Affinage

TRRAP

Transformation/transcription domain-associated protein · UniProt Q9Y4A5

Length
3859 aa
Mass
437.6 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRRAP is a large, catalytically inactive pseudokinase of the PIKK family that serves as the principal activator-docking subunit within multiple histone acetyltransferase complexes—SAGA/STAGA, NuA4/TIP60, and PCAF—where it couples transcriptional activator binding to HAT recruitment at target promoters, thereby controlling histone H3/H4 acetylation and gene expression (PMID:9885573, PMID:9708738, PMID:11423663, PMID:12963728). Through direct physical interaction with activators including c-Myc, E2F, p53, E1A, HSF1, and SP1, TRRAP recruits GCN5- or TIP60-containing HAT activity to regulate cell-cycle gene transcription (Mad1/Mad2, E2F targets, histone genes), RNA polymerase III targets, and mitotic gene programs; its loss causes chromosome missegregation, checkpoint failure, premature differentiation, and neurodegeneration (PMID:15549134, PMID:24792116, PMID:33594975, PMID:17848523). Beyond transcriptional activation, TRRAP localizes to DNA double-strand breaks where it promotes chromatin accessibility for homologous recombination and associates with the MRN complex to facilitate non-homologous end joining, is itself targeted for APC/C-mediated degradation at mitotic entry to prevent histone hyperacetylation, and directly represses IRF9 transcription to restrain interferon-stimulated gene expression (PMID:16341205, PMID:16382133, PMID:23318449, PMID:35244540). TRRAP also stabilizes mutant p53 through its N-terminal HEAT repeats by opposing MDM2-mediated degradation and modulates chromatin-associated β-catenin ubiquitination via SCF recruitment (PMID:29653964, PMID:19066453).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    The identification of TRRAP as an ATM/PI3K-related protein that directly binds c-Myc and E2F transactivation domains and is essential for oncogenic transformation established TRRAP as a transcriptional cofactor for proto-oncoproteins, opening the question of its biochemical mechanism.

    Evidence Co-immunoprecipitation, transdominant mutants, antisense RNA, transformation assay in mammalian cells; parallel MS identification of yeast Tra1 as a SAGA subunit

    PMID:9708738 PMID:9885573

    Open questions at the time
    • Catalytic activity or enzymatic role unknown
    • No information on whether TRRAP itself carries kinase activity despite the PI3K-like domain
    • Mechanism of how TRRAP connects to transcription unresolved
  2. 2000 High

    Demonstration that TRRAP recruits GCN5 histone acetyltransferase activity to c-Myc target genes provided the mechanistic link between activator–TRRAP binding and chromatin modification, explaining TRRAP's role as a HAT-complex scaffold rather than a kinase.

    Evidence Co-immunoprecipitation, in vitro HAT activity assay, functional transcription assays in mammalian cells

    PMID:10611234

    Open questions at the time
    • Whether TRRAP functions in HAT complexes other than GCN5-containing ones was unknown
    • Direct activator–Tra1 contact not yet demonstrated biochemically
  3. 2001 High

    Multiple studies converged to show that TRRAP's PI3K-like domain is required for HAT complex assembly (not catalysis), that acidic activators directly contact the Tra1/TRRAP subunit within both SAGA and NuA4 complexes, and that TRRAP is essential for embryonic viability and mitotic progression, establishing it as a non-catalytic scaffold with essential cell-cycle functions.

    Evidence Photo-cross-linking of activators to yeast Tra1; domain mutagenesis of the ATM-related domain abolishing HAT complex formation; conditional knockout in mice causing peri-implantation lethality and mitotic defects; E2F and E1A binding studies

    PMID:11418595 PMID:11423663 PMID:11445536 PMID:11544477 PMID:11781841

    Open questions at the time
    • How TRRAP mediates mitotic exit mechanistically was unclear
    • Whether TRRAP has functions beyond HAT complex scaffolding unknown
    • The structural basis for activator docking unresolved
  4. 2002 High

    Extension of the activator–TRRAP paradigm to p53 (at the mdm2 promoter) and to selective activation of silent genes like TERT showed that TRRAP-dependent HAT recruitment is a general mechanism for de novo gene activation by diverse transcription factors.

    Evidence GST pull-down of p53–TRRAP, ChIP at mdm2 promoter, antisense knockdown; ChIP and transformation assays distinguishing TRRAP-dependent (TERT) vs. -independent Myc targets

    PMID:12077335 PMID:12138177

    Open questions at the time
    • Whether TRRAP is needed for all p53 targets or a subset unclear
    • Structural determinants of activator specificity on TRRAP unresolved
  5. 2003 High

    Detailed biochemical purification defined the subunit composition of the mammalian TRRAP/TIP60 complex and showed c-Myc co-recruits TRRAP and GCN5 through the STAGA complex, delineating TRRAP's participation in at least two distinct HAT complexes with different catalytic subunits.

    Evidence Biochemical purification from HeLa nuclear extracts with mass spectrometry; co-IP and transactivation assays for STAGA

    PMID:12660246 PMID:12963728

    Open questions at the time
    • Functional specialization of TRRAP/TIP60 vs. TRRAP/GCN5 at specific genomic targets unknown
    • How the same TRRAP molecule selects between different HAT complexes unresolved
  6. 2004 High

    The demonstration that Trrap loss causes mitotic checkpoint failure specifically through reduced transcription of Mad1 and Mad2—rescued by their ectopic expression—placed TRRAP at the top of a transcriptional cascade controlling the spindle assembly checkpoint.

    Evidence Conditional knockout, ChIP at Mad1/Mad2 promoters showing cell-cycle-dependent TIP60/PCAF occupancy, rescue experiment

    PMID:15549134

    Open questions at the time
    • Whether TRRAP controls other checkpoint genes unknown
    • Mechanism selecting TIP60 vs. PCAF at these promoters unclear
  7. 2005 High

    TRRAP/TIP60 was found to localize to DNA double-strand breaks in vivo, where it promotes histone H4 hyperacetylation and chromatin accessibility required for homologous recombination repair, extending TRRAP's role beyond transcription to the DNA damage response.

    Evidence ChIP at defined DSB sites, RNAi depletion reducing HR repair, chromatin relaxation rescue

    PMID:16341205

    Open questions at the time
    • Whether TRRAP recruitment to DSBs is direct or mediated by damage sensors unknown
    • Relationship to ATM signaling at breaks not defined
  8. 2006 High

    Discovery of a distinct TRRAP–MRN complex, separate from TRRAP–GCN5 and TRRAP–TIP60, that promotes NHEJ revealed TRRAP participates in both major DSB repair pathways through different complex forms.

    Evidence Double immunopurification, mass spectrometry, gel filtration, in vitro NHEJ assay in TRRAP-depleted cells and knockout ES cells

    PMID:16382133

    Open questions at the time
    • Whether TRRAP–MRN has HAT activity or a distinct biochemical function unknown
    • Signal that directs TRRAP to HR vs. NHEJ pathway unresolved
  9. 2007 High

    Two studies broadened TRRAP's transcriptional scope: c-Myc recruits GCN5/TRRAP to RNA polymerase III genes, and NPAT recruits the TIP60 complex (including TRRAP) to histone gene promoters at G1/S, showing TRRAP acts at both pol II and pol III loci in a cell-cycle-regulated manner.

    Evidence ChIP at tRNA/5S rRNA and histone gene promoters; RNAi knockdown of TRRAP or TIP60 inhibiting target gene activation

    PMID:17848523 PMID:17967892

    Open questions at the time
    • Whether TRRAP is needed at all pol III genes or a specific subset unknown
    • Full set of cell-cycle-dependent TRRAP targets undefined
  10. 2013 High

    Two parallel advances showed TRRAP is itself a regulated protein—targeted for APC/C-mediated degradation at mitotic entry to prevent histone hyperacetylation and chromosome segregation errors—and a genome-wide regulator of ESC pluripotency through co-occupancy with Oct4 at chromatin.

    Evidence APC/C ubiquitination assay with Cdc20/Cdh1; conditional knockout in ESCs with ChIP-seq and chromatin analysis

    PMID:23318449 PMID:23362228

    Open questions at the time
    • The APC/C degron motifs on TRRAP not mapped
    • Whether TRRAP degradation is the sole mechanism limiting mitotic histone acetylation unknown
  11. 2014 High

    In vivo conditional deletion in neural progenitors demonstrated that TRRAP's HAT recruitment at E2F cell-cycle target promoters is required to maintain progenitor proliferation and prevent premature neuronal differentiation, with rescue by cell-cycle regulators establishing epistasis.

    Evidence Conditional knockout in cortical apical progenitors, ChIP, transcriptomics, BrdU labeling, rescue with cell-cycle gene overexpression

    PMID:24792116

    Open questions at the time
    • Whether TRRAP's role in neural progenitors is solely through E2F targets or includes additional pathways unclear
    • Human relevance for microcephaly not tested
  12. 2017 High

    Cryo-EM structures of yeast Tra1 alone and within the SAGA complex at near-atomic resolution revealed an extensive HEAT/TPR solenoid architecture resembling DNA-PKcs, with activator-interaction mutations clustering in the N-terminal Finger region, providing the first structural framework for understanding TRRAP function.

    Evidence Cryo-EM at 3.7 Å (Tra1 alone) and ~5.7 Å (Tra1 within SAGA), mutagenesis mapping

    PMID:28767037 PMID:29146944

    Open questions at the time
    • Human TRRAP structure not determined
    • How structural changes propagate from activator binding to HAT module activation unknown
    • No structure of TRRAP in the TIP60 complex
  13. 2018 High

    TRRAP was shown to stabilize mutant p53 through an N-terminal 109-amino-acid HEAT repeat region that opposes MDM2-mediated degradation, and separately to control multiciliated cell differentiation downstream of Notch2 signaling, revealing tissue-specific and disease-relevant TRRAP functions.

    Evidence CRISPR-Cas9 domain mapping of TRRAP in lymphoma cells; shRNA screen in airway epithelium with ChIP and RNA-seq

    PMID:29588376 PMID:29653964

    Open questions at the time
    • Whether TRRAP–p53 stabilization requires HAT activity unclear
    • Direct binding interface between TRRAP HEAT repeats and p53 not structurally resolved
  14. 2021 High

    Trrap deletion in Purkinje neurons demonstrated that TRRAP controls SP1-dependent transcription of microtubule dynamics genes (including Stathmin3/4), with rescue by ectopic Stathmin expression, revealing TRRAP as a regulator of neuronal survival through cytoskeletal gene programs.

    Evidence Conditional knockout, integrated transcriptomics/epigenomics/proteomics, SP1 ChIP, Stathmin3/4 rescue

    PMID:33594975

    Open questions at the time
    • Whether TRRAP directly acetylates SP1 or acts through TIP60/GCN5 not fully delineated
    • Mechanism of SP1 recruitment dependence on TRRAP unclear
  15. 2022 High

    Three studies revealed new dimensions of TRRAP regulation and function: HSF1 recruits TRRAP-TIP60 in a PLK1-phosphorylation-dependent manner during heat shock; the TTT/TELO2 complex promotes TRRAP assembly into HAT complexes; and TRRAP directly represses IRF9 transcription, establishing a previously unrecognized transcriptional repressor role.

    Evidence Co-IP and ChIP with phosphomutant HSF1; auxin-inducible degron depletion with nascent RNA-seq and CUT&RUN; SP1 acetylation-site mutagenesis with ChIP in neural stem cells

    PMID:35244540 PMID:35906200 PMID:36618986

    Open questions at the time
    • How TRRAP switches between activator and repressor modes mechanistically unknown
    • Whether TTT-mediated TRRAP assembly is regulated by signaling pathways unresolved
    • The repressor function has not been validated in other cell types

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for human TRRAP's interactions with diverse activators, how TRRAP is allocated between its multiple HAT complexes in a context-dependent manner, the full scope of TRRAP's repressor functions, and whether TRRAP's pseudokinase domain has any non-catalytic signaling role.
  • No high-resolution structure of human TRRAP or its complexes
  • Mechanism determining TRRAP partitioning among SAGA, TIP60, and MRN complexes unknown
  • Pseudokinase domain function beyond scaffolding not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0140110 transcription regulator activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 5 GO:0005694 chromosome 2
Pathway
R-HSA-74160 Gene expression (Transcription) 8 R-HSA-4839726 Chromatin organization 6 R-HSA-1640170 Cell Cycle 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 2 R-HSA-73894 DNA Repair 2
Partners
E2F1GCN5MYCSP1TELO2TIP60TP53USP7
Complex memberships
NuA4/TIP60SAGA/STAGATRRAP-MRN

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 ATM/PI3-kinase-related protein that interacts specifically with the c-Myc N-terminal transactivation domain and the E2F-1 transactivation domain; expression of transdominant TRRAP mutants or antisense RNA blocks c-Myc- and E1A-mediated oncogenic transformation, establishing TRRAP as an essential cofactor for these oncoproteins. Co-immunoprecipitation, transdominant mutant overexpression, antisense RNA inhibition, transformation assay Cell High 9708738
2000 TRRAP recruits histone acetyltransferase activity catalyzed by hGCN5 to c-Myc target genes, providing a biochemical mechanism for Myc-mediated transcriptional activation and opposing Mad-family repression via histone deacetylase recruitment. Co-immunoprecipitation, HAT activity assay, functional transcription assays Molecular and Cellular Biology High 10611234
1998 The yeast TRRAP ortholog Tra1 is a stable subunit of the SAGA histone acetyltransferase/transcriptional adaptor complex, confirmed by mass spectrometry, immunoblotting, and immunoprecipitation, and is also a component of at least two other HAT complexes. Mass spectrometry, immunoblotting, immunoprecipitation of purified SAGA complex Molecular Cell High 9885573
2001 In yeast, the Tra1 subunit (TRRAP ortholog) of SAGA and NuA4 HAT complexes is directly contacted by acidic transcriptional activators via affinity chromatography and photo-cross-linking label transfer; C-terminal mutations in Tra1 disrupt activator interactions and cause gene-specific transcriptional defects correlated with reduced promoter histone acetylation. Affinity chromatography, photo-cross-linking label transfer, targeted mutagenesis, promoter ChIP Science High 11423663
2001 Null mutation of Trrap in mice causes peri-implantation lethality due to blocked blastocyst proliferation; conditional Cre-loxP-mediated deletion shows Trrap is required for mitotic exit, with Trrap-deficient cells showing cytokinesis failure, endoreduplication, chromosome missegregation, disrupted spindles, and compromised Cdk1 activity. Conditional knockout (Cre-loxP), cell cycle analysis, immunofluorescence, Cdk1 kinase assay Nature Genetics High 11544477
2001 The ATM-related (PI3K-like) domain of TRRAP is required for assembly of a functional HAT complex; mutation in this domain inhibits Myc-mediated oncogenic transformation and blocks HAT complex recruitment. The Myc-binding region maps to a separable domain from the ATM-related domain. Domain mutagenesis, HAT complex co-immunoprecipitation, transformation assay, domain mapping Genes & Development High 11445536
2001 E2F-1 and E2F-4 transactivation domains bind GCN5 acetyltransferase and TRRAP in vivo; TRRAP and GCN5 co-expression stimulates E2F-mediated transactivation; mutations in the transactivation domain that reduce GCN5/TRRAP binding correlate with reduced HAT activity and transcriptional activation. Co-immunoprecipitation in vivo, HAT activity assay, transactivation reporter assay, mutagenesis The Journal of Biological Chemistry High 11418595
2001 Adenovirus E1A requires TRRAP interaction for cellular transformation; a TRRAP-interaction domain in E1A (residues 12–54) is sufficient to restore Myc transforming function and recruit TRRAP; overexpression of a competing TRRAP fragment blocks E1A–TRRAP interaction and suppresses transformation. Co-immunoprecipitation, transformation assay, dominant-negative competition, chimeric protein rescue Oncogene High 11781841
2002 TRRAP functionally cooperates with p53 to activate mdm2 transcription; p53 directly binds a TRRAP domain (activator docking site) in vitro; p53-dependent recruitment of TRRAP to the mdm2 promoter is followed by increased histone acetylation, and antisense TRRAP blocks p53-dependent mdm2 transcription. GST pull-down, chromatin immunoprecipitation (ChIP), antisense RNA inhibition, transactivation assay Molecular and Cellular Biology High 12138177
2002 TRRAP binding and recruitment of histone H3/H4 acetyltransferase activity are required for c-Myc or N-Myc activation of the silent TERT gene and for oncogenic transformation, but TRRAP is dispensable for partial induction of basally expressed genes; L-Myc's reduced TRRAP binding correlates with reduced TERT activation and transformation. Co-immunoprecipitation, ChIP, transformation assay, HAT activity assay, domain mutagenesis Molecular and Cellular Biology High 12077335
2003 c-Myc co-recruits TRRAP and GCN5 through direct physical interactions of its N-terminal transactivation domain with the human STAGA coactivator complex; this requires both the SPT3/GCN5 interaction domain of TRRAP and the HAT activity of GCN5 for transcriptional synergy. Co-immunoprecipitation, transactivation assay, mutagenesis, HAT activity assay The Journal of Biological Chemistry High 12660246
2003 MRGBP, TRCp120, DMAP1, MRG15, and MRGX are identified as new subunits of the mammalian TRRAP/TIP60 HAT complex through biochemical purification from HeLa nuclear extracts. Biochemical purification from HeLa nuclear extracts, co-immunoprecipitation, mass spectrometry The Journal of Biological Chemistry High 12963728
2003 Adenovirus E1A binds a TRRAP complex containing GCN5 during infection; E1A associates with significant HAT activity in vitro attributable partly to GCN5; E1A represses c-Myc- and E2F-1-directed transactivation by sequestering GCN5 and/or TRRAP. Co-immunoprecipitation in vivo, in vitro HAT activity assay, transactivation reporter assay Oncogene Medium 12743606
2004 Loss of Trrap in mammalian cells leads to chromosome missegregation and mitotic checkpoint failure caused by defective Trrap-mediated transcription of Mad1 and Mad2; Trrap associates with TIP60 and PCAF at Mad1/Mad2 promoters in a cell-cycle-dependent manner and promotes histone H3/H4 acetylation there; ectopic Mad1/Mad2 expression fully restores the mitotic checkpoint in Trrap-deficient cells. Conditional knockout, ChIP, HAT activity assay, rescue experiment, chromosome segregation analysis The EMBO Journal High 15549134
2005 YL1 protein is identified as a new subunit of the mammalian TRRAP/TIP60 HAT complex and also a component of the SRCAP chromatin-remodeling complex, suggesting YL1 plays multiple roles in chromatin modification. Biochemical purification, co-immunoprecipitation, mass spectrometry The Journal of Biological Chemistry Medium 15647280
2005 Trrap and TIP60 HAT 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; chromatin relaxation rescues the repair defect, indicating TRRAP/TIP60 promotes chromatin accessibility for HR repair. ChIP at DSB sites, RNAi depletion, HR repair assay, chromatin relaxation rescue experiment Nature Cell Biology High 16341205
2006 TRRAP stably associates with the MRN (MRE11-RAD50-NBS1) repair complex (distinct from TRRAP-GCN5 and TRRAP-TIP60 HAT complexes); TRRAP-depleted cells show reduced non-homologous end-joining (NHEJ) activity in vitro and in vivo, implicating TRRAP as a molecular link between DSB repair and chromatin remodeling. Double immunopurification, mass spectrometry, gel filtration, in vitro NHEJ assay, siRNA knockdown, TRRAP knockout ES cells Molecular and Cellular Biology High 16382133
2006 Drosophila Nipped-A (TRRAP ortholog) is required for Notch and mastermind coactivator activity during wing development and colocalizes with mastermind on polytene chromosomes; reducing Nipped-A decreases mastermind binding, and components of both SAGA (Ada2b) and TIP60 (domino) complexes are required for mastermind function. Genetic analysis, polytene chromosome immunostaining, colocalization, genetic epistasis Molecular and Cellular Biology Medium 16508010
2005 TRRAP (as hGCN5/TRRAP complex) co-activates BRCA1 transactivation; BRCA1 cancer-associated mutations in its C-terminal domain abolish physical interaction with TRRAP; hGCN5 HAT activity is indispensable for BRCA1-mediated gene regulation and DNA repair; TRRAP/hGCN5 forms a complex with hMSH2/hMSH6 as a novel subclass of hGCN5/TRRAP HAT complex. Co-immunoprecipitation, biochemical purification, HAT activity assay, mutagenesis, transactivation assay The Journal of Biological Chemistry Medium 16260778
2007 c-Myc activates RNA polymerase III transcription of tRNA and 5S rRNA genes by recruiting GCN5 and TRRAP to these genes, leading to selective histone H3 hyperacetylation and increased TFIIIB occupancy, followed by pol III recruitment and transcriptional induction. ChIP, RNA pol III transcription assay, kinetic ChIP analysis Proceedings of the National Academy of Sciences High 17848523
2007 NPAT interacts with components of the TIP60 HAT complex (including TRRAP and TIP60) through a conserved motif also found in E2F and E1A; TRRAP and TIP60 associate with histone gene promoters in an NPAT-dependent manner at G1/S, with increased H4 acetylation; RNAi suppression of TRRAP or TIP60 inhibits histone gene activation. Co-immunoprecipitation, ChIP at G1/S boundary, RNAi knockdown, transcription assay Molecular and Cellular Biology High 17967892
2008 TRRAP interacts with Skp1/SCF ubiquitin ligase complex and mediates its recruitment to beta-catenin target promoters in chromatin; TRRAP deletion reduces beta-catenin ubiquitination on chromatin, causing beta-catenin accumulation and hyperactivation of the Wnt pathway. Co-immunoprecipitation, ChIP, RNAi knockdown, ubiquitination assay, Wnt pathway reporter Cell Cycle Medium 19066453
2009 Conditional deletion of Trrap in mice depletes hematopoietic stem/progenitor cells via a cell-autonomous mechanism involving p53-independent apoptosis and deregulation of Myc transcription factors. Conditional knockout (Cre-loxP), bone marrow transplantation, FACS, cell-autonomous rescue experiment Journal of Immunology Medium 19880447
2010 In fission yeast, tra1 (TRRAP ortholog) mutation renders cells semi-wee and causes accumulation of inactive Wee1 protein; this requires the Cdr1/Cdr2 negative regulators of Wee1; HDAC inhibition reverts the phenotype, suggesting Tra1-associated HAT activity controls the timing of mitotic entry via Wee1/Cdc2. Genetic screen, yeast genetics, epistasis with cdr1/cdr2 deletion, HDAC inhibitor treatment, Wee1 protein analysis Genetics Medium 20194963
2010 In budding yeast, Tra1 GID (Gal4-interaction defective) mutants are not recruited by Gal4 to the promoter and cannot support Gal4-directed transcription; Gal4 and Tra1 bind cooperatively and predominantly on DNA; other activators' interactions with Tra1 are unaffected by GID mutations, revealing specificity of Gal4–Tra1 interaction. Large-scale genetic screen, ChIP, in vivo interaction assays, transactivation assay Proceedings of the National Academy of Sciences Medium 22308403
2013 TRRAP is targeted for degradation during mitosis by the APC/C ubiquitin ligase via its activators Cdc20 and Cdh1; ectopic expression of Cdc20 and Cdh1 reduces TRRAP levels and induces ubiquitination; TRRAP overexpression or stabilization causes lagging chromosomes, chromosome bridges, multipolar spindles, cohesion loss, and chromatin condensation defects; mitotic delay correlates with global histone H4 hyperacetylation. APC/C ubiquitination assay, co-expression of Cdc20/Cdh1, cell cycle analysis, immunofluorescence, histone acetylation assay Oncogene High 23318449
2013 Conditional deletion of Trrap in mouse embryonic stem cells triggers unscheduled differentiation associated with loss of histone acetylation, chromatin condensation, uncoupling of H3K4me2/H3K27me3, and downregulation of Nanog, Oct4, and Sox2; ChIP-seq shows significant overlap between Oct4 and Trrap binding in ESCs; failure to downregulate Trrap prevents ESC differentiation. Conditional knockout, ChIP-seq, genome-wide chromatin analysis, gene expression profiling Stem Cells High 23362228
2014 Deletion of Trrap in cortical apical neural progenitors impairs HAT recruitment and transcriptional machinery specifically at E2F cell-cycle target gene promoters, causing cell-cycle lengthening, premature differentiation into basal progenitors and neurons, and microcephaly; overexpression of cell-cycle regulators rescues the differentiation defects. Conditional knockout, ChIP, transcriptomic analysis, in vivo rescue with cell-cycle regulators, BrdU labeling Cell Stem Cell High 24792116
2014 MYC TAD directly contacts both TRRAP and GCN5 within native STAGA via protein crosslinking; GCN5 binds an N-terminal sub-domain of MYC TAD (residues 21–108) through M2/M3 sequence motifs; mutations in M2/M3 strongly inhibit MYC acetylation by GCN5 and reduce MYC binding and transactivation of the GCN5-dependent TERT promoter. Protein crosslinking within native complex, deletion mapping, co-immunoprecipitation, ChIP, transactivation assay Biochimica et Biophysica Acta High 24705139
2015 The deubiquitinase HAUSP physically interacts with and co-localizes with TRRAP, and deubiquitinates TRRAP; HAUSP overexpression increases TRRAP and c-MYC protein and mRNA levels, and increases c-MYC transactivation in a TRRAP-dependent manner. Co-immunoprecipitation, in vivo deubiquitination assay, immunocytochemistry, luciferase reporter assay, qRT-PCR Cellular Oncology Medium 25925205
2017 Cryo-EM structure of yeast Tra1 (TRRAP ortholog) at 3.7 Å reveals an extensive network of alpha-helical solenoids in a diamond ring conformation, structurally reminiscent of DNA-PKcs; fitting into SAGA EM reconstruction shows limited contact surfaces, indicating Tra1 does not act as a molecular scaffold within SAGA; activator-interaction mutations cluster in the N-terminal Finger region. Cryo-EM structure determination, EM fitting, mutagenesis mapping eLife High 28767037
2017 Cryo-EM structure of the entire SAGA complex resolves Tra1 (TRRAP ortholog) at ~5.7 Å average resolution, tracing most of the main chain of this 430 kDa subunit and revealing its structural integration within SAGA. Cryo-EM structure of native SAGA complex Nature Communications High 29146944
2018 TRRAP is a critical positive regulator of both mutant and wild-type p53 protein levels in lymphoma; a 109-amino-acid N-terminal HEAT repeat region of TRRAP is crucial for mutant p53 stabilization; TRRAP silencing causes mutant p53 degradation via the MDM2-proteasome axis; HDAC1/2/3 inhibition similarly decreases p53 levels. RNAi screen, CRISPR-Cas9 domain mapping, mass spectrometry of p53 interactome, proteasome inhibitor experiments Blood High 29653964
2018 TRRAP acts downstream of Notch2-mediated basal progenitor cell fate decisions and upstream of Multicilin to control multiciliated cell (MCC) differentiation in airway epithelium; TRRAP binds promoters and regulates expression of a network of MCC differentiation genes, including several ciliopathy-associated genes. shRNA pooled screen, immunofluorescence, signaling pathway modulation (Notch2), ChIP, RNA-seq The Journal of Cell Biology High 29588376
2019 Depletion of TRRAP or its co-factor KAT5 (TIP60) inhibits HCC cell growth through p53-independent and p21-independent senescence with G2/M arrest; integrated genomics identifies mitotic genes (including TOP2A) as key TRRAP/KAT5 targets; TOP2A depletion alone recapitulates the senescence phenotype. CRISPR kinome screen, RNA-seq, cell cycle analysis, senescence assay, epistasis via TOP2A depletion Hepatology High 31188495
2019 The MYC:TRRAP interaction occurs at the MYC Homology Box 2 (MB2) within the intrinsically disordered MYC transactivation domain; upon binding TRRAP, MB2 may acquire a defined stable conformation detectable by biophysical analysis. Biophysical analysis (structural/biochemical characterization of MYC:TRRAP complex), domain mapping PLoS ONE Low 31790487
2021 Trrap deletion in mouse Purkinje neurons causes neurodegeneration; TRRAP acts via SP1 to control transcription of microtubule dynamics genes; TRRAP is required for SP1 binding at the promoters of target genes; ectopic Stathmin3/4 expression rescues microtubule and neuronal defects of TRRAP-deficient neurons. Conditional knockout, transcriptomics, epigenomics (ChIP-seq), proteomics, SP1 ChIP, rescue with Stathmin3/4 eLife High 33594975
2022 HSF1 recruits the TRRAP-TIP60 acetyltransferase complex to the HSP72 promoter during heat shock in a manner dependent on HSF1 phosphorylation at S419 by PLK1; this promotes chromatin opening and tumorigenesis. Co-immunoprecipitation, ChIP, phosphomutant analysis, kinase inhibitor experiments Nature Communications Medium 35906200
2022 The 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 (master regulator of interferon-stimulated genes), revealing an unexpected transcriptional repressor role for TRRAP. Auxin-inducible degron depletion, transcriptomics (nascent RNA), CUT&RUN, ChIP, kinetic analyses eLife High 35244540
2022 TRRAP-mediated acetylation of SP1 at specific lysine residues (K639 and K703) modulates Sp1 stability and its binding to target gene promoters; deacetylation of Sp1 at K639 increases promoter binding and antagonizes TRRAP binding; deacetylated K639 corrects differentiation defects of Trrap-deleted adult neural stem cells. Conditional knockout in adult NSCs, site-specific mutagenesis of Sp1 acetylation sites, ChIP, differentiation assay Computational and Structural Biotechnology Journal Medium 36618986
2023 TRRAP overexpression specifically increases NANOG protein stability by interfering with FBXW8 (E3 ubiquitin ligase)-mediated NANOG ubiquitination; the TRRAP domain (amino acids 1898–2400) binds NANOG and when overexpressed abrogates FBXW8-mediated ubiquitination; TRRAP knockdown reduces cancer stem cell markers and tumor growth. Co-immunoprecipitation, ubiquitination assay, deletion mapping, xenograft model International Journal of Molecular Sciences Medium 37047234

Source papers

Stage 0 corpus · 100 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 561 9708738
2005 Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nature cell biology 493 16341205
2000 The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Molecular and cellular biology 372 10611234
2001 Recruitment of HAT complexes by direct activator interactions with the ATM-related Tra1 subunit. Science (New York, N.Y.) 296 11423663
1992 Molecular analysis of the C. elegans sex-determining gene tra-1: a gene encoding two zinc finger proteins. Cell 230 1339311
2003 Identification of new subunits of the multiprotein mammalian TRRAP/TIP60-containing histone acetyltransferase complex. The Journal of biological chemistry 192 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
1987 A genetic analysis of the sex-determining gene, tra-1, in the nematode Caenorhabditis elegans. Genes & development 181 3428597
1998 The ATM-related cofactor Tra1 is a component of the purified SAGA complex. Molecular cell 165 9885573
2000 Mab-3 is a direct tra-1 target gene regulating diverse aspects of C. elegans male sexual development and behavior. Development (Cambridge, England) 140 11003845
2007 Orchestration of chromatin-based processes: mind the TRRAP. Oncogene 130 17694078
2007 A CUL-2 ubiquitin ligase containing three FEM proteins degrades TRA-1 to regulate C. elegans sex determination. Developmental cell 122 17609115
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 111 12660246
2001 Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. Nature genetics 110 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
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
2010 An RNAi screen identifies TRRAP as a regulator of brain tumor-initiating cell differentiation. Cell stem cell 103 20085741
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
1996 Evolution of sex determination in caenorhabditis: unusually high divergence of tra-1 and its functional consequences. Genetics 84 8889522
1993 Zinc fingers in sex determination: only one of the two C. elegans Tra-1 proteins binds DNA in vitro. Nucleic acids research 80 8367286
2010 TRRAP and the maintenance of stemness in gliomas. Cell stem cell 76 20085736
2008 dmd-3, a doublesex-related gene regulated by tra-1, governs sex-specific morphogenesis in C. elegans. Development (Cambridge, England) 72 18550714
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
2010 Domains of Tra1 important for activator recruitment and transcription coactivator functions of SAGA and NuA4 complexes. Molecular and cellular biology 67 21149579
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 64 16382133
2004 Conservation of the global sex determination gene tra-1 in distantly related nematodes. Genes & development 63 15155582
1990 The tra-1 gene determines sexual phenotype cell-autonomously in C. elegans. Cell 63 2261640
2011 Tra1 has specific regulatory roles, rather than global functions, within the SAGA co-activator complex. The EMBO journal 56 21642955
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
2002 Functional and mutational analysis of conjugative transfer region 1 (Tra1) from the IncHI1 plasmid R27. Journal of bacteriology 50 11914349
2013 TRA-1 ChIP-seq reveals regulators of sexual differentiation and multilevel feedback in nematode sex determination. Proceedings of the National Academy of Sciences of the United States of America 49 24046365
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 44 15549134
2001 The TRA-1 transcription factor binds TRA-2 to regulate sexual fates in Caenorhabditis elegans. The EMBO journal 44 11250902
1994 Regulation of transfer genes of promiscuous IncP alpha plasmid RK2: repression of Tra1 region transcription both by relaxosome proteins and by the Tra2 regulator TrbA. Microbiology (Reading, England) 42 7812437
2019 Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability. American journal of human genetics 41 30827496
2005 An hGCN5/TRRAP histone acetyltransferase complex co-activates BRCA1 transactivation function through histone modification. The Journal of biological chemistry 38 16260778
2017 Cryo-EM structure of the SAGA and NuA4 coactivator subunit Tra1 at 3.7 angstrom resolution. eLife 35 28767037
2017 Structure of the transcription activator target Tra1 within the chromatin modifying complex SAGA. Nature communications 34 29146944
2006 The PLZF-like protein TRA-4 cooperates with the Gli-like transcription factor TRA-1 to promote female development in C. elegans. Developmental cell 33 17011494
1999 TRA-1 regulates the cellular distribution of the tra-2 mRNA in C. elegans. Nature 33 10391248
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
1995 Dominant feminizing mutations implicate protein-protein interactions as the main mode of regulation of the nematode sex-determining gene tra-1. Genes & development 32 7851791
1993 Molecular cloning and duplication of the nematode sex-determining gene tra-1. Genetics 32 8384144
2019 New insights into the evolutionary conservation of the sole PIKK pseudokinase Tra1/TRRAP. Biochemical Society transactions 28 31769470
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
2007 Structure/function analysis of the phosphatidylinositol-3-kinase domain of yeast tra1. Genetics 27 17660562
2005 TRRAP as a hepatic coactivator of LXR and FXR function. Biochemical and biophysical research communications 27 15649435
2013 Histone acetyltransferase cofactor Trrap maintains self-renewal and restricts differentiation of embryonic stem cells. Stem cells (Dayton, Ohio) 26 23362228
2012 Analysis of Gal4-directed transcription activation using Tra1 mutants selectively defective for interaction with Gal4. Proceedings of the National Academy of Sciences of the United States of America 25 22308403
2008 Systematic genetic array analysis links the Saccharomyces cerevisiae SAGA/SLIK and NuA4 component Tra1 to multiple cellular processes. BMC genetics 25 18616809
2001 RNA-Regulated TRA-1 nuclear export controls sexual fate. Developmental cell 25 11703944
1997 TRA1, a novel mRNA highly expressed in leukemogenic mouse monocytic sublines but not in nonleukemogenic sublines. Blood 25 9108418
2018 TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma. Blood 24 29653964
2010 Mutational analysis of the C-terminal FATC domain of Saccharomyces cerevisiae Tra1. Current genetics 24 20635087
2002 Adenovirus E1A requires the yeast SAGA histone acetyltransferase complex and associates with SAGA components Gcn5 and Tra1. Oncogene 24 11857084
2019 Formation of a structurally-stable conformation by the intrinsically disordered MYC:TRRAP complex. PloS one 23 31790487
2022 HSF1 phosphorylation establishes an active chromatin state via the TRRAP-TIP60 complex and promotes tumorigenesis. Nature communications 22 35906200
1999 Retroviral insertions in Evi12, a novel common virus integration site upstream of Tra1/Grp94, frequently coincide with insertions in the gene encoding the peripheral cannabinoid receptor Cnr2. Journal of virology 21 10196250
2021 Beyond HAT Adaptor: TRRAP Liaisons with Sp1-Mediated Transcription. International journal of molecular sciences 20 34830324
2005 STAR proteins quaking-6 and GLD-1 regulate translation of the homologues GLI1 and tra-1 through a conserved RNA 3'UTR-based mechanism. Developmental biology 20 16198329
2009 Caenorhabditis elegans p97 controls germline-specific sex determination by controlling the TRA-1 level in a CUL-2-dependent manner. Journal of cell science 19 19773360
2009 xol-1, the master sex-switch gene in C. elegans, is a transcriptional target of the terminal sex-determining factor TRA-1. Development (Cambridge, England) 19 19906855
2022 The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells. eLife 18 35244540
2013 The histone acetyltransferase component TRRAP is targeted for destruction during the cell cycle. Oncogene 18 23318449
2021 HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration. eLife 17 33594975
2019 Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss. Clinical genetics 17 31231791
2012 Genetic evidence links the ASTRA protein chaperone component Tti2 to the SAGA transcription factor Tra1. Genetics 17 22505622
1989 Mutagenesis of the Tra1 core region of RK2 by using Tn5: identification of plasmid-specific transfer genes. Journal of bacteriology 17 2544570
1980 Cloning the Tra1 region of RP1. Plasmid 17 6100930
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
1994 Regulatory rearrangements and smg-sensitive alleles of the C. elegans sex-determining gene tra-1. Developmental genetics 16 7520378
2023 TRRAP Enhances Cancer Stem Cell Characteristics by Regulating NANOG Protein Stability in Colon Cancer Cells. International journal of molecular sciences 14 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
2018 The Pseudokinase Domain of Saccharomyces cerevisiae Tra1 Is Required for Nuclear Localization and Incorporation into the SAGA and NuA4 Complexes. G3 (Bethesda, Md.) 12 29626083
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
1995 Localization of the human achaete-scute homolog gene (ASCL1) distal to phenylalanine hydroxylase (PAH) and proximal to tumor rejection antigen (TRA1) on chromosome 12q22-q23. Genomics 10 8595908
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
2020 TRA1: A Locus Responsible for Controlling Agrobacterium-Mediated Transformability in Barley. Frontiers in plant science 7 32373138
1993 Identification and characterization of RP1 Tra1 cistrons involved in pilus function and plasmid mobilization. Journal of bacteriology 7 8093446
2021 The Diarylheptanoid Curcumin Induces MYC Inhibition and Cross-Links This Oncoprotein to the Coactivator TRRAP. Frontiers in oncology 6 33937075
2021 The SAGA and NuA4 component Tra1 regulates Candida albicans drug resistance and pathogenesis. Genetics 6 34849885
2021 Involvement of the zebrafish trrap gene in craniofacial development. Scientific reports 6 34934055
2019 Sfp1 links TORC1 and cell growth regulation to the yeast SAGA-complex component Tra1 in response to polyQ proteotoxicity. Traffic (Copenhagen, Denmark) 6 30740854
2001 Large de novo deletion in chromosome 12 affecting the PAH, IGF1, ASCL1, and TRA1 genes. Journal of molecular medicine (Berlin, Germany) 5 11434725