{"gene":"KAT5","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2006,"finding":"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.","method":"In vitro acetylation assay, site-directed mutagenesis (K120R), knockdown studies, reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro acetylation, mutagenesis of acetylation site, functional rescue experiments in cells","pmids":["17189186"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Phosphorylation assays, chromodomain binding experiments, ATM acetylation assays, c-Abl kinase assays, chromatin alteration experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical assays, mutagenesis, and functional validation in a single rigorous study","pmids":["23708966"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Chromodomain binding assays, ATM acetylation assays, co-immunoprecipitation","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review summarizing experimental findings from primary papers, multiple methods cited","pmids":["20160506"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Yeast two-hybrid screen, co-immunoprecipitation, luciferase reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and reporter assay, single lab","pmids":["10364196"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Co-immunoprecipitation, reporter gene assay, endogenous interaction studies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of endogenous proteins and functional reporter assays, single lab","pmids":["12551922"],"is_preprint":false},{"year":2004,"finding":"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.","method":"siRNA knockdown, reporter assay, Western blotting, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with specific cellular readouts, single lab","pmids":["15310756"],"is_preprint":false},{"year":2006,"finding":"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.","method":"siRNA knockdown, reporter assays, apoptosis assays, ChIP","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdowns of both components with specific readouts, single lab","pmids":["16601686"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Co-immunoprecipitation (direct binding), siRNA knockdown, ATM/CHK2 phosphorylation assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and functional epistasis with signaling readouts, single lab","pmids":["16705183"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, ATM activity assays, protein stability assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods, single lab","pmids":["18397884"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Co-immunoprecipitation, RNAi, Western blotting, H2AX acetylation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — physical interaction confirmed by Co-IP, functional readout via H2AX acetylation, single lab","pmids":["19895790"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Co-immunoprecipitation, immunocytochemistry, RNAi, histone acetylation assays","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/pulldown, indirect evidence of functional interaction, single lab","pmids":["19800870"],"is_preprint":false},{"year":2010,"finding":"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.","method":"In vitro and in vivo stability assays, ChIP, histone acetylation assays, functional rescue experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro and in vivo assays, ChIP, mechanistic mutagenesis, multiple orthogonal methods in a single rigorous study","pmids":["20542002"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, fluorescence microscopy, ERK phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal interaction methods, localization with functional readout, single lab","pmids":["11262386"],"is_preprint":false},{"year":2000,"finding":"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.","method":"In vitro binding assay, HAT activity assay with mutagenesis, reporter gene assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro assay with mutagenesis, functional reporter assay; single lab","pmids":["10720489"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Temperature-sensitive genetics, DNA damage sensitivity assays, two-hybrid, microscopy","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined phenotypes, yeast ortholog model","pmids":["18505873"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization, siRNA knockdown, clonogenic survival assay, epistasis analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction confirmed by three methods, epistasis established by functional assay, single lab with multiple orthogonal approaches","pmids":["18263878"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Gene targeting/knockout mouse, EdU labeling, TUNEL assay, blastocyst culture","journal":"Developmental dynamics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined cellular phenotypes and multiple readouts","pmids":["19842187"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, in vitro acetyltransferase assay, ubiquitination assay, siRNA knockdown, ATM activity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding, in vitro activity assay, deubiquitination mechanism established, multiple orthogonal methods","pmids":["25865756"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Mutagenesis of autoacetylation sites, co-immunoprecipitation, half-life assays, co-localization, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of modification sites, biochemical interaction, functional phenotype, multiple orthogonal methods","pmids":["25301942"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, ChIP, reporter assay, knockdown in Drosophila and human cells","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with functional readout, conserved in two organisms","pmids":["27320910"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, epistasis analysis, ATM activation assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP-based competition assay, epistasis by depletion, single lab","pmids":["27524627"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Conditional heterozygous knockout mouse, HR assay, tumor formation assay, gene expression analysis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with defined molecular readout, single lab","pmids":["26915295"],"is_preprint":false},{"year":2016,"finding":"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.","method":"siRNA knockdown, reporter assay, invasion assay, MT1-MMP expression analysis","journal":"Clinical & experimental metastasis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown with phenotypic readout but limited mechanistic depth on pathway placement, single lab","pmids":["26464124"],"is_preprint":false},{"year":2016,"finding":"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.","method":"ChIP, RNA-seq, knockdown, H3K9me3 assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and RNA-seq with mechanistic follow-up, single lab","pmids":["30053221"],"is_preprint":false},{"year":2018,"finding":"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.","method":"ChIP, histone acetylation assays, genetic knockdown/overexpression, latency reversal assays in primary CD4+ T cells","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific paralog discrimination, ChIP, primary cell model, multiple orthogonal methods","pmids":["29684085"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Phosphorylation assays, acetylation assays, autophagy flux assays, kinase inhibitors, mutagenesis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — kinase assay and acetylation assay, mutagenesis of phosphorylation site, single lab","pmids":["28032867"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, in vitro acetylation assay, mutagenesis (K333), reporter assay, in vivo tumor models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro acetylation with site-specific mutagenesis, Co-IP, in vivo model, multiple orthogonal methods","pmids":["29520103"],"is_preprint":false},{"year":2018,"finding":"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.","method":"ChIP, siRNA knockdown of complex members, HBV transcription assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional knockdowns, multiple complex subunits tested, single lab","pmids":["29321313"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Cryo-EM structure determination (4.7 Å and 7.6 Å resolution)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure of multi-subunit complex at near-atomic resolution with detailed domain assignments","pmids":["29559617"],"is_preprint":false},{"year":2019,"finding":"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.","method":"In vitro acetylation assay, mass spectrometry, mutagenesis (phosphorylation-dead MARCKS), SIRT2 overexpression rescue, in vivo diabetic mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro acetylation with site identification, mutagenesis, genetic rescue in vivo, multiple orthogonal methods","pmids":["30655546"],"is_preprint":false},{"year":2017,"finding":"TIP60 acetylates Sp1 at K639, inhibiting Sp1 binding to the TERT promoter and repressing TERT/telomerase expression in HPV-associated cervical cancer.","method":"ChIP, mass spectrometry, acetylation assay, mutagenesis, expression analysis","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro acetylation with site identification by MS, ChIP, single lab","pmids":["29045464"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Overexpression, knockdown, in vivo Kat5 knockout mouse, cGAS acetylation assay, DNA-binding assay, viral infection assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO mouse, acetylation assay, DNA-binding assay, multiple orthogonal methods","pmids":["32817552"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Conditional knockout mouse, ChIP-seq, RNA-seq, H2A.Z acetylation assay, HSC functional assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with genome-wide profiling, acetyltransferase-dependent phenotype, multiple orthogonal methods","pmids":["32542325"],"is_preprint":false},{"year":2021,"finding":"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.","method":"O-GlcNAcylation assay, ubiquitination assay, Co-IP, ChIP, gain/loss-of-function, in vivo metastasis model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — PTM identified (O-GlcNAcylation), ubiquitination regulated, downstream acetylation substrates identified, in vivo model","pmids":["34650217"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Catalytic mutant KAT5 (KAT-dead) rescue experiments in Tip60-depleted ESCs, RNA-seq, ATAC-seq, mouse embryo phenotyping","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — enzymatic-dead mutagenesis with full transcriptomic and chromatin-accessibility readouts, in vivo validation","pmids":["28445719"],"is_preprint":false},{"year":2015,"finding":"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.","method":"In vitro acetylation assay, mutagenesis (K95), ChIP, chromatin occupancy assay, reporter assay","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro acetylation with site mutagenesis, ChIP, functional assay, mechanistic switching demonstrated","pmids":["26291311"],"is_preprint":false},{"year":2015,"finding":"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.","method":"ATM acetylation assay, ATM signaling assays, KAT5 knockdown, S-phase checkpoint assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acetyltransferase function linked to checkpoint, KO/KD with specific readouts, single lab","pmids":["26420831"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, in vitro kinase assay, Tip60 phosphorylation assay, ATM acetylation assay, VRK1 knockdown/kinase-dead rescue","journal":"Cancers","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay, kinase-dead rescue, epistasis established, multiple orthogonal methods","pmids":["33076429"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Yeast two-hybrid, co-immunoprecipitation, fluorescence microscopy, luciferase reporter assay, in vivo Gpr50-/- mouse","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by two methods, localization with functional consequence, in vivo validation, single lab","pmids":["21858214"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, in vitro acetylation assay, mutagenesis (K170), localization microscopy, migration/adhesion assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro acetylation with site identification, Co-IP, functional assay, single lab","pmids":["28623334"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Co-immunoprecipitation, ChIP, acetylation assay, mutagenesis of RXKK motif, reporter assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro acetylation with site mutagenesis, ChIP, reporter assay, single lab","pmids":["17996965"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Fluorescence microscopy, acetylation-mimicking and non-acetylating AR mutants, knockdown, Western blotting","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis of acetylation site with localization readout, single lab","pmids":["19938016"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation, H2AX acetylation assay, HR assay, siRNA knockdown","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, HR assay, specific acetylation readout, single lab","pmids":["23777805"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Podocyte-specific conditional KO mouse, comet assay, bisulfite sequencing, gene transfer, albumin assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with molecular and functional readouts, gene transfer rescue, in vivo model","pmids":["30699357"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Inducible Cre/CRISPR KO, H2A.Z acetylation assay, cell cycle analysis, mitosis imaging, RNA-seq","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple deletion systems, specific histone mark identified, tumor-suppressor independence established, genome-wide transcriptomics","pmids":["35853868"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Proteomics, knockdown, H2A.Z acetylation assay, ChIP-seq, ATAC-seq, directed differentiation assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — genome-wide profiling, specific histone mark identified, epistasis to bivalent chromatin activation, multiple orthogonal methods","pmids":["36417913"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Conditional KO mouse model, ChIP, H2A.Z acetylation assay, leukemia development assay","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO, ChIP linking Tip60 to specific locus, substrate identified, multiple methods","pmids":["33967269"],"is_preprint":false},{"year":2019,"finding":"KAT5 acetylates and stabilizes C-MYC protein by inhibiting its ubiquitin-mediated degradation, promoting anaplastic thyroid cancer invasion and metastasis.","method":"Co-immunoprecipitation, acetylation assay, ubiquitination assay, overexpression/knockdown, in vivo metastasis model","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, acetylation and ubiquitination assays, in vivo model, single lab","pmids":["30400007"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Histone acetylation assay with purified variant KAT5 complexes, transcriptomic analysis of patient fibroblasts","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — purified variant complexes assayed for HAT activity, domain-function correlation established","pmids":["32822602"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Cryo-EM structure of endogenous complex, functional activity assays, nucleosome-binding modeling","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure of endogenous complex with functional validation, rigorous structural biology","pmids":["39260417"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Cryo-EM structure (3.2 Å), TRRAP depletion with ChIP-seq for H2A.Z","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic resolution structure with functional validation by genome-wide ChIP-seq","pmids":["39154037"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Cryo-EM, TRRAP depletion, ChIP-seq","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural and functional genomics in same study with defined mechanistic consequence","pmids":["39088653"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Inducible forebrain-specific KO mouse, ChIP-seq (H4K12ac), RNA-seq, immunostaining for apoptotic markers","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ChIP-seq linking histone mark to transcriptional and cellular phenotype, multiple readouts","pmids":["31700011"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Genetic knockdown, transcriptome analysis, immunostaining, epistasis analysis (Drosophila ortholog)","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined molecular and cellular phenotypes, Drosophila ortholog model","pmids":["29997178"],"is_preprint":false},{"year":2023,"finding":"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.","method":"RNA immunoprecipitation (RIP), rMATS analysis of RNA-seq, AD fly brain model, human AD tissue comparison","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP establishes RNA-binding, functional splicing rescue, conserved in human tissue, single lab","pmids":["36849418"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization studies, deletion mapping","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and co-localization established interaction but no downstream functional consequence demonstrated, single lab","pmids":["10486269"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Pull-down, co-immunoprecipitation, ChIP, Re-ChIP, reporter assay, HAT domain mutagenesis","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction assays, ChIP, HAT-dependent functional readout, single lab","pmids":["18239623"],"is_preprint":false}],"current_model":"KAT5/TIP60 is a MYST-family lysine acetyltransferase that functions as the catalytic subunit of the ~20-subunit NuA4/TIP60-EP400 complex (whose EP400 scaffold merges ancestral yeast SWR1 and NuA4 activities into one supercomplex); it acetylates histones H4, H2A, and H2A.Z (specifically K7) to regulate transcription, chromatin accessibility, and bivalent gene activation, and it also acetylates multiple non-histone substrates — including ATM (activating its kinase after DNA double-strand breaks through a chromodomain-H3K9me3-sensing mechanism requiring c-Abl-mediated KAT5 tyrosine phosphorylation), p53-K120 (specifying apoptosis over arrest), AR (controlling nuclear localization), SOX4-K95, SMAD3-K333, cGAS N-terminus, MARCKS-K165, C-MYC, Sp1-K639, and Rev-erbbeta — while its own activity is regulated by autoacetylation (erased by SIRT1 and HDAC3), phosphorylation by VRK1 and GSK3β, ubiquitin-mediated degradation controlled by ATF2/Cul3 and stabilized by ATF3/USP7, and O-GlcNAcylation that opposes ubiquitination; loss of KAT5 causes embryonic lethality in mice, HSC failure, neuronal loss, and p53/ARF-independent mitotic arrest."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1999,"claim":"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","pmids":["10364196"],"confidence":"Medium","gaps":["Did not define the molecular basis (acetylation vs. scaffolding) of coactivation","No structural or substrate-level detail"]},{"year":2006,"claim":"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","pmids":["17189186","15310756","16601686"],"confidence":"High","gaps":["Mechanism of how K120ac biases promoter selectivity not fully resolved","Interplay with p400 inhibition incompletely defined"]},{"year":2010,"claim":"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","pmids":["20160506","23708966"],"confidence":"High","gaps":["How H3K9me3 reading allosterically activates catalysis not structurally resolved","Quantitative kinetics of ATM acetylation unknown"]},{"year":2013,"claim":"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","pmids":["23708966","23777805"],"confidence":"High","gaps":["Phosphorylation site stoichiometry in vivo not quantified","Coordination with other DSB-response PTMs unresolved"]},{"year":2016,"claim":"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)","pmids":["18397884","27524627","28032867"],"confidence":"Medium","gaps":["Relative contribution of each regulatory input in vivo unclear","Tissue-specificity of these controls not mapped"]},{"year":2015,"claim":"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","pmids":["25865756","33076429","26420831"],"confidence":"High","gaps":["How autoacetylation, phosphorylation, and ubiquitination are temporally ordered not established"]},{"year":2014,"claim":"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","pmids":["25301942","19895790"],"confidence":"High","gaps":["Structural consequence of autoacetylation on catalysis not resolved","Whether SIRT1 and HDAC3 act on the same lysines unclear"]},{"year":2018,"claim":"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","pmids":["29520103","30655546","29045464","30400007"],"confidence":"High","gaps":["General rules governing substrate selection beyond adaptor recruitment unknown","In vivo stoichiometry of substrate acetylation not measured"]},{"year":2020,"claim":"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","pmids":["32817552","32542325"],"confidence":"High","gaps":["Whether cGAS acetylation occurs within the NuA4 complex or by free KAT5 unclear","Direct vs. indirect contribution to HSC gene programs not fully separated"]},{"year":2022,"claim":"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","pmids":["35853868","36417913","31700011"],"confidence":"High","gaps":["How H2A.Z-K7ac mechanistically licenses H3K4me3 deposition not resolved","Relationship between mitotic arrest and bivalent activation phenotypes unclear"]},{"year":2024,"claim":"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","pmids":["39260417","39154037","39088653","29559617"],"confidence":"High","gaps":["Structural basis for nucleosome substrate engagement not fully resolved","How regulatory PTMs reshape the assembled complex unknown"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,26,29,30,31,35,41,47]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[11,24,32,44,45,48]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,32,44,48]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,19,40,56]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[54]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[18,32,44,49]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[24,27,45,46]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18,12]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,15,21,36,43]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[32,44,45,56]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[32,44,45,49]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[44]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[31,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[16,34,45,52]}],"complexes":["NuA4/TIP60-EP400 complex"],"partners":["EP400","TRRAP","RUVBL1","RUVBL2","ATM","TP53","AR","C-MYC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92993","full_name":"Histone acetyltransferase KAT5","aliases":["60 kDa Tat-interactive protein","Tip60","Histone acetyltransferase HTATIP","HIV-1 Tat interactive protein","Lysine acetyltransferase 5","Protein 2-hydroxyisobutyryltransferase KAT5","Protein acetyltransferase KAT5","Protein crotonyltransferase KAT5","Protein lactyltransferase KAT5","cPLA(2)-interacting protein"],"length_aa":513,"mass_kda":58.6,"function":"Catalytic subunit of the NuA4 histone acetyltransferase complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H2A and H4 (PubMed:12776177, PubMed:14966270, PubMed:15042092, PubMed:15121871, PubMed:15310756, PubMed:16387653, PubMed:19909775, PubMed:25865756, PubMed:27153538, PubMed:29174981, PubMed:29335245, PubMed:32822602, PubMed:33076429). Histone acetylation alters nucleosome-DNA interactions and promotes interaction of the modified histones with other proteins which positively regulate transcription (PubMed:12776177, PubMed:14966270, PubMed:15042092, PubMed:15121871, PubMed:15310756). The NuA4 histone acetyltransferase complex is required for the activation of transcriptional programs associated with proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair (PubMed:17709392, PubMed:19783983, PubMed:32832608). The NuA4 complex plays a direct role in repair of DNA double-strand breaks (DSBs) by promoting homologous recombination (HR): the complex inhibits TP53BP1 binding to chromatin via MBTD1, which recognizes and binds histone H4 trimethylated at 'Lys-20' (H4K20me), and KAT5 that catalyzes acetylation of 'Lys-15' of histone H2A (H2AK15ac), thereby blocking the ubiquitination mark required for TP53BP1 localization at DNA breaks (PubMed:27153538, PubMed:32832608). Also involved in DSB repair by mediating acetylation of 'Lys-5' of histone H2AX (H2AXK5ac), promoting NBN/NBS1 assembly at the sites of DNA damage (PubMed:17709392, PubMed:26438602). The NuA4 complex plays a key role in hematopoietic stem cell maintenance and is required to maintain acetylated H2A.Z/H2AZ1 at MYC target genes (By similarity). The NuA4 complex is also required for spermatid development by promoting acetylation of histones: histone hyperacetylation is required for histone replacement during the transition from round to elongating spermatids (By similarity). Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome (PubMed:24463511). Also acetylates non-histone proteins, such as BMAL1, ATM, AURKB, CHKA, CGAS, ERCC4/XPF, LPIN1, TP53/p53, NDC80/HEC1, NR1D2, RAN, SOX4, FOXP3, SQSTM1, ULK1 and RUBCNL/Pacer (PubMed:16141325, PubMed:17189187, PubMed:17360565, PubMed:17996965, PubMed:24835996, PubMed:26829474, PubMed:29040603, PubMed:30409912, PubMed:30704899, PubMed:31857589, PubMed:32034146, PubMed:32817552, PubMed:34077757). Directly acetylates and activates ATM (PubMed:16141325). Promotes nucleotide excision repair (NER) by mediating acetylation of ERCC4/XPF, thereby promoting formation of the ERCC4-ERCC1 complex (PubMed:32034146). Relieves NR1D2-mediated inhibition of APOC3 expression by acetylating NR1D2 (PubMed:17996965). Acts as a regulator of regulatory T-cells (Treg) by catalyzing FOXP3 acetylation, thereby promoting FOXP3 transcriptional repressor activity (PubMed:17360565, PubMed:24835996). Involved in skeletal myoblast differentiation by mediating acetylation of SOX4 (PubMed:26291311). Catalyzes acetylation of APBB1/FE65, increasing its transcription activator activity (PubMed:33938178). Promotes transcription elongation during the activation phase of the circadian cycle by catalyzing acetylation of BMAL1, promoting elongation of circadian transcripts (By similarity). Together with GSK3 (GSK3A or GSK3B), acts as a regulator of autophagy: phosphorylated at Ser-86 by GSK3 under starvation conditions, leading to activate acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Acts as a regulator of the cGAS-STING innate antiviral response by catalyzing acetylation the N-terminus of CGAS, thereby promoting CGAS DNA-binding and activation (PubMed:32817552). Also regulates lipid metabolism by mediating acetylation of CHKA or LPIN1 (PubMed:34077757). Promotes lipolysis of lipid droplets following glucose deprivation by mediating acetylation of isoform 1 of CHKA, thereby promoting monomerization of CHKA and its conversion into a tyrosine-protein kinase (PubMed:34077757). Acts as a regulator of fatty-acid-induced triacylglycerol synthesis by catalyzing acetylation of LPIN1, thereby promoting the synthesis of diacylglycerol (PubMed:29765047). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA), S-lactoyl-CoA (lactyl-CoA) and 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), and is able to mediate protein crotonylation, lactylation and 2-hydroxyisobutyrylation, respectively (PubMed:29192674, PubMed:34608293, PubMed:38961290). Acts as a key regulator of chromosome segregation and kinetochore-microtubule attachment during mitosis by mediating acetylation or crotonylation of target proteins (PubMed:26829474, PubMed:29040603, PubMed:30409912, PubMed:34608293). Catalyzes acetylation of AURKB at kinetochores, increasing AURKB activity and promoting accurate chromosome segregation in mitosis (PubMed:26829474). Acetylates RAN during mitosis, promoting microtubule assembly at mitotic chromosomes (PubMed:29040603). Acetylates NDC80/HEC1 during mitosis, promoting robust kinetochore-microtubule attachment (PubMed:30409912). Catalyzes crotonylation of MAPRE1/EB1, thereby ensuring accurate spindle positioning in mitosis (PubMed:34608293). Catalyzes lactylation of NBN/NBS1 in response to DNA damage, thereby promoting DNA double-strand breaks (DSBs) via homologous recombination (HR) (PubMed:38961290) (Microbial infection) Catalyzes the acetylation of flavivirus NS3 protein to modulate their RNA-binding and -unwinding activities leading to facilitate viral replication","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q92993/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/KAT5","classification":"Common Essential","n_dependent_lines":885,"n_total_lines":1208,"dependency_fraction":0.7326158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TRRAP","stoichiometry":4.0},{"gene":"H2AFZ","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KAT5","total_profiled":1310},"omim":[{"mim_id":"621534","title":"FAMILY WITH SEQUENCE SIMILARITY 135, MEMBER B; FAM135B","url":"https://www.omim.org/entry/621534"},{"mim_id":"620175","title":"RUBICON-LIKE AUTOPHAGY ENHANCER; RUBCNL","url":"https://www.omim.org/entry/620175"},{"mim_id":"619103","title":"NEURODEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES, SLEEP DISTURBANCE, AND BRAIN ABNORMALITIES; NEDFASB","url":"https://www.omim.org/entry/619103"},{"mim_id":"617103","title":"ZINC FINGER PROTEIN 668; ZNF668","url":"https://www.omim.org/entry/617103"},{"mim_id":"616856","title":"BROMODOMAIN- AND PHD FINGER-CONTAINING PROTEIN 3; BRPF3","url":"https://www.omim.org/entry/616856"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KAT5"},"hgnc":{"alias_symbol":["TIP60","PLIP","cPLA2","HTATIP1","ESA1"],"prev_symbol":["HTATIP"]},"alphafold":{"accession":"Q92993","domains":[{"cath_id":"2.30.30.140","chopping":"10-61","consensus_level":"high","plddt":91.0294,"start":10,"end":61},{"cath_id":"3.30.60.60","chopping":"226-285","consensus_level":"medium","plddt":94.606,"start":226,"end":285},{"cath_id":"3.40.630.30","chopping":"289-506","consensus_level":"medium","plddt":93.8361,"start":289,"end":506}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92993","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92993-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92993-F1-predicted_aligned_error_v6.png","plddt_mean":75.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KAT5","jax_strain_url":"https://www.jax.org/strain/search?query=KAT5"},"sequence":{"accession":"Q92993","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92993.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92993/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92993"}},"corpus_meta":[{"pmid":"8381049","id":"PMC_8381049","title":"cPLA2 is phosphorylated and activated by MAP kinase.","date":"1993","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8381049","citation_count":1729,"is_preprint":false},{"pmid":"17189186","id":"PMC_17189186","title":"Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis.","date":"2006","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/17189186","citation_count":609,"is_preprint":false},{"pmid":"17728759","id":"PMC_17728759","title":"Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response.","date":"2007","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/17728759","citation_count":273,"is_preprint":false},{"pmid":"16904321","id":"PMC_16904321","title":"Tip60 in DNA damage response and growth control: many tricks in one HAT.","date":"2006","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16904321","citation_count":266,"is_preprint":false},{"pmid":"16698308","id":"PMC_16698308","title":"Cellular functions of TIP60.","date":"2006","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16698308","citation_count":221,"is_preprint":false},{"pmid":"10364196","id":"PMC_10364196","title":"Tip60 is a nuclear hormone receptor coactivator.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10364196","citation_count":217,"is_preprint":false},{"pmid":"20160506","id":"PMC_20160506","title":"Tip60: connecting chromatin to DNA damage signaling.","date":"2010","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/20160506","citation_count":188,"is_preprint":false},{"pmid":"31813625","id":"PMC_31813625","title":"Metabolic Control of Astrocyte Pathogenic Activity via 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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.\",\n      \"method\": \"In vitro acetylation assay, site-directed mutagenesis (K120R), knockdown studies, reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro acetylation, mutagenesis of acetylation site, functional rescue experiments in cells\",\n      \"pmids\": [\"17189186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphorylation assays, chromodomain binding experiments, ATM acetylation assays, c-Abl kinase assays, chromatin alteration experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical assays, mutagenesis, and functional validation in a single rigorous study\",\n      \"pmids\": [\"23708966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Chromodomain binding assays, ATM acetylation assays, co-immunoprecipitation\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review summarizing experimental findings from primary papers, multiple methods cited\",\n      \"pmids\": [\"20160506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, luciferase reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and reporter assay, single lab\",\n      \"pmids\": [\"10364196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assay, endogenous interaction studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of endogenous proteins and functional reporter assays, single lab\",\n      \"pmids\": [\"12551922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, reporter assay, Western blotting, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with specific cellular readouts, single lab\",\n      \"pmids\": [\"15310756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, reporter assays, apoptosis assays, ChIP\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdowns of both components with specific readouts, single lab\",\n      \"pmids\": [\"16601686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (direct binding), siRNA knockdown, ATM/CHK2 phosphorylation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and functional epistasis with signaling readouts, single lab\",\n      \"pmids\": [\"16705183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ATM activity assays, protein stability assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods, single lab\",\n      \"pmids\": [\"18397884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, Western blotting, H2AX acetylation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — physical interaction confirmed by Co-IP, functional readout via H2AX acetylation, single lab\",\n      \"pmids\": [\"19895790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, immunocytochemistry, RNAi, histone acetylation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/pulldown, indirect evidence of functional interaction, single lab\",\n      \"pmids\": [\"19800870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro and in vivo stability assays, ChIP, histone acetylation assays, functional rescue experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro and in vivo assays, ChIP, mechanistic mutagenesis, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"20542002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, fluorescence microscopy, ERK phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal interaction methods, localization with functional readout, single lab\",\n      \"pmids\": [\"11262386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assay, HAT activity assay with mutagenesis, reporter gene assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro assay with mutagenesis, functional reporter assay; single lab\",\n      \"pmids\": [\"10720489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Temperature-sensitive genetics, DNA damage sensitivity assays, two-hybrid, microscopy\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined phenotypes, yeast ortholog model\",\n      \"pmids\": [\"18505873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization, siRNA knockdown, clonogenic survival assay, epistasis analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction confirmed by three methods, epistasis established by functional assay, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"18263878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Gene targeting/knockout mouse, EdU labeling, TUNEL assay, blastocyst culture\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined cellular phenotypes and multiple readouts\",\n      \"pmids\": [\"19842187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetyltransferase assay, ubiquitination assay, siRNA knockdown, ATM activity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding, in vitro activity assay, deubiquitination mechanism established, multiple orthogonal methods\",\n      \"pmids\": [\"25865756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Mutagenesis of autoacetylation sites, co-immunoprecipitation, half-life assays, co-localization, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of modification sites, biochemical interaction, functional phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"25301942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, reporter assay, knockdown in Drosophila and human cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with functional readout, conserved in two organisms\",\n      \"pmids\": [\"27320910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, epistasis analysis, ATM activation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP-based competition assay, epistasis by depletion, single lab\",\n      \"pmids\": [\"27524627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional heterozygous knockout mouse, HR assay, tumor formation assay, gene expression analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with defined molecular readout, single lab\",\n      \"pmids\": [\"26915295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, reporter assay, invasion assay, MT1-MMP expression analysis\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown with phenotypic readout but limited mechanistic depth on pathway placement, single lab\",\n      \"pmids\": [\"26464124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP, RNA-seq, knockdown, H3K9me3 assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and RNA-seq with mechanistic follow-up, single lab\",\n      \"pmids\": [\"30053221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP, histone acetylation assays, genetic knockdown/overexpression, latency reversal assays in primary CD4+ T cells\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific paralog discrimination, ChIP, primary cell model, multiple orthogonal methods\",\n      \"pmids\": [\"29684085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphorylation assays, acetylation assays, autophagy flux assays, kinase inhibitors, mutagenesis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — kinase assay and acetylation assay, mutagenesis of phosphorylation site, single lab\",\n      \"pmids\": [\"28032867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, mutagenesis (K333), reporter assay, in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro acetylation with site-specific mutagenesis, Co-IP, in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"29520103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP, siRNA knockdown of complex members, HBV transcription assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional knockdowns, multiple complex subunits tested, single lab\",\n      \"pmids\": [\"29321313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM structure determination (4.7 Å and 7.6 Å resolution)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure of multi-subunit complex at near-atomic resolution with detailed domain assignments\",\n      \"pmids\": [\"29559617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro acetylation assay, mass spectrometry, mutagenesis (phosphorylation-dead MARCKS), SIRT2 overexpression rescue, in vivo diabetic mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro acetylation with site identification, mutagenesis, genetic rescue in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"30655546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIP60 acetylates Sp1 at K639, inhibiting Sp1 binding to the TERT promoter and repressing TERT/telomerase expression in HPV-associated cervical cancer.\",\n      \"method\": \"ChIP, mass spectrometry, acetylation assay, mutagenesis, expression analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro acetylation with site identification by MS, ChIP, single lab\",\n      \"pmids\": [\"29045464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression, knockdown, in vivo Kat5 knockout mouse, cGAS acetylation assay, DNA-binding assay, viral infection assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO mouse, acetylation assay, DNA-binding assay, multiple orthogonal methods\",\n      \"pmids\": [\"32817552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mouse, ChIP-seq, RNA-seq, H2A.Z acetylation assay, HSC functional assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with genome-wide profiling, acetyltransferase-dependent phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"32542325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"O-GlcNAcylation assay, ubiquitination assay, Co-IP, ChIP, gain/loss-of-function, in vivo metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — PTM identified (O-GlcNAcylation), ubiquitination regulated, downstream acetylation substrates identified, in vivo model\",\n      \"pmids\": [\"34650217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Catalytic mutant KAT5 (KAT-dead) rescue experiments in Tip60-depleted ESCs, RNA-seq, ATAC-seq, mouse embryo phenotyping\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — enzymatic-dead mutagenesis with full transcriptomic and chromatin-accessibility readouts, in vivo validation\",\n      \"pmids\": [\"28445719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro acetylation assay, mutagenesis (K95), ChIP, chromatin occupancy assay, reporter assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro acetylation with site mutagenesis, ChIP, functional assay, mechanistic switching demonstrated\",\n      \"pmids\": [\"26291311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"ATM acetylation assay, ATM signaling assays, KAT5 knockdown, S-phase checkpoint assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acetyltransferase function linked to checkpoint, KO/KD with specific readouts, single lab\",\n      \"pmids\": [\"26420831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, Tip60 phosphorylation assay, ATM acetylation assay, VRK1 knockdown/kinase-dead rescue\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay, kinase-dead rescue, epistasis established, multiple orthogonal methods\",\n      \"pmids\": [\"33076429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, fluorescence microscopy, luciferase reporter assay, in vivo Gpr50-/- mouse\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by two methods, localization with functional consequence, in vivo validation, single lab\",\n      \"pmids\": [\"21858214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, mutagenesis (K170), localization microscopy, migration/adhesion assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro acetylation with site identification, Co-IP, functional assay, single lab\",\n      \"pmids\": [\"28623334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, acetylation assay, mutagenesis of RXKK motif, reporter assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro acetylation with site mutagenesis, ChIP, reporter assay, single lab\",\n      \"pmids\": [\"17996965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Fluorescence microscopy, acetylation-mimicking and non-acetylating AR mutants, knockdown, Western blotting\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of acetylation site with localization readout, single lab\",\n      \"pmids\": [\"19938016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, H2AX acetylation assay, HR assay, siRNA knockdown\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, HR assay, specific acetylation readout, single lab\",\n      \"pmids\": [\"23777805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Podocyte-specific conditional KO mouse, comet assay, bisulfite sequencing, gene transfer, albumin assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with molecular and functional readouts, gene transfer rescue, in vivo model\",\n      \"pmids\": [\"30699357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Inducible Cre/CRISPR KO, H2A.Z acetylation assay, cell cycle analysis, mitosis imaging, RNA-seq\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple deletion systems, specific histone mark identified, tumor-suppressor independence established, genome-wide transcriptomics\",\n      \"pmids\": [\"35853868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomics, knockdown, H2A.Z acetylation assay, ChIP-seq, ATAC-seq, directed differentiation assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genome-wide profiling, specific histone mark identified, epistasis to bivalent chromatin activation, multiple orthogonal methods\",\n      \"pmids\": [\"36417913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional KO mouse model, ChIP, H2A.Z acetylation assay, leukemia development assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO, ChIP linking Tip60 to specific locus, substrate identified, multiple methods\",\n      \"pmids\": [\"33967269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KAT5 acetylates and stabilizes C-MYC protein by inhibiting its ubiquitin-mediated degradation, promoting anaplastic thyroid cancer invasion and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, acetylation assay, ubiquitination assay, overexpression/knockdown, in vivo metastasis model\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, acetylation and ubiquitination assays, in vivo model, single lab\",\n      \"pmids\": [\"30400007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Histone acetylation assay with purified variant KAT5 complexes, transcriptomic analysis of patient fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purified variant complexes assayed for HAT activity, domain-function correlation established\",\n      \"pmids\": [\"32822602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM structure of endogenous complex, functional activity assays, nucleosome-binding modeling\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure of endogenous complex with functional validation, rigorous structural biology\",\n      \"pmids\": [\"39260417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM structure (3.2 Å), TRRAP depletion with ChIP-seq for H2A.Z\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic resolution structure with functional validation by genome-wide ChIP-seq\",\n      \"pmids\": [\"39154037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM, TRRAP depletion, ChIP-seq\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural and functional genomics in same study with defined mechanistic consequence\",\n      \"pmids\": [\"39088653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Inducible forebrain-specific KO mouse, ChIP-seq (H4K12ac), RNA-seq, immunostaining for apoptotic markers\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ChIP-seq linking histone mark to transcriptional and cellular phenotype, multiple readouts\",\n      \"pmids\": [\"31700011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic knockdown, transcriptome analysis, immunostaining, epistasis analysis (Drosophila ortholog)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined molecular and cellular phenotypes, Drosophila ortholog model\",\n      \"pmids\": [\"29997178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"RNA immunoprecipitation (RIP), rMATS analysis of RNA-seq, AD fly brain model, human AD tissue comparison\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP establishes RNA-binding, functional splicing rescue, conserved in human tissue, single lab\",\n      \"pmids\": [\"36849418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization studies, deletion mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and co-localization established interaction but no downstream functional consequence demonstrated, single lab\",\n      \"pmids\": [\"10486269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Pull-down, co-immunoprecipitation, ChIP, Re-ChIP, reporter assay, HAT domain mutagenesis\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction assays, ChIP, HAT-dependent functional readout, single lab\",\n      \"pmids\": [\"18239623\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KAT5/TIP60 is a MYST-family lysine acetyltransferase that functions as the catalytic subunit of the ~20-subunit NuA4/TIP60-EP400 complex (whose EP400 scaffold merges ancestral yeast SWR1 and NuA4 activities into one supercomplex); it acetylates histones H4, H2A, and H2A.Z (specifically K7) to regulate transcription, chromatin accessibility, and bivalent gene activation, and it also acetylates multiple non-histone substrates — including ATM (activating its kinase after DNA double-strand breaks through a chromodomain-H3K9me3-sensing mechanism requiring c-Abl-mediated KAT5 tyrosine phosphorylation), p53-K120 (specifying apoptosis over arrest), AR (controlling nuclear localization), SOX4-K95, SMAD3-K333, cGAS N-terminus, MARCKS-K165, C-MYC, Sp1-K639, and Rev-erbbeta — while its own activity is regulated by autoacetylation (erased by SIRT1 and HDAC3), phosphorylation by VRK1 and GSK3β, ubiquitin-mediated degradation controlled by ATF2/Cul3 and stabilized by ATF3/USP7, and O-GlcNAcylation that opposes ubiquitination; loss of KAT5 causes embryonic lethality in mice, HSC failure, neuronal loss, and p53/ARF-independent mitotic arrest.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#32, #49]. 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 [#49, #50, #51]. 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 [#32, #44, #45]. De novo missense variants disabling the chromodomain or acetyl-CoA binding site abolish H4 acetylation and cause a neurodevelopmental syndrome [#48]. 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 [#1, #2, #37, #20]. 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 [#0, #41, #35, #26, #31, #29, #30, #47, #40]. 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 [#18, #8, #17, #33]. Homozygous loss is embryonic-lethal in mice, underscoring an essential developmental role [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that TIP60 is not merely a chromatin enzyme but a context-dependent transcriptional coregulator, first by linking it physically to nuclear hormone receptors.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, and luciferase reporters for AR/ER/PR transactivation\",\n      \"pmids\": [\"10364196\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the molecular basis (acetylation vs. scaffolding) of coactivation\", \"No structural or substrate-level detail\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined how TIP60 acetylation of p53-K120 specifies cell fate, answering why p53 commits to apoptosis versus arrest.\",\n      \"evidence\": \"In vitro acetylation, K120R mutagenesis, knockdown, and reporter assays\",\n      \"pmids\": [\"17189186\", \"15310756\", \"16601686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of how K120ac biases promoter selectivity not fully resolved\", \"Interplay with p400 inhibition incompletely defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the chromodomain-H3K9me3 reader mechanism by which DNA damage activates TIP60 acetyltransferase activity toward ATM.\",\n      \"evidence\": \"Chromodomain binding assays, ATM acetylation assays, Co-IP; MRN-dependent targeting\",\n      \"pmids\": [\"20160506\", \"23708966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H3K9me3 reading allosterically activates catalysis not structurally resolved\", \"Quantitative kinetics of ATM acetylation unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that upstream tyrosine phosphorylation by c-Abl is the trigger that licenses the chromodomain-H3K9me3 interaction, placing TIP60 activation within a kinase cascade.\",\n      \"evidence\": \"Phosphorylation, chromodomain binding, and ATM acetylation assays with kinase manipulation\",\n      \"pmids\": [\"23708966\", \"23777805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation site stoichiometry in vivo not quantified\", \"Coordination with other DSB-response PTMs unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved layers of TIP60 regulation in the damage response — phospho-activation, ubiquitin turnover, and competitive recruitment to ATM.\",\n      \"evidence\": \"Co-IP, knockdown, protein stability and ATM activation assays (ATF2/Cul3, NOTCH1/FOXO3a, GSK3β)\",\n      \"pmids\": [\"18397884\", \"27524627\", \"28032867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each regulatory input in vivo unclear\", \"Tissue-specificity of these controls not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, in vitro acetyltransferase and deubiquitination assays, kinase-dead rescue\",\n      \"pmids\": [\"25865756\", \"33076429\", \"26420831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How autoacetylation, phosphorylation, and ubiquitination are temporally ordered not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established autoacetylation as an intrinsic activity switch, erased by SIRT1 (promoting degradation) and HDAC3 (promoting stability), reconciling opposing deacetylase effects.\",\n      \"evidence\": \"Six-site autoacetylation mutagenesis, half-life and apoptosis assays, Co-IP\",\n      \"pmids\": [\"25301942\", \"19895790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural consequence of autoacetylation on catalysis not resolved\", \"Whether SIRT1 and HDAC3 act on the same lysines unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro acetylation with site-specific mutagenesis, Co-IP, ChIP, and in vivo tumor models\",\n      \"pmids\": [\"29520103\", \"30655546\", \"29045464\", \"30400007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"General rules governing substrate selection beyond adaptor recruitment unknown\", \"In vivo stoichiometry of substrate acetylation not measured\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vivo Kat5 knockout, acetylation and DNA-binding assays, ChIP-seq/RNA-seq, viral and HSC functional assays\",\n      \"pmids\": [\"32817552\", \"32542325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cGAS acetylation occurs within the NuA4 complex or by free KAT5 unclear\", \"Direct vs. indirect contribution to HSC gene programs not fully separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Inducible KO/CRISPR deletion, H2A.Z-K7 acetylation assays, cell-cycle imaging, ChIP-seq, ATAC-seq, directed differentiation\",\n      \"pmids\": [\"35853868\", \"36417913\", \"31700011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H2A.Z-K7ac mechanistically licenses H3K4me3 deposition not resolved\", \"Relationship between mitotic arrest and bivalent activation phenotypes unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cryo-EM at 3.2–4.7 Å with TRRAP-depletion ChIP-seq for H2A.Z\",\n      \"pmids\": [\"39260417\", \"39154037\", \"39088653\", \"29559617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for nucleosome substrate engagement not fully resolved\", \"How regulatory PTMs reshape the assembled complex unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 26, 29, 30, 31, 35, 41, 47]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [11, 24, 32, 44, 45, 48]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 32, 44, 48]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 19, 40, 56]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [54]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [18, 32, 44, 49]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [24, 27, 45, 46]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 15, 21, 36, 43]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [32, 44, 45, 56]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [32, 44, 45, 49]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [44]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [31, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [16, 34, 45, 52]}\n    ],\n    \"complexes\": [\"NuA4/TIP60-EP400 complex\"],\n    \"partners\": [\"EP400\", \"TRRAP\", \"RUVBL1\", \"RUVBL2\", \"ATM\", \"TP53\", \"AR\", \"c-MYC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}