Affinage

KAT5

Histone acetyltransferase KAT5 · UniProt Q92993

Length
513 aa
Mass
58.6 kDa
Annotated
2026-06-10
100 papers in source corpus 57 papers cited in narrative 57 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

KAT5/TIP60 is a MYST-family lysine acetyltransferase that serves as the catalytic engine of the multisubunit NuA4/TIP60-EP400 chromatin-modifying complex, coupling histone acetylation to transcriptional activation, chromatin accessibility, DNA-damage signaling, and cell-fate decisions (PMID:32542325, PMID:39260417). Within this complex, the EP400 scaffold integrates RUVBL1-RUVBL2, ACTL6A-ACTB, and a flexibly tethered TRRAP module whose loss redistributes H2A.Z and its acetylation genome-wide (PMID:39260417, PMID:39154037, PMID:39088653). KAT5 acetylates histone H4 and H2A.Z — specifically H2A.Z-K7 — and this activity drives bivalent gene activation, neuronal fate specification, hematopoietic stem cell maintenance, and proper mitotic chromosome alignment; its loss causes a p53/INK4A/ARF-independent mitotic arrest (PMID:32542325, PMID:35853868, PMID:36417913). De novo missense variants disabling the chromodomain or acetyl-CoA binding site abolish H4 acetylation and cause a neurodevelopmental syndrome (PMID:32822602). Beyond chromatin, KAT5 is a hub for the DNA double-strand break response: its chromodomain reads H3K9me3 to activate its acetyltransferase activity toward ATM, a step requiring c-Abl- and VRK1-mediated phosphorylation of KAT5 and recruitment via the FOXO3a-ATM axis (PMID:23708966, PMID:20160506, PMID:33076429, PMID:27524627). KAT5 acetylates a broad non-histone substrate repertoire that specifies distinct outcomes — p53-K120 to direct apoptosis over arrest, AR to control nuclear localization, and SOX4-K95, SMAD3-K333, cGAS, MARCKS-K165, Sp1-K639, C-MYC, and Rev-erbβ in their respective transcriptional and signaling programs (PMID:17189186, PMID:19938016, PMID:26291311, PMID:29520103, PMID:32817552, PMID:30655546, PMID:29045464, PMID:30400007, PMID:17996965). KAT5 abundance and activity are tightly controlled by autoacetylation reversed by SIRT1 and HDAC3, by ubiquitin-mediated degradation via ATF2/Cul3 opposed by ATF3/USP7-driven stabilization, and by O-GlcNAcylation that antagonizes ubiquitination (PMID:25301942, PMID:18397884, PMID:25865756, PMID:34650217). Homozygous loss is embryonic-lethal in mice, underscoring an essential developmental role (PMID:19842187).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 Medium

    Established that TIP60 is not merely a chromatin enzyme but a context-dependent transcriptional coregulator, first by linking it physically to nuclear hormone receptors.

    Evidence Yeast two-hybrid, reciprocal Co-IP, and luciferase reporters for AR/ER/PR transactivation

    PMID:10364196

    Open questions at the time
    • Did not define the molecular basis (acetylation vs. scaffolding) of coactivation
    • No structural or substrate-level detail
  2. 2006 High

    Defined how TIP60 acetylation of p53-K120 specifies cell fate, answering why p53 commits to apoptosis versus arrest.

    Evidence In vitro acetylation, K120R mutagenesis, knockdown, and reporter assays

    PMID:15310756 PMID:16601686 PMID:17189186

    Open questions at the time
    • Mechanism of how K120ac biases promoter selectivity not fully resolved
    • Interplay with p400 inhibition incompletely defined
  3. 2010 High

    Identified the chromodomain-H3K9me3 reader mechanism by which DNA damage activates TIP60 acetyltransferase activity toward ATM.

    Evidence Chromodomain binding assays, ATM acetylation assays, Co-IP; MRN-dependent targeting

    PMID:20160506 PMID:23708966

    Open questions at the time
    • How H3K9me3 reading allosterically activates catalysis not structurally resolved
    • Quantitative kinetics of ATM acetylation unknown
  4. 2013 High

    Showed that upstream tyrosine phosphorylation by c-Abl is the trigger that licenses the chromodomain-H3K9me3 interaction, placing TIP60 activation within a kinase cascade.

    Evidence Phosphorylation, chromodomain binding, and ATM acetylation assays with kinase manipulation

    PMID:23708966 PMID:23777805

    Open questions at the time
    • Phosphorylation site stoichiometry in vivo not quantified
    • Coordination with other DSB-response PTMs unresolved
  5. 2016 Medium

    Resolved layers of TIP60 regulation in the damage response — phospho-activation, ubiquitin turnover, and competitive recruitment to ATM.

    Evidence Co-IP, knockdown, protein stability and ATM activation assays (ATF2/Cul3, NOTCH1/FOXO3a, GSK3β)

    PMID:18397884 PMID:27524627 PMID:28032867

    Open questions at the time
    • Relative contribution of each regulatory input in vivo unclear
    • Tissue-specificity of these controls not mapped
  6. 2015 High

    Demonstrated that TIP60 stability and catalytic activity are co-regulated by ATF3/USP7 and reversed by VRK1-dependent phosphorylation, tying enzyme half-life to DNA-damage competence.

    Evidence Co-IP, in vitro acetyltransferase and deubiquitination assays, kinase-dead rescue

    PMID:25865756 PMID:26420831 PMID:33076429

    Open questions at the time
    • How autoacetylation, phosphorylation, and ubiquitination are temporally ordered not established
  7. 2014 High

    Established autoacetylation as an intrinsic activity switch, erased by SIRT1 (promoting degradation) and HDAC3 (promoting stability), reconciling opposing deacetylase effects.

    Evidence Six-site autoacetylation mutagenesis, half-life and apoptosis assays, Co-IP

    PMID:19895790 PMID:25301942

    Open questions at the time
    • Structural consequence of autoacetylation on catalysis not resolved
    • Whether SIRT1 and HDAC3 act on the same lysines unclear
  8. 2018 High

    Expanded the non-histone substrate map to SMAD3-K333, MARCKS-K165, and Sp1-K639, showing adaptor-mediated recruitment (TRIB3) and PTM-cross-talk that propagate signaling and cancer phenotypes.

    Evidence In vitro acetylation with site-specific mutagenesis, Co-IP, ChIP, and in vivo tumor models

    PMID:29045464 PMID:29520103 PMID:30400007 PMID:30655546

    Open questions at the time
    • General rules governing substrate selection beyond adaptor recruitment unknown
    • In vivo stoichiometry of substrate acetylation not measured
  9. 2020 High

    Connected TIP60 to innate immunity and stem-cell maintenance, showing cGAS acetylation enhances DNA sensing while H2A.Z-acetylation/c-Myc target activation sustains HSCs.

    Evidence In vivo Kat5 knockout, acetylation and DNA-binding assays, ChIP-seq/RNA-seq, viral and HSC functional assays

    PMID:32542325 PMID:32817552

    Open questions at the time
    • Whether cGAS acetylation occurs within the NuA4 complex or by free KAT5 unclear
    • Direct vs. indirect contribution to HSC gene programs not fully separated
  10. 2022 High

    Pinpointed H2A.Z-K7 as a specific TIP60 product whose loss drives p53/ARF-independent mitotic arrest and impairs bivalent/neuronal gene activation, linking a single histone mark to defined developmental outcomes.

    Evidence Inducible KO/CRISPR deletion, H2A.Z-K7 acetylation assays, cell-cycle imaging, ChIP-seq, ATAC-seq, directed differentiation

    PMID:31700011 PMID:35853868 PMID:36417913

    Open questions at the time
    • How H2A.Z-K7ac mechanistically licenses H3K4me3 deposition not resolved
    • Relationship between mitotic arrest and bivalent activation phenotypes unclear
  11. 2024 High

    Delivered near-atomic architecture of the endogenous human TIP60-EP400 complex, defining EP400 as the integrating scaffold and TRRAP as a flexible targeting module required for proper genome-wide H2A.Z deposition.

    Evidence Cryo-EM at 3.2–4.7 Å with TRRAP-depletion ChIP-seq for H2A.Z

    PMID:29559617 PMID:39088653 PMID:39154037 PMID:39260417

    Open questions at the time
    • Structural basis for nucleosome substrate engagement not fully resolved
    • How regulatory PTMs reshape the assembled complex unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse upstream signals (phosphorylation, autoacetylation, O-GlcNAcylation, ubiquitination) are integrated to direct KAT5 between its histone and specific non-histone substrates in a given cellular context remains unresolved.
  • No unified model linking PTM state to substrate choice
  • Substrate-targeting role of the assembled NuA4/TIP60 complex vs. free KAT5 undefined
  • Mechanism connecting structural arrangement to substrate selectivity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0042393 histone binding 6 GO:0016740 transferase activity 4 GO:0140110 transcription regulator activity 4 GO:0003723 RNA binding 1
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 4 GO:0005829 cytosol 2
Pathway
R-HSA-73894 DNA Repair 5 R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1640170 Cell Cycle 1
Partners
ARATMC-MYCEP400RUVBL1RUVBL2TP53TRRAP
Complex memberships
NuA4/TIP60-EP400 complex

Evidence

Reading pass · 57 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Tip60 (KAT5) acetylates p53 specifically at lysine 120 (K120) within the DNA-binding domain; this modification is required for p53-dependent apoptosis but dispensable for p53-mediated growth arrest. Acetylation-defective mutant K120R abrogates apoptosis but not growth arrest. In vitro acetylation assay, site-directed mutagenesis (K120R), knockdown studies, reporter assays Molecular cell High 17189186
2013 KAT5 (TIP60) is tyrosine-phosphorylated after DNA damage by c-Abl; this phosphorylation promotes KAT5 binding to the histone mark H3K9me3 via its chromodomain, which activates KAT5 acetyltransferase activity, leading to acetylation and activation of ATM kinase and subsequent DNA-damage-checkpoint activation. Phosphorylation assays, chromodomain binding experiments, ATM acetylation assays, c-Abl kinase assays, chromatin alteration experiments Nature High 23708966
2010 KAT5/Tip60 chromodomain interacts with histone H3 trimethylated on lysine 9 (H3K9me3), and this interaction activates Tip60 acetyltransferase activity to acetylate and activate ATM in response to DNA double-strand breaks; MRN complex targets ATM and Tip60 to DSBs. Chromodomain binding assays, ATM acetylation assays, co-immunoprecipitation Cell cycle (Georgetown, Tex.) Medium 20160506
1999 Tip60 (KAT5) interacts with the androgen receptor (AR) in a ligand-dependent manner and enhances AR-mediated transactivation, as well as transactivation through estrogen and progesterone receptors; co-immunoprecipitation confirmed Tip60–AR interaction in vitro. Yeast two-hybrid screen, co-immunoprecipitation, luciferase reporter assay The Journal of biological chemistry Medium 10364196
2003 Tip60 (KAT5) associates with HDAC7 through its N-terminal zinc finger region and with STAT3 endogenously; Tip60 recruits HDAC7 to repress STAT3-driven transcription, functioning as a co-repressor for STAT3. Co-immunoprecipitation, reporter gene assay, endogenous interaction studies The Journal of biological chemistry Medium 12551922
2004 Tip60 knockdown reduces p21 accumulation and impairs p53-dependent activation of the endogenous p21 promoter, indicating Tip60 is required as a p53 co-activator. Tip60 also interferes with Mdm2-mediated degradation of p53 under normal conditions by affecting p53 subcellular localization. siRNA knockdown, reporter assay, Western blotting, subcellular fractionation The Journal of biological chemistry Medium 15310756
2006 Tip60 and p400 are both required for UV-induced apoptosis; Tip60 promotes proapoptotic p53 target gene expression by stimulating p53 DNA-binding activity. p400 represses p21 expression in unstressed cells and inhibits Tip60 function, an inhibition relieved by DNA damage. siRNA knockdown, reporter assays, apoptosis assays, ChIP The EMBO journal Medium 16601686
2006 p14ARF directly binds Tip60 and upregulates its expression; Tip60 is required for ATM/CHK2 activation in the p53-independent G2 checkpoint triggered by p14ARF or alkylating agents. Co-immunoprecipitation (direct binding), siRNA knockdown, ATM/CHK2 phosphorylation assays Molecular and cellular biology Medium 16705183
2008 ATF2 in cooperation with Cul3 ubiquitin ligase promotes proteasomal degradation of TIP60 under non-stressed conditions; ionizing radiation decreases ATF2 association with TIP60 on chromatin, enhancing TIP60 stability and HAT activity, thereby promoting ATM activation. Co-immunoprecipitation, siRNA knockdown, ATM activity assays, protein stability assays The Journal of biological chemistry Medium 18397884
2009 Sirt1 physically interacts with Tip60 and negatively regulates Tip60-mediated acetylation of H2AX. Sirt1 overexpression represses H2AX acetylation; Sirt1 depletion causes excessive H2AX acetylation. Sirt1 also deacetylates acetylated Tip60 and promotes proteasome-dependent Tip60 degradation in vivo. Co-immunoprecipitation, RNAi, Western blotting, H2AX acetylation assays Biochemical and biophysical research communications Medium 19895790
2009 UHRF1 co-immunoprecipitates with Tip60, DNMT1, and HDAC1 in a macro-molecular complex; Tip60 co-localizes with UHRF1/DNMT1. UHRF1 downregulation by RNAi enhances Tip60 expression but decreases H2AK5 acetylation, indicating Tip60 activity within this complex. Co-immunoprecipitation, immunocytochemistry, RNAi, histone acetylation assays Biochemical and biophysical research communications Low 19800870
2010 HPV E6 protein destabilizes TIP60 both in vivo and in vitro; TIP60 binds the HPV major early promoter and acetylates histone H4 to recruit Brd4, a repressor of HPV E6 expression. E6-mediated TIP60 degradation de-represses HPV promoters and abrogates p53-dependent apoptotic pathways. In vitro and in vivo stability assays, ChIP, histone acetylation assays, functional rescue experiments Molecular cell High 20542002
2001 Tip60 and HDAC7 interact with the endothelin receptor A (ETA); upon ET-1 stimulation, ETA internalizes to the perinuclear compartment and Tip60/HDAC7 translocate from nucleus to the same compartment where they co-localize with ETA. Tip60 co-expression strongly increases ET-1-induced ERK1/2 phosphorylation. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, fluorescence microscopy, ERK phosphorylation assay The Journal of biological chemistry Medium 11262386
2000 Tip60 directly binds CREB in vitro and inhibits CREB activation by protein kinase A. This inhibition is independent of Tip60 HAT activity (HAT-dead mutant retains inhibitory function). Tip60 HAT activity requires conserved residues in the acetyl-CoA binding motif. In vitro binding assay, HAT activity assay with mutagenesis, reporter gene assay Biochemical and biophysical research communications Medium 10720489
2008 Tip60 (Mst1/KAT5 ortholog in S. pombe) is required for DNA damage response and chromosome segregation; temperature-sensitive mst1 mutants show sensitivity to DNA-damaging agents and spindle poisons, increased Rad22 repair foci, and defects in recovery from HU arrest. Two-hybrid identified interactions with Rad22, Hip1, Skb1, and Msc1. Temperature-sensitive genetics, DNA damage sensitivity assays, two-hybrid, microscopy Genetics Medium 18505873
2008 Tip60 interacts directly with FANCD2 (confirmed by yeast two-hybrid, Co-IP, and co-localization); Tip60 depletion in normal fibroblasts decreases survival after mitomycin C (interstrand crosslink damage). Tip60 depletion does not reduce FANCD2 monoubiquitination or nuclear foci formation, placing Tip60 downstream of FANCD2 monoubiquitination in the Fanconi anemia pathway. Yeast two-hybrid, co-immunoprecipitation, co-localization, siRNA knockdown, clonogenic survival assay, epistasis analysis The Journal of biological chemistry High 18263878
2009 Homozygous knockout of Tip60 (Htatip) in mouse causes embryonic lethality at the blastocyst stage; Tip60-null blastocysts fail to hatch and survive, with suppressed cell proliferation and increased cell death. Gene targeting/knockout mouse, EdU labeling, TUNEL assay, blastocyst culture Developmental dynamics High 19842187
2015 ATF3 directly binds Tip60 at a region adjacent to the catalytic domain to promote Tip60 acetyltransferase activity. ATF3-Tip60 interaction also promotes Tip60 stability through USP7-mediated deubiquitination. ATF3 knockdown decreases Tip60 expression and suppresses ATM signaling. Co-immunoprecipitation, in vitro acetyltransferase assay, ubiquitination assay, siRNA knockdown, ATM activity assays Nature communications High 25865756
2014 TIP60 undergoes autoacetylation at six lysine residues; mutagenesis of all six to arginine abolishes autoacetylation. HDAC3 deacetylates these residues, stabilizes TIP60 (increases half-life), and co-localizes with TIP60 in nucleus and cytoplasm. SIRT1 also deacetylates TIP60 but promotes proteasomal degradation. Deacetylation of TIP60 by either SIRT1 or HDAC3 reduces DNA-damage-induced apoptosis. Mutagenesis of autoacetylation sites, co-immunoprecipitation, half-life assays, co-localization, apoptosis assays The Journal of biological chemistry High 25301942
2016 TIP60 complex is a conserved coactivator of HIF1A; HIF1A interacts with and recruits TIP60 to chromatin. TIP60 is dispensable for HIF1A chromatin association but required for HIF1A-dependent chromatin modification and RNA polymerase II activation in hypoxia. Co-immunoprecipitation, ChIP, reporter assay, knockdown in Drosophila and human cells Cell reports Medium 27320910
2016 NOTCH1 prevents binding of FOXO3a and KAT5/Tip60 to ATM by competing with FOXO3a for ATM binding; loss of FOXO3a-ATM interaction leads to loss of KAT5/Tip60 association with ATM, impairing ATM activation at DSBs. Co-immunoprecipitation, siRNA knockdown, epistasis analysis, ATM activation assays Cell reports Medium 27524627
2016 Tip60 controls homologous recombination (HR)-directed DNA repair in mammary epithelial cells; Tip60 heterozygosity in a p53-null mouse model reduces DNA repair and promotes mammary tumorigenesis. Conditional heterozygous knockout mouse, HR assay, tumor formation assay, gene expression analysis Cell death and differentiation Medium 26915295
2016 TIP60 knockdown in glioblastoma cells promotes adhesion, spreading, and MT1-MMP transcription by activating NF-κB pathway, leading to increased invasion; Tip60 suppresses NF-κB-dependent MT1-MMP expression. siRNA knockdown, reporter assay, invasion assay, MT1-MMP expression analysis Clinical & experimental metastasis Low 26464124
2016 TIP60 regulates expression of ERV-silencing enzymes SUV39H1 and SETDB1 in a BRD4-dependent manner; loss of TIP60 reduces global H3K9me3 levels and de-represses endogenous retroviral elements, activating STING-IRF7 inflammatory response. ChIP, RNA-seq, knockdown, H3K9me3 assay Nucleic acids research Medium 30053221
2018 KAT5 (TIP60), but not paralogs KAT7 or KAT8, acetylates histone H4 on the HIV-1 provirus to promote Brd4 recruitment to the LTR, suppressing Tat-mediated transcription elongation and promoting HIV-1 latency. ChIP, histone acetylation assays, genetic knockdown/overexpression, latency reversal assays in primary CD4+ T cells PLoS pathogens High 29684085
2016 GSK3β phosphorylates TIP60, triggering TIP60-mediated acetylation of ULK1 to activate autophagy in response to ER stress; inhibition of GSK3β or TIP60 acetyltransferase activity attenuates ER stress-induced autophagy. Phosphorylation assays, acetylation assays, autophagy flux assays, kinase inhibitors, mutagenesis Cell death & disease Medium 28032867
2018 TRIB3 acts as an adaptor to recruit KAT5 to SMAD3; KAT5 catalyzes phosphorylation-dependent K333 acetylation of SMAD3, sustaining SMAD3 transcriptional activity. Metformin suppresses SMAD3 phosphorylation and reduces KAT5/SMAD3 interaction, attenuating KAT5-mediated SMAD3 acetylation. Co-immunoprecipitation, in vitro acetylation assay, mutagenesis (K333), reporter assay, in vivo tumor models Oncogene High 29520103
2018 TIP60 complex (including EP400, TRRAP, BAF53a, RUVBL1, RUVBL2) binds the HBV precore/core promoter and suppresses HBV transcription; TIP60 acetylates histone H4 on HBV cccDNA to recruit Brd4. ChIP, siRNA knockdown of complex members, HBV transcription assays Journal of virology Medium 29321313
2018 The NuA4/TIP60 complex in S. cerevisiae has a defined cryo-EM architecture: Tra1 and Eaf1 form the assembly scaffold; the Eaf1 SANT domain binds LBE and FATC domains of Tra1 by ionic interactions; actin/Arp4 associate peripherally with Eaf1 HSA domain; TINTIN and piccolo modules pack against Tra1 FAT/HEAT repeats. Cryo-EM structure determination (4.7 Å and 7.6 Å resolution) Nature communications High 29559617
2019 Tip60 acetylates MARCKS at lysine 165; this acetylation is prerequisite for subsequent MARCKS phosphorylation. High glucose (maternal diabetes) induces MARCKS acetylation by Tip60, and SIRT2 deacetylates MARCKS. Phosphorylated MARCKS dissociates from organelles, causing mitochondrial and ER stress leading to neural tube defects. In vitro acetylation assay, mass spectrometry, mutagenesis (phosphorylation-dead MARCKS), SIRT2 overexpression rescue, in vivo diabetic mouse model Nature communications High 30655546
2017 TIP60 acetylates Sp1 at K639, inhibiting Sp1 binding to the TERT promoter and repressing TERT/telomerase expression in HPV-associated cervical cancer. ChIP, mass spectrometry, acetylation assay, mutagenesis, expression analysis PLoS pathogens Medium 29045464
2020 KAT5 acetylates cGAS at multiple lysine residues in its N-terminal domain, promoting cGAS DNA-binding ability and enhancing innate immune signaling; KAT5-deficient mice show impaired cytokine responses and increased susceptibility to DNA virus infection. Overexpression, knockdown, in vivo Kat5 knockout mouse, cGAS acetylation assay, DNA-binding assay, viral infection assay Proceedings of the National Academy of Sciences of the United States of America High 32817552
2020 KAT5 (Tip60) is required for hematopoietic stem cell (HSC) maintenance through its acetyltransferase activity; conditional KO of Kat5 depletes HSCs. Tip60 co-localizes with c-Myc, activates Myc target genes, and acetylates H2A.Z; Tip60 deletion reduces acH2A.Z/H2A.Z ratio at active chromatin. Conditional knockout mouse, ChIP-seq, RNA-seq, H2A.Z acetylation assay, HSC functional assays Blood High 32542325
2021 O-GlcNAcylation of KAT5 in PCK1-deficient hepatoma cells suppresses KAT5 ubiquitination, thereby stabilizing KAT5 protein. Stabilized KAT5 epigenetically activates TWIST1 via histone H4 acetylation and enhances MMP9/MMP14 expression via c-Myc acetylation, promoting EMT and HCC metastasis. O-GlcNAcylation assay, ubiquitination assay, Co-IP, ChIP, gain/loss-of-function, in vivo metastasis model Oncogene High 34650217
2017 Tip60 (KAT5) functions independently of its KAT activity in ESC self-renewal, but requires KAT activity for differentiation into mesoderm and endoderm; KAT-deficient ESCs show impaired differentiation and post-implantation developmental defects. Catalytic mutant KAT5 (KAT-dead) rescue experiments in Tip60-depleted ESCs, RNA-seq, ATAC-seq, mouse embryo phenotyping Cell reports High 28445719
2015 KAT5 acetylates SOX4 at lysine 95; this acetylation is required for Cald1 promoter activity at the onset of C2C12 myoblast differentiation. KAT5 chromodomain facilitates SOX4 recruitment to the Cald1 promoter and chromatin remodeling; molecular switching between KAT5 and HDAC1 on SOX4 determines target gene expression. In vitro acetylation assay, mutagenesis (K95), ChIP, chromatin occupancy assay, reporter assay Cell death & disease High 26291311
2015 KAT5 (Tip60) and ATM co-operate to protect replicating chromatin against formaldehyde damage; KAT5 acetyltransferase activity is responsible for ATM acetylation and activation in response to low-dose formaldehyde, and both KAT5 and ATM are required for the intra-S-phase checkpoint triggered by formaldehyde. ATM acetylation assay, ATM signaling assays, KAT5 knockdown, S-phase checkpoint assays Nucleic acids research Medium 26420831
2020 VRK1 chromatin kinase directly interacts with and phosphorylates Tip60/KAT5; this phosphorylation is required for Tip60-mediated ATM acetylation and subsequent ATM autophosphorylation in response to DNA damage. VRK1 acts upstream of ATM activation and is ATM-independent. Co-immunoprecipitation, in vitro kinase assay, Tip60 phosphorylation assay, ATM acetylation assay, VRK1 knockdown/kinase-dead rescue Cancers High 33076429
2011 GPR50 interacts with TIP60 (confirmed by yeast two-hybrid and co-immunoprecipitation); co-expression of GPR50 increases perinuclear localization of GPR50 and induces nuclear translocation of the GPR50 cytoplasmic tail. GPR50 enhances TIP60 co-activation of glucocorticoid receptor signaling. Yeast two-hybrid, co-immunoprecipitation, fluorescence microscopy, luciferase reporter assay, in vivo Gpr50-/- mouse PloS one Medium 21858214
2017 TIP60 interacts with unliganded PXR (nuclear receptor) via its NR Box to the LBD of PXR; TIP60 acetylates PXR at lysine 170, inducing PXR intranuclear reorganization. PXR augments TIP60 catalytic activity for histones. The TIP60-PXR complex promotes cell migration and adhesion. Co-immunoprecipitation, in vitro acetylation assay, mutagenesis (K170), localization microscopy, migration/adhesion assays Scientific reports Medium 28623334
2007 Rev-erbbeta recruits Tip60 to the apoCIII promoter; Tip60 acetylates Rev-erbbeta at its RXKK motif, relieving Rev-erbbeta-mediated transcriptional repression of apoCIII. HDAC1 interacts with Rev-erbbeta and antagonizes Tip60 activity. Co-immunoprecipitation, ChIP, acetylation assay, mutagenesis of RXKK motif, reporter assay Biochimica et biophysica acta Medium 17996965
2019 Tip60 promotes nuclear localization of androgen receptor (AR) by acetylating AR in its nuclear localization signal sequence; acetylation-mimicking mutations cause AR nuclear localization even without androgen, while non-acetylation mutations cause cytoplasmic retention despite androgen stimulation. Fluorescence microscopy, acetylation-mimicking and non-acetylating AR mutants, knockdown, Western blotting The Prostate Medium 19938016
2013 ZNF668 interacts with Tip60 and is required for IR-induced H2AX hyperacetylation; ZNF668 knockdown reduces Tip60-H2AX interaction, impairs chromatin relaxation, decreases recruitment of repair proteins, and impairs homologous recombination repair. Co-immunoprecipitation, H2AX acetylation assay, HR assay, siRNA knockdown Cell cycle (Georgetown, Tex.) Medium 23777805
2019 KAT5-mediated DNA damage repair is required for maintenance of kidney podocytes; podocyte-specific KAT5-KO mice develop albuminuria with increased DNA DSBs and increased methylation of the nephrin promoter with decreased nephrin expression. KAT5 restoration by gene transfer attenuates albuminuria. Podocyte-specific conditional KO mouse, comet assay, bisulfite sequencing, gene transfer, albumin assay Cell reports High 30699357
2022 Loss of TIP60 (KAT5) abolishes H2A.Z acetylation specifically at lysine 7; TIP60 deletion causes cell cycle arrest at mitosis (failure to align chromosomes in metaphase plate) independent of p53, INK4A, and ARF tumor suppressors. Inducible Cre/CRISPR KO, H2A.Z acetylation assay, cell cycle analysis, mitosis imaging, RNA-seq Cell death & disease High 35853868
2022 Tip60-mediated acetylation of H2A.Z is required for neuronal fate specification; loss of Tip60 or acetyl-H2A.Z impairs H3K4me3 deposition and activation of bivalent chromatin genes, without affecting chromatin accessibility or transcription more broadly. Proteomics, knockdown, H2A.Z acetylation assay, ChIP-seq, ATAC-seq, directed differentiation assay Molecular cell High 36417913
2021 Tip60 is required for expression of Hoxa9 and Meis1 in MLL-AF10 and MLL-ENL leukemia by acetylating H2A.Z at the Hoxa9 locus; Tip60 is recruited by MLL-AF10 and MLL-ENL fusion proteins. Conditional deletion of Tip60 prevents MLL-fusion leukemia development. Conditional KO mouse model, ChIP, H2A.Z acetylation assay, leukemia development assay Leukemia High 33967269
2019 KAT5 acetylates and stabilizes C-MYC protein by inhibiting its ubiquitin-mediated degradation, promoting anaplastic thyroid cancer invasion and metastasis. Co-immunoprecipitation, acetylation assay, ubiquitination assay, overexpression/knockdown, in vivo metastasis model Endocrine-related cancer Medium 30400007
2020 De novo missense variants in KAT5 at the chromodomain (R53H) or acetyl-CoA binding site (C369S, S413A) decrease or abolish the ability of the resulting NuA4/TIP60 complexes to acetylate histone H4 tail in chromatin, causing a neurodevelopmental syndrome. Histone acetylation assay with purified variant KAT5 complexes, transcriptomic analysis of patient fibroblasts American journal of human genetics High 32822602
2024 Cryo-EM structure of the endogenous human TIP60-EP400 complex (TIP60-C) reveals a three-lobed architecture: SWR1-like (SWR1L) and NuA4-like (NuA4L) lobes associated with a TRRAP module. EP400 traverses the junction twice and scaffolds the complex. NuA4L is rearranged relative to yeast NuA4; TRRAP is flexibly tethered to NuA4L rather than robustly connected as in yeast. Cryo-EM structure of endogenous complex, functional activity assays, nucleosome-binding modeling Nature High 39260417
2024 Cryo-EM structure (3.2 Å) of human TIP60 complex shows EP400 as backbone integrating motor module, ARP module, and TRRAP module; RUVBL1-RUVBL2 hexamer is the rigid core; ACTL6A-ACTB heterodimer and extra ACTL6A make hydrophobic contacts with EP400 HSA helix. TRRAP loss leads to genome-wide redistribution of H2A.Z and its acetylation. Cryo-EM structure (3.2 Å), TRRAP depletion with ChIP-seq for H2A.Z Nature communications High 39154037
2024 Cryo-EM of human NuA4/TIP60 shows EP400 scaffolds distinct functional modules; TRRAP loss causes NuA4/TIP60 mislocalization and redistribution of H2A.Z and H2A.Z acetylation across the genome, demonstrating TRRAP is required for proper chromatin targeting of the complex. Cryo-EM, TRRAP depletion, ChIP-seq Science (New York, N.Y.) High 39088653
2019 TIP60/KAT5 is required for neuronal viability in hippocampal CA1; TIP60 deficiency causes H4K12 hypoacetylation at TSS of downregulated genes, transcriptional dysfunction, Caspase 3 activation, and eventual neuronal loss. Inducible forebrain-specific KO mouse, ChIP-seq (H4K12ac), RNA-seq, immunostaining for apoptotic markers Scientific reports High 31700011
2018 Myc and the Tip60 chromatin remodeling complex regulate expression of aPKC in Drosophila neuroblasts; knockdown of Tip60 complex members causes loss of cortical polarity, symmetric division, and premature differentiation through nuclear entry of Prospero. Genetic knockdown, transcriptome analysis, immunostaining, epistasis analysis (Drosophila ortholog) The EMBO journal Medium 29997178
2023 Tip60 preferentially interacts with pre-mRNAs from its chromatin gene targets in Drosophila brain and human hippocampus; this RNA-binding function is disrupted in AD-model Drosophila brains and human AD hippocampus. Tip60-RNA targeting modulates alternative splicing decisions and increasing Tip60 in fly brain prevents some splicing alterations. RNA immunoprecipitation (RIP), rMATS analysis of RNA-seq, AD fly brain model, human AD tissue comparison The Journal of neuroscience Medium 36849418
1999 Tip60 physically interacts with the intracellular domain of human IL-9 receptor alpha-chain (hIL-9Ralpha); residues 411-423 in hIL-9Ralpha and 100-147 in Tip60 mediate the interaction; Tip60 co-immunoprecipitates and co-localizes with hIL-9Ralpha in cells. Yeast two-hybrid, co-immunoprecipitation, co-localization studies, deletion mapping Biochemical and biophysical research communications Low 10486269
2008 TIP60 (HTATIP) directly interacts with C/EBPalpha; TIP60 occupies the C/EBPalpha and GCSF-R promoters in vivo (ChIP); TIP60 co-activates C/EBPalpha-dependent transcription in a HAT domain-dependent manner. Pull-down, co-immunoprecipitation, ChIP, Re-ChIP, reporter assay, HAT domain mutagenesis Leukemia Medium 18239623

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 cPLA2 is phosphorylated and activated by MAP kinase. Cell 1729 8381049
2006 Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Molecular cell 609 17189186
2007 Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 273 17728759
2006 Tip60 in DNA damage response and growth control: many tricks in one HAT. Trends in cell biology 266 16904321
2006 Cellular functions of TIP60. The international journal of biochemistry & cell biology 221 16698308
1999 Tip60 is a nuclear hormone receptor coactivator. The Journal of biological chemistry 217 10364196
2010 Tip60: connecting chromatin to DNA damage signaling. Cell cycle (Georgetown, Tex.) 188 20160506
2019 Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS. Cell 171 31813625
2019 PLA2G4A/cPLA2-mediated lysosomal membrane damage leads to inhibition of autophagy and neurodegeneration after brain trauma. Autophagy 147 31238788
2013 KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling. Nature 134 23708966
2004 Role of the histone acetyl transferase Tip60 in the p53 pathway. The Journal of biological chemistry 118 15310756
2010 Destabilization of TIP60 by human papillomavirus E6 results in attenuation of TIP60-dependent transcriptional regulation and apoptotic pathway. Molecular cell 111 20542002
2003 Tip60 is a co-repressor for STAT3. The Journal of biological chemistry 97 12551922
2009 Homozygous disruption of the Tip60 gene causes early embryonic lethality. Developmental dynamics : an official publication of the American Association of Anatomists 94 19842187
2020 KAT5 acetylates cGAS to promote innate immune response to DNA virus. Proceedings of the National Academy of Sciences of the United States of America 91 32817552
2021 Inhibition of PLA2G4E/cPLA2 promotes survival of random skin flaps by alleviating Lysosomal membrane permeabilization-Induced necroptosis. Autophagy 88 34872436
2006 p14ARF activates a Tip60-dependent and p53-independent ATM/ATR/CHK pathway in response to genotoxic stress. Molecular and cellular biology 86 16705183
2016 The TIP60 Complex Is a Conserved Coactivator of HIF1A. Cell reports 83 27320910
2010 Tip60 promotes prostate cancer cell proliferation by translocation of androgen receptor into the nucleus. The Prostate 82 19938016
2006 Tip60 and p400 are both required for UV-induced apoptosis but play antagonistic roles in cell cycle progression. The EMBO journal 80 16601686
2016 Regulation of ER stress-induced autophagy by GSK3β-TIP60-ULK1 pathway. Cell death & disease 68 28032867
2022 Resveratrol Attenuate Myocardial Injury by Inhibiting Ferroptosis Via Inducing KAT5/GPX4 in Myocardial Infarction. Frontiers in pharmacology 65 35685642
2009 UHRF1 recruits the histone acetyltransferase Tip60 and controls its expression and activity. Biochemical and biophysical research communications 64 19800870
2021 Ketamine suppresses proliferation and induces ferroptosis and apoptosis of breast cancer cells by targeting KAT5/GPX4 axis. Biochemical and biophysical research communications 60 34800882
2015 A bivalent role of TIP60 histone acetyl transferase in human cancer. Epigenomics 59 26638912
2009 Sirt1 physically interacts with Tip60 and negatively regulates Tip60-mediated acetylation of H2AX. Biochemical and biophysical research communications 59 19895790
2018 Architecture of the Saccharomyces cerevisiae NuA4/TIP60 complex. Nature communications 56 29559617
2016 The acetyltransferase Tip60 contributes to mammary tumorigenesis by modulating DNA repair. Cell death and differentiation 56 26915295
2001 Tip60 and HDAC7 interact with the endothelin receptor a and may be involved in downstream signaling. The Journal of biological chemistry 54 11262386
2018 Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression. Oncogene 52 29520103
2016 NOTCH1 Inhibits Activation of ATM by Impairing the Formation of an ATM-FOXO3a-KAT5/Tip60 Complex. Cell reports 52 27524627
2021 O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis. Oncogene 51 34650217
2018 The KAT5-Acetyl-Histone4-Brd4 axis silences HIV-1 transcription and promotes viral latency. PLoS pathogens 49 29684085
2008 Regulation of TIP60 by ATF2 modulates ATM activation. The Journal of biological chemistry 49 18397884
2001 Tip60 is a cell-type-specific transcriptional regulator. Journal of biochemistry 47 11275565
2022 LINC00839 promotes colorectal cancer progression by recruiting RUVBL1/Tip60 complexes to activate NRF1. EMBO reports 44 35876654
2008 Proteomic identification of the MYST domain histone acetyltransferase TIP60 (HTATIP) as a co-activator of the myeloid transcription factor C/EBPalpha. Leukemia 41 18239623
2022 cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment. Journal of experimental & clinical cancer research : CR 40 35135586
1996 Cytosolic phospholipase A2 (cPLA2) and lipid mediator release in the brain. Journal of lipid mediators and cell signalling 40 8906538
2015 The stress-responsive gene ATF3 regulates the histone acetyltransferase Tip60. Nature communications 39 25865756
2000 Tip60 inhibits activation of CREB protein by protein kinase A. Biochemical and biophysical research communications 39 10720489
2009 LRP1 controls cPLA2 phosphorylation, ABCA1 expression and cellular cholesterol export. PloS one 38 19718435
2023 Elamipretide alleviates pyroptosis in traumatically injured spinal cord by inhibiting cPLA2-induced lysosomal membrane permeabilization. Journal of neuroinflammation 37 36609266
2017 KAT-Independent Gene Regulation by Tip60 Promotes ESC Self-Renewal but Not Pluripotency. Cell reports 37 28445719
2018 TIP60 represses activation of endogenous retroviral elements. Nucleic acids research 35 30053221
2008 Schizosaccharomyces pombe histone acetyltransferase Mst1 (KAT5) is an essential protein required for damage response and chromosome segregation. Genetics 35 18505873
2024 The ERK-cPLA2-ACSL4 axis mediating M2 macrophages ferroptosis impedes mucosal healing in ulcerative colitis. Free radical biology & medicine 34 38367927
2019 Tip60- and sirtuin 2-regulated MARCKS acetylation and phosphorylation are required for diabetic embryopathy. Nature communications 34 30655546
2019 Lipopolysaccharide promoted proliferation and adipogenesis of preadipocytes through JAK/STAT and AMPK-regulated cPLA2 expression. International journal of medical sciences 34 30662340
2018 Tip60: updates. Journal of applied genetics 34 29549519
2020 Lysine acetyltransferase Tip60 is required for hematopoietic stem cell maintenance. Blood 33 32542325
1995 Recent insights into the structure, function and biology of cPLA2. Agents and actions. Supplements 33 7610992
2019 Decreased KAT5 Expression Impairs DNA Repair and Induces Altered DNA Methylation in Kidney Podocytes. Cell reports 32 30699357
2018 Myc and the Tip60 chromatin remodeling complex control neuroblast maintenance and polarity in Drosophila. The EMBO journal 32 29997178
2016 RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation. Molecular neurobiology 32 27771900
2024 Structure of the human TIP60-C histone exchange and acetyltransferase complex. Nature 31 39260417
2022 Tip60-mediated H2A.Z acetylation promotes neuronal fate specification and bivalent gene activation. Molecular cell 31 36417913
2020 FosB recruits KAT5 to potentiate the growth and metastasis of papillary thyroid cancer in a DPP4-dependent manner. Life sciences 31 32891613
1999 Tip60 interacts with human interleukin-9 receptor alpha-chain. Biochemical and biophysical research communications 31 10486269
2018 Elevation of androgen receptor promotes prostate cancer metastasis by induction of epithelial-mesenchymal transition and reduction of KAT5. Cancer science 30 30142696
2002 Characterization and expression of the mouse tat interactive protein 60 kD (TIP60) gene. Gene 30 12036595
2015 KAT5-mediated SOX4 acetylation orchestrates chromatin remodeling during myoblast differentiation. Cell death & disease 29 26291311
2024 Structural insights into the human NuA4/TIP60 acetyltransferase and chromatin remodeling complex. Science (New York, N.Y.) 28 39088653
2016 KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma. International journal of oncology 28 26780987
2015 ATM and KAT5 safeguard replicating chromatin against formaldehyde damage. Nucleic acids research 28 26420831
2020 VRK1 Phosphorylates Tip60/KAT5 and Is Required for H4K16 Acetylation in Response to DNA Damage. Cancers 27 33076429
2014 Regulation of histone acetyltransferase TIP60 function by histone deacetylase 3. The Journal of biological chemistry 27 25301942
2013 KAT5 and KAT6B are in positive regulation on cell proliferation of prostate cancer through PI3K-AKT signaling. International journal of clinical and experimental pathology 27 24294372
2019 KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC. Endocrine-related cancer 26 30400007
2017 TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter. PLoS pathogens 26 29045464
2011 GPR50 interacts with TIP60 to modulate glucocorticoid receptor signalling. PloS one 26 21858214
2008 Tip60 is required for DNA interstrand cross-link repair in the Fanconi anemia pathway. The Journal of biological chemistry 26 18263878
2024 Structure of the human TIP60 complex. Nature communications 25 39154037
2020 De Novo KAT5 Variants Cause a Syndrome with Recognizable Facial Dysmorphisms, Cerebellar Atrophy, Sleep Disturbance, and Epilepsy. American journal of human genetics 25 32822602
2020 TIP60 in aging and neurodegeneration. Ageing research reviews 25 33091598
2016 MDR1 mediated chemoresistance: BMI1 and TIP60 in action. Biochimica et biophysica acta 25 27295567
2022 Loss of TIP60 (KAT5) abolishes H2AZ lysine 7 acetylation and causes p53, INK4A, and ARF-independent cell cycle arrest. Cell death & disease 24 35853868
2021 Role of histone acetyltransferases MOF and Tip60 in genome stability. DNA repair 24 34399315
2022 HDAC5 Loss Enhances Phospholipid-Derived Arachidonic Acid Generation and Confers Sensitivity to cPLA2 Inhibition in Pancreatic Cancer. Cancer research 23 36102738
2020 Metabolic Roles of Androgen Receptor and Tip60 in Androgen-Dependent Prostate Cancer. International journal of molecular sciences 23 32927797
2017 Novel complex of HAT protein TIP60 and nuclear receptor PXR promotes cell migration and adhesion. Scientific reports 23 28623334
2011 PLU1 histone demethylase decreases the expression of KAT5 and enhances the invasive activity of the cells. The Biochemical journal 23 21574959
2019 TIP60/KAT5 is required for neuronal viability in hippocampal CA1. Scientific reports 22 31700011
2018 TIP60 Complex Inhibits Hepatitis B Virus Transcription. Journal of virology 22 29321313
2018 Tip60 Suppresses Cholangiocarcinoma Proliferation and Metastasis via PI3k-AKT. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 22 30308494
2016 Tip60 regulates MT1-MMP transcription and invasion of glioblastoma cells through NF-κB pathway. Clinical & experimental metastasis 22 26464124
2019 Quantifying Tip60 (Kat5) stratifies breast cancer. Scientific reports 21 30846725
2018 Modulation of Nuclear Receptor Function by Chromatin Modifying Factor TIP60. Endocrinology 21 29420715
2013 Zinc finger protein 668 interacts with Tip60 to promote H2AX acetylation after DNA damage. Cell cycle (Georgetown, Tex.) 21 23777805
2021 Circular RNA circRHOT1 contributes to pathogenesis of non-small cell lung cancer by epigenetically enhancing C-MYC expression through recruiting KAT5. Aging 20 34406978
2007 The orphan nuclear receptor Rev-erbbeta recruits Tip60 and HDAC1 to regulate apolipoprotein CIII promoter. Biochimica et biophysica acta 20 17996965
2017 Tip60: Main Functions and Its Inhibitors. Mini reviews in medicinal chemistry 18 27670582
2022 Aspirin Suppressed PD-L1 Expression through Suppressing KAT5 and Subsequently Inhibited PD-1 and PD-L1 Signaling to Attenuate OC Development. Journal of oncology 17 35392432
2012 Stress-induced cell-cycle activation in Tip60 haploinsufficient adult cardiomyocytes. PloS one 17 22348108
2021 Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia. Leukemia 16 33967269
2002 Transient expression of TIP60 protein during early chick heart development. Developmental dynamics : an official publication of the American Association of Anatomists 16 11891991
2023 Tip60's Novel RNA-Binding Function Modulates Alternative Splicing of Pre-mRNA Targets Implicated in Alzheimer's Disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 15 36849418
2023 TIP60 is required for tumorigenesis in non-small cell lung cancer. Cancer science 15 36916958
2021 Conditional depletion of the acetyltransferase Tip60 protects against the damaging effects of myocardial infarction. Journal of molecular and cellular cardiology 15 34610340
2017 The role of cPLA2 in Methylglyoxal-induced cell apoptosis of HUVECs. Toxicology and applied pharmacology 15 28341536

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