chaperone-like not fully resolved
    • Role outside lymphoma contexts untested
  21. 2019 Medium

    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

    PMID:31769470

    Open questions at the time
    • Review rather than primary data
    • Atomic-level chaperone handoff mechanism not detailed
  22. 2019 High

    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

    PMID:31188495

    Open questions at the time
    • Breadth of the mitotic gene program controlled not fully mapped
    • Tumor-context selectivity of the dependency unclear
  23. 2021 High

    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

    PMID:33594975

    Open questions at the time
    • How TRRAP enables SP1 promoter binding mechanistically not fully resolved
    • Generality to other neuronal types unknown
  24. 2022 High

    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

    PMID:35244540

    Open questions at the time
    • Mechanism of repression by an acetyltransferase scaffold unresolved
    • Direct versus indirect IRF9 regulation needs further dissection
  25. 2022 High

    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

    PMID:35906200

    Open questions at the time
    • Order of TRRAP recruitment relative to other co-activators not fully timed
    • Generality across heat-shock genes untested
  26. 2022 Medium

    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

    PMID:36618986

    Open questions at the time
    • Identity of the HAT acetylating SP1 K639 not pinned down
    • Single-lab study
  27. 2023 Medium

    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

    PMID:37047234

    Open questions at the time
    • Whether NANOG stabilization is chromatin-coupled unclear
    • Single-lab study
  28. 2024 Medium

    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

    PMID:39073416

    Open questions at the time
    • Site of USP9X-mediated deubiquitination on TRRAP unknown
    • Single-lab study
  29. 2025 Medium

    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

    PMID:40104050

    Open questions at the time
    • Whether CHD8 and TRRAP form a stable complex or transiently cooperate unclear
    • Single-lab study
  30. 2025 Medium

    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)

    PMID:bio_10.1101_2025.06.16.659507

    Open questions at the time
    • Preprint not yet peer reviewed
    • Structural basis of acidic-patch binding to TRRAP not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 4 GO:0042393 histone binding 3
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 2
Partners
E2F1GCN5KAT5MYCNPATTP53USP7
Complex memberships
MRN (MRE11-RAD50-NBS1) complexPCAF complexSAGA/STAGATIP60/NuA4 HAT complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. Co-immunoprecipitation, transdominant mutant overexpression, antisense RNA, oncogenic transformation assay Cell High 9708738
2000 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. Co-immunoprecipitation, histone acetyltransferase activity assay, functional transcription/transformation assays Molecular and cellular biology High 10611234
2001 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. Domain deletion/mutation analysis, HAT complex assembly assays, oncogenic transformation assays Genes & development High 11445536
2001 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. Knockout mouse (null and inducible Cre-loxP), cell cycle analysis, immunofluorescence of mitotic markers, Cdk1 activity assay Nature genetics High 11544477
2001 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. Co-immunoprecipitation, transactivation reporter assay, HAT activity assay, site-directed mutagenesis of E2F transactivation domain The Journal of biological chemistry High 11418595
2001 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. Co-immunoprecipitation, TRRAP fragment competition, transformation assay, E1A deletion mutants Oncogene High 11781841
2002 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. TRRAP binding-defective Myc mutants, ChIP for histone acetylation at TERT promoter, transformation assay, gene expression analysis Molecular and cellular biology High 12077335
2002 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. GST pulldown (direct binding), ChIP, antisense TRRAP knockdown, transcriptional reporter assay, pharmacological HDAC inhibition Molecular and cellular biology High 12138177
2003 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. Co-immunoprecipitation, GST pulldown, in vivo transcription reporter assay, HAT activity assay, dominant-negative TRRAP The Journal of biological chemistry High 12660246
2003 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. Biochemical purification from HeLa nuclear extracts, mass spectrometry, co-immunoprecipitation The Journal of biological chemistry High 12963728
2003 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. Co-immunoprecipitation during adenovirus infection, in vitro HAT activity assay, transcription reporter assay Oncogene Medium 12743606
2004 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. Conditional knockout mouse cells, ChIP, siRNA knockdown, immunofluorescence, epistasis rescue experiment (Mad1/Mad2 overexpression), cell cycle analysis The EMBO journal High 15549134
2005 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. Biochemical purification from HeLa cells, mass spectrometry, co-immunoprecipitation The Journal of biological chemistry Medium 15647280
2005 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. ChIP at DSB sites, siRNA knockdown, HR repair assay, pharmacological chromatin relaxation (rescue experiment), ATM signaling assay Nature cell biology High 16341205
2005 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. Co-immunoprecipitation, biochemical purification, transcriptional reporter assay, HAT activity analysis, BRCA1 cancer mutation mapping The Journal of biological chemistry Medium 16260778
2005 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. GST pulldown domain mapping, antisense RNA knockdown, transcriptional reporter assay, RT-PCR of target genes Biochemical and biophysical research communications Medium 15649435
2006 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. Double immunopurification, mass spectrometry, gel filtration, NHEJ assay in vitro, siRNA knockdown, knockout ES cells Molecular and cellular biology High 16382133
2006 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. Drosophila genetics, polytene chromosome immunostaining, co-localization, genetic epistasis Molecular and cellular biology Medium 16508010
2007 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. ChIP, ChIP time-course, siRNA knockdown, Pol III transcription assay Proceedings of the National Academy of Sciences of the United States of America High 17848523
2007 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. Co-immunoprecipitation, ChIP at G1/S phase, siRNA knockdown, histone gene expression assay Molecular and cellular biology High 17967892
2008 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. Co-immunoprecipitation, ChIP, siRNA knockdown, ubiquitination assay, Wnt reporter assay Cell cycle Medium 19066453
2010 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. Fission yeast genetic screen, tra1 deletion/mutation, epistasis with cdr1/cdr2 deletions, HDAC inhibitor treatment, cell size/mitotic entry analysis, Wee1 protein analysis Genetics Medium 20194963
2013 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. Co-expression ubiquitination assay, TRRAP overexpression/stabilization, mitotic phenotype scoring (immunofluorescence), histone H4 acetylation assay, truncation mutant analysis Oncogene Medium 23318449
2013 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. Conditional knockout (Cre-loxP), ChIP-seq, RT-PCR, immunofluorescence, chromatin condensation analysis Stem cells High 23362228
2014 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. Protein crosslinking within native complex, GST pulldown with purified GCN5, site-directed mutagenesis of MYC TAD, ChIP, GCN5 acetyltransferase activity assay Biochimica et biophysica acta High 24705139
2014 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. 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 Cell stem cell High 24792116
2015 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. Co-immunoprecipitation, immunocytochemistry, in vivo deubiquitination assay, Western blot, qRT-PCR, luciferase reporter assay Cellular oncology Medium 25205925
2018 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. RNAi screen, CRISPR-Cas9 screen with deletion mapping, Western blot, mass spectrometry of mutp53 interactome, TRRAP overexpression, pharmacological HDAC inhibition Blood High 29653964
2018 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. shRNA screen, immunofluorescence, ChIP-seq/genomic analysis, Notch pathway modulation The Journal of cell biology Medium 29588376
2019 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. CRISPR screen, siRNA knockdown, cell cycle analysis, RNA-seq, ChIP-seq (inferred from integrated genomics), epistasis by TOP2A knockdown Hepatology High 31188495
2019 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. Structural/evolutionary analysis combined with biochemical complex purification and functional studies (reviewed) Biochemical Society transactions Medium 31769470
2019 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. Biophysical characterization (described as biophysical states analysis), interaction domain mapping PloS one Low 31790487
2021 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. Conditional knockout in Purkinje neurons, transcriptomics, epigenomics (ChIP-seq), proteomics, SP1 ChIP, rescue by Stathmin3/4 overexpression eLife High 33594975
2021 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. siRNA knockdown, high-content automated lipid droplet imaging, lipid and expression assays Clinical and translational science Low 34156146
2022 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. ChIP, co-immunoprecipitation, phosphorylation-defective HSF1 mutants (S419A), functional transcription assay, histone modification analysis Nature communications High 35906200
2022 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. Auxin-inducible degron alleles for endogenous depletion, RNA-seq, nascent RNA analysis, CUT&RUN, ChIP, kinetic analyses eLife High 35244540
2022 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. Conditional Trrap knockout in adult neural stem cells, acetylation site-directed mutagenesis of Sp1, in vitro and in vivo differentiation assays, ChIP Computational and structural biotechnology journal Medium 36618986
2023 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. Co-immunoprecipitation, TRRAP deletion mutant domain mapping, ubiquitination assay, siRNA knockdown, NANOG rescue overexpression, xenograft mouse model International journal of molecular sciences Medium 37047234
2024 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. Co-immunoprecipitation, cycloheximide chase assay, ubiquitination assay, siRNA knockdown, TRRAP rescue overexpression, xenograft mouse model Naunyn-Schmiedeberg's archives of pharmacology Medium 39073416
2025 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. 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 iScience Medium 40104050
2025 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. Site-saturation mutagenesis screening, cell-based transformation/functional assays, multiple cell models, in vivo validation bioRxivpreprint Medium bio_10.1101_2025.06.16.659507

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell 562 9708738
2005 Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nature cell biology 496 16341205
2000 The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Molecular and cellular biology 373 10611234
2003 Identification of new subunits of the multiprotein mammalian TRRAP/TIP60-containing histone acetyltransferase complex. The Journal of biological chemistry 193 12963728
2005 The mammalian YL1 protein is a shared subunit of the TRRAP/TIP60 histone acetyltransferase and SRCAP complexes. The Journal of biological chemistry 184 15647280
2007 Orchestration of chromatin-based processes: mind the TRRAP. Oncogene 131 17694078
2003 c-Myc transformation domain recruits the human STAGA complex and requires TRRAP and GCN5 acetylase activity for transcription activation. The Journal of biological chemistry 112 12660246
2001 Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. Nature genetics 111 11544477
2002 TRRAP-dependent and TRRAP-independent transcriptional activation by Myc family oncoproteins. Molecular and cellular biology 107 12077335
2001 The ATM-related domain of TRRAP is required for histone acetyltransferase recruitment and Myc-dependent oncogenesis. Genes & development 106 11445536
2010 An RNAi screen identifies TRRAP as a regulator of brain tumor-initiating cell differentiation. Cell stem cell 104 20085741
2007 TRRAP and GCN5 are used by c-Myc to activate RNA polymerase III transcription. Proceedings of the National Academy of Sciences of the United States of America 104 17848523
2001 E2F transcriptional activation requires TRRAP and GCN5 cofactors. The Journal of biological chemistry 101 11418595
2002 Transcriptional regulation of the mdm2 oncogene by p53 requires TRRAP acetyltransferase complexes. Molecular and cellular biology 96 12138177
2010 TRRAP and the maintenance of stemness in gliomas. Cell stem cell 76 20085736
2002 TIP49, but not TRRAP, modulates c-Myc and E2F1 dependent apoptosis. Oncogene 72 12185582
2001 Recruitment of TRRAP required for oncogenic transformation by E1A. Oncogene 69 11781841
2003 The adenovirus E1A oncoprotein recruits the cellular TRRAP/GCN5 histone acetyltransferase complex. Oncogene 68 12743606
2006 The transcriptional histone acetyltransferase cofactor TRRAP associates with the MRN repair complex and plays a role in DNA double-strand break repair. Molecular and cellular biology 66 16382133
2019 Depletion of TRRAP Induces p53-Independent Senescence in Liver Cancer by Down-Regulating Mitotic Genes. Hepatology (Baltimore, Md.) 55 31188495
2007 Transcriptional activation of histone genes requires NPAT-dependent recruitment of TRRAP-Tip60 complex to histone promoters during the G1/S phase transition. Molecular and cellular biology 53 17967892
2014 Trrap-dependent histone acetylation specifically regulates cell-cycle gene transcription to control neural progenitor fate decisions. Cell stem cell 51 24792116
2006 Nipped-A, the Tra1/TRRAP subunit of the Drosophila SAGA and Tip60 complexes, has multiple roles in Notch signaling during wing development. Molecular and cellular biology 49 16508010
2014 MYC interacts with the human STAGA coactivator complex via multivalent contacts with the GCN5 and TRRAP subunits. Biochimica et biophysica acta 45 24705139
2004 HAT cofactor Trrap regulates the mitotic checkpoint by modulation of Mad1 and Mad2 expression. The EMBO journal 45 15549134
2019 Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability. American journal of human genetics 42 30827496
2005 An hGCN5/TRRAP histone acetyltransferase complex co-activates BRCA1 transactivation function through histone modification. The Journal of biological chemistry 38 16260778
2006 Down-regulation of TRRAP-dependent hTERT and TRRAP-independent CAD activation by Myc/Max contributes to the differentiation of HL60 cells after exposure to DMSO. International immunopharmacology 32 16714225
2019 New insights into the evolutionary conservation of the sole PIKK pseudokinase Tra1/TRRAP. Biochemical Society transactions 29 31769470
2005 TRRAP as a hepatic coactivator of LXR and FXR function. Biochemical and biophysical research communications 28 15649435
2015 HAUSP regulates c-MYC expression via de-ubiquitination of TRRAP. Cellular oncology (Dordrecht, Netherlands) 27 25925205
2009 Histone acetyltransferase cofactor Trrap is essential for maintaining the hematopoietic stem/progenitor cell pool. Journal of immunology (Baltimore, Md. : 1950) 27 19880447
2013 Histone acetyltransferase cofactor Trrap maintains self-renewal and restricts differentiation of embryonic stem cells. Stem cells (Dayton, Ohio) 26 23362228
2019 Formation of a structurally-stable conformation by the intrinsically disordered MYC:TRRAP complex. PloS one 25 31790487
2018 TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma. Blood 24 29653964
2022 HSF1 phosphorylation establishes an active chromatin state via the TRRAP-TIP60 complex and promotes tumorigenesis. Nature communications 23 35906200
2021 Beyond HAT Adaptor: TRRAP Liaisons with Sp1-Mediated Transcription. International journal of molecular sciences 20 34830324
2022 The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells. eLife 19 35244540
2021 HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration. eLife 18 33594975
2013 The histone acetyltransferase component TRRAP is targeted for destruction during the cell cycle. Oncogene 18 23318449
2019 Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss. Clinical genetics 17 31231791
2016 Analysis of TRRAP as a Potential Molecular Marker and Therapeutic Target for Breast Cancer. Journal of breast cancer 16 27066097
2010 Transformation/transcription domain-associated protein (TRRAP)-mediated regulation of Wee1. Genetics 16 20194963
2008 HAT cofactor TRRAP mediates beta-catenin ubiquitination on the chromatin and the regulation of the canonical Wnt pathway. Cell cycle (Georgetown, Tex.) 16 19066453
2023 TRRAP Enhances Cancer Stem Cell Characteristics by Regulating NANOG Protein Stability in Colon Cancer Cells. International journal of molecular sciences 15 37047234
2018 TRRAP is a central regulator of human multiciliated cell formation. The Journal of cell biology 14 29588376
2018 De novo variant of TRRAP in a patient with very early onset psychosis in the context of non-verbal learning disability and obsessive-compulsive disorder: a case report. BMC medical genetics 14 30424743
2014 Absence of DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 hotspot mutations in patients with various subtypes of ovarian carcinomas. Biomedical reports 13 25469243
2016 The adenoviral E1A N-terminal domain represses MYC transcription in human cancer cells by targeting both p300 and TRRAP and inhibiting MYC promoter acetylation of H3K18 and H4K16. Genes & cancer 12 27382434
2013 Mutational analysis of the GNA11, MMP27, FGD1, TRRAP and GRM3 genes in thyroid cancer. Oncology letters 11 24137342
2018 TRRAP stimulates the tumorigenic potential of ovarian cancer stem cells. BMB reports 10 29936929
2022 TRRAP-mediated acetylation on Sp1 regulates adult neurogenesis. Computational and structural biotechnology journal 9 36618986
2021 Lipid droplet screen in human hepatocytes identifies TRRAP as a regulator of cellular triglyceride metabolism. Clinical and translational science 7 34156146
2021 The Diarylheptanoid Curcumin Induces MYC Inhibition and Cross-Links This Oncoprotein to the Coactivator TRRAP. Frontiers in oncology 6 33937075
2021 Involvement of the zebrafish trrap gene in craniofacial development. Scientific reports 6 34934055
2024 USP9X deubiquitinates TRRAP to promote glioblastoma cell proliferation and migration and M2 macrophage polarization. Naunyn-Schmiedeberg's archives of pharmacology 4 39073416
2021 Luminescence complementation technology for the identification of MYC:TRRAP inhibitors. Oncotarget 4 34676047
2023 The chromatin remodeling factors EP300 and TRRAP are novel SMYD3 interactors involved in the emerging 'nonmutational epigenetic reprogramming' cancer hallmark. Computational and structural biotechnology journal 3 37954147
2025 Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss. International journal of molecular sciences 2 40004049
2025 A CHD8-TRRAP axis facilitates MYC and E2F target gene regulation in human neural stem cells. iScience 2 40104050
2025 Further Exploring the TRRAP Genotype-Phenotype Correlations: Report of Three New Patients With A Focus on Skeletal Anomalies. Clinical genetics 2 40583039
2014 Tissue-specific inactivation of HAT cofactor TRRAP reveals its essential role in B cells. Cell cycle (Georgetown, Tex.) 2 24675885
2026 Long-Term Follow Up of Two Patients With Variants in the Cluster 1031-1159 of TRRAP Gene: Expanding the Phenotype of Developmental Delay With or Without Dysmorphic Facies and Autism. American journal of medical genetics. Part A 0 41952423

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