Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: KAT5
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:65,712,018-65,719,604 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities | 619103 | Autosomal dominant | 3 |
The KAT5 gene encodes an essential lysine acetyltransferase that is involved in histone acetylation, thereby regulating gene expression and chromatin remodeling. KAT5 belongs to the family of MYST proteins, which contain an approximately 300-amino acid domain that includes atypical zinc finger and histone acetyltransferase (HAT) domains. KAT5 also contains a chromodomain. KAT5 has been implicated in various cellular activities, including DNA repair, apoptosis, transcriptional regulation, and cell proliferation (summary by Hu et al., 2009 and Humbert et al., 2020).
Kamine et al. (1996) used a 2-hybrid cloning system in yeast to identify a partial human B-lymphoblastoid cDNA encoding TIP60, a polypeptide that interacts specifically with the N-terminal 31 amino acids of HIV-1 Tat, the region which contains the essential cysteine-rich portion of the Tat activation domain. The TIP60 polypeptide encoded by the partial cDNA also bound to purified Tat in vitro. By screening activated human T- and B-cell lines, Kamine et al. (1996) identified full-length TIP60. The deduced 383-amino acid protein has a calculated molecular mass of 44 kD. TIP60 shares significant similarity with yeast Sas2, which is thought to function in gene silencing. Northern blot analysis detected a 1.9-kb transcript in human monocyte, T-lymphocyte, and HeLa cell lines.
Reifsnyder et al. (1996) described the yeast Sas2 gene, which encodes a protein important to transcriptional silencing and exit from the cell cycle. By database analysis, they found that the human sequences most closely related to yeast Sas2 are those of MOZ (601408) and TIP60.
By 5-prime and 3-prime RACE of a heart cDNA library, Ran and Pereira-Smith (2000) obtained 2 TIP60 splice variants that they called TIP60-alpha and TIP60-beta. TIP60-alpha uses all TIP60 exons and encodes a deduced 513-amino acid protein. TIP50-beta skips exon 5 and encodes a deduced 461-amino acid protein that lacks 52 amino acids near the N terminus, including a proline-rich region. RT-PCR analysis detected variable expression of both transcripts in human heart, kidney, and brain and in human cell lines and normal fibroblasts. Immunohistochemical analysis showed that both TIP60-alpha and TIP60-beta localized to the nucleus in a speckled pattern, with exclusion from the nucleolus. TIP60-beta was also detected in the cytoplasm. EST database analysis suggested that both variants are also expressed in mouse.
Using a yeast interaction trap 2-hybrid screen, Sheridan et al. (2001) independently identified the TIP60-beta isoform, which they called PLIP (phospholipase-interacting protein), through its interaction with a group IV cytosolic phospholipase A2, cPLA2 (see PLA2G4A, 600522). Sheridan et al. (2001) determined that both TIP60 proteins contain a MYST domain, homologous to those of Sas2 and MOZ, that includes a HAT domain and a C2HC zinc finger domain. Both TIP60 proteins also have 2 potential ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) kinase phosphorylation sites and a potential cyclin-dependent kinase phosphorylation site. By Western blot analysis, Sheridan et al. (2001) identified bands at 60 kD and 50 kD, representing both isoforms, in several cell lines, including some of human origin.
By EST database analysis and RT-PCR of HeLa cell mRNA, Legube and Trouche (2003) cloned a splice variant of TIP60 that retains intron 1. The deduced 546-amino acid protein has a 33-amino acid N-terminal insertion prior to the chromodomain. PCR analysis detected transcripts with intron 1 in HeLa cells, Jurkat human T cells, and mouse NIH-3T3 fibroblasts. ESTs for the long TIP60 variant were detected in mouse and bovine databases. The nucleotide sequence of intron 1 is highly conserved in mouse and human, and the predicted amino acid sequences differ by only 1 residue. The presence of the extra amino acids from intron 1 did not affect phosphorylation or stability of human TIP60.
Kamine et al. (1996) found that mutation of essential cysteine residues in Tat abolished interaction with TIP60. Transient overexpression of full-length TIP60 resulted in a 4-fold augmentation of Tat transactivation of the HIV-1 promoter without increasing the basal activity of the HIV promoter or activating the heterologous RSV promoter. Kamine et al. (1996) suggested that TIP60 might be a cofactor of Tat involved in the regulation of HIV gene expression.
Yamamoto and Horikoshi (1997) demonstrated that the purified recombinant MYST domain of HTATIP had HAT activity, using as substrates H2A (see 613499), H3 (see 602810), and H4 (see 602822), but not H2B (see 609904), in core histone mixtures.
By yeast 2-hybrid analysis, Brady et al. (1999) determined that the ligand-binding domain of androgen receptor (AR; 313700) interacted with human brain TIP60. The interaction was not ligand dependent, but binding was enhanced in the presence of dihydrotestosterone. TIP60 contained no intrinsic transcriptional activity, but it enhanced AR-mediated transactivation of a reporter gene in transfected cells in a ligand-dependent manner. TIP60 also enhanced transactivation mediated by progesterone receptor (PGR; 607311) and estrogen receptor (see ESR1; 133430) in a ligand-dependent manner.
Ikura et al. (2000) showed that ectopic expression of mutated HTATIP lacking histone acetylase activity resulted in cells with defective double-strand DNA break repair that lose apoptotic competence.
In transfection experiments, Sheridan et al. (2001) demonstrated that both HTATIP and PLIP coimmunoprecipitated and colocalized with cPLA2. Using serum withdrawal to induce growth arrest and apoptosis in mouse renal mesangial cells, they found cytosolic to nuclear translocation of endogenous complexes that correlated with onset of apoptosis. PLIP was also found to potentiate apoptosis and prostaglandin production following serum withdrawal.
Amyloid-beta precursor protein (APP; 104760), a widely expressed cell surface protein, is cleaved in the transmembrane region by gamma-secretase. Gamma-cleavage of APP produces the extracellular amyloid beta peptide of Alzheimer disease (104300) and releases an intracellular tail fragment. Cao and Sudhof (2001) demonstrated that the cytoplasmic tail of APP forms a multimeric complex with the nuclear adaptor protein Fe65 (602709) and the HAT TIP60. This complex potently stimulated transcription via heterologous Gal4 or LexA DNA binding domains, suggesting that release of the cytoplasmic tail of APP by gamma-cleavage may function in gene expression.
Baek et al. (2002) demonstrated that interleukin-1-beta (IL1B; 147720) causes nuclear export of a specific NCOR (600849) corepressor complex, resulting in derepression of a specific subset of nuclear factor-kappa-B (NFKB; see 164011)-regulated genes. These genes are exemplified by the tetraspanin KAI1 (600623), which regulates membrane receptor function. Nuclear export of the NCOR/TAB2 (605101)/HDAC3 (605166) complex by IL1B is temporally linked to selective recruitment of a TIP60 coactivator complex. KAI1 is also directly activated by a ternary complex, dependent on the acetyltransferase activity of TIP60, that consists of the presenilin-dependent C-terminal cleavage product of APP, FE65, and TIP60, identifying a specific in vivo gene target of an APP-dependent transcription complex in the brain.
Kim et al. (2005) reported that the downregulation of a metastasis suppressor gene, KAI1, in prostate cancer cells involves the inhibitory actions of beta-catenin (116806), along with a reptin (TIP48, or RUVBL2; 604788) chromatin remodeling complex. The coordinated actions of beta-catenin-reptin components that mediate the repressive state serve to antagonize a TIP60 coactivator complex that is required for activation; the balance of these opposing complexes controls the expression of KAI1 and metastatic potential. The molecular mechanisms underlying the antagonistic regulation of beta-catenin-reptin and the TIP60 coactivator complexes for the metastasis suppressor gene, KAI1, are likely to be prototypic of a selective downregulation strategy for many genes, including a subset of NF-kappa-B (see 164011) target genes.
ATM (607585) regulates the cellular response to DNA damage through phosphorylation of proteins involved in cell cycle checkpoints and DNA repair. Sun et al. (2005) determined that DNA damage in HeLa cells induced rapid acetylation of ATM that was dependent on TIP60. Suppression of TIP60 blocked activation of ATM kinase activity and prevented ATM-dependent phosphorylation of p53 (TP53; 191170) and CHK2 (CHEK2; 604373). Furthermore, inactivation of TIP60 sensitized cells to ionizing radiation. ATM formed a stable complex with TIP60, and DNA damage activated the HAT activity of the ATM-TIP60 complex. Activation of TIP60 by DNA damage and recruitment of the ATM-TIP60 complex to sites of DNA damage were independent of ATM kinase activity.
Tang et al. (2006) found that K120 within the DNA-binding domain of p53 was acetylated in several human cell lines, and acetylation of K120 was significantly enhanced upon DNA damage. This modification of p53 was catalyzed by TIP60. A tumor-derived p53 mutant, K120R, which is defective for TIP60-mediated acetylation, abrogated p53-dependent activation of apoptosis but had no significant effect on cell growth arrest.
Sykes et al. (2006) showed that the p53 K120R mutation selectively blocked transcription of proapoptotic target genes such as BAX (600040) and PUMA (605854). Depletion of TIP60 or MOF (MYST1; 609912), another enzyme that can acetylate p53 at K120, inhibited the ability of p53 to activate BAX and PUMA transcription. Sykes et al. (2006) further showed that acetyl-K120 form of p53 specifically accumulated at proapoptotic target genes.
Spinocerebellar ataxia-1 (SCA1; 164400) is a neurodegenerative disease caused by expansion of a CAG trinucleotide repeat encoding a polyglutamine stretch in ataxin-1 (ATXN1; 601556). Using a conditional transgenic mouse model of SCA1, Serra et al. (2006) showed that delaying postnatal expression of mutant human ATXN1 until completion of cerebellar maturation led to a substantial reduction in disease severity in adults compared with early postnatal expression of mutant ATXN1. Microarray analysis revealed that genes regulated by Rora (600825), a transcription factor critical for cerebellar development, were downregulated at an early stage of disease in Purkinje cells of SCA1 transgenic mice. Rora mRNA and protein levels were reduced in Purkinje cells of SCA1 transgenic mice, and the effect of mutant ATXN1 on Rora protein levels appeared to be independent of its effect on Rora mRNA levels. Partial loss of Rora enhanced the pathogenicity of mutant ATXN1 in transgenic mice. Coimmunoprecipitation and pull-down analyses suggested the existence of a complex containing Atxn1, Rora, and the Rora coactivator Tip60, with Atxn1 and Tip60 interacting directly. Serra et al. (2006) concluded that RORA and TIP60 have a role in SCA1 and proposed that their findings provide a mechanism by which compromised cerebellar development contributes to the severity of neurodegeneration in an adult.
By peptide analysis of nuclear proteins that interacted with CEBP-alpha (CEBPA; 116897), Bararia et al. (2008) identified TIP60 as a CEBPA binding partner. The interaction was confirmed by coprecipitation analysis and protein pull-down assays. TIP60 enhanced the ability of CEBPA to transactivate a TK (TK1; 188300) promoter containing 2 CCAAT sites, and the HAT activity of TIP60 was required for its cooperativity with CEBPA. Domain analysis revealed that TIP60 interacted with the DNA-binding and transactivation domains of CEBPA. Immunoprecipitation analysis showed that TIP60 was recruited to the promoters of CEBPA and GCSFR (CSF3R; 138971) following beta-estradiol-induced differentiation of K562 myelogenous leukemia cells, which was concomitant with histone acetylation at the CEBPA and GCSFR promoters.
NuA4/TIP60 Histone Acetyltransferase Complex
The NuA4 HAT complex is responsible for acetylation of the N-terminal tails of histone H4 and H2A in yeast. Its catalytic subunit, Esa1, is homologous to human TIP60. Using affinity purification, Western blot analysis, cell fractionation, immunoprecipitation, and mass spectrometry, Doyon et al. (2004) found that TIP60 and its splice variant, TIP60B/PLIP, were part of a multisubunit NuA4 complex with HAT activity in several human cell lines. They identified human homologs for 11 of the 12 yeast NuA4 subunits, TIP60, TRRAP (603015), domino (EP400; 606265), EPC1 (610999)/EPC2 (611000), DMAP1 (DNMAP1; 605077), ING3 (607493), BAF53A (ACTL6A; 604958), actin (see 102610), MRG15 (MORF4L1; 607303), GAS41 (YEATS4; 602116), and EAF6 (611001), as well as 3 subunits specific to the human NuA4 complex, RUVBL1 (603449), RUVBL2, and BRD8 (602848). Doyon et al. (2004) showed that ING3 linked NuA4 to p53 function in vivo. MRG15 and DMAP1 were also present in distinct complexes harboring histone deacetylase and SWI2 (SMARCA2; 600014)-related ATPase activities, respectively. A recombinant trimeric complex of TIP60, EPC1, and ING3 was sufficient to reconstitute nucleosomal HAT activity in vitro. Doyon et al. (2004) concluded that the NuA4 complex is conserved in eukaryotes and has primary roles in transcription, cellular response to DNA damage, and cell cycle control.
Phosphorylation of the human histone variant H2AX (601772) and H2Av, its homolog in Drosophila melanogaster, occurs rapidly at sites of DNA double-strand breaks. Kusch et al. (2004) demonstrated that the Drosophila Tip60 chromatin-remodeling complex acetylated nucleosomal phospho-H2Av and exchanged it with an unmodified H2Av. Both the histone acetyltransferase Tip60 as well as the ATPase Domino/p400 catalyzed the exchange of phospho-H2Av. Thus, Kusch et al. (2004) concluded that their data reveal a previously unknown mechanism for selective histone exchange that uses the concerted action of 2 distinct chromatin-remodeling enzymes within the same multiprotein complex.
Using RNA interference in mouse embryonic stem (ES) cells, Fazzio et al. (2008) found that depletion of any of 7 components of the Tip60-p400 HAT and nucleosome remodeling complex, including Tip60, caused the same phenotype. Unlike normal ES cells, which grow in spherical 3-dimensional colonies, ES cells depleted of any the 7 Tip60-p400 HAT components showed a flattened and elongated morphology, with monolayer growth and reduced cell-cell contacts. These knockdown cells continued to cycle, with reduced cells in S phase and increased cells in G2 phase. The effect of Tip60-p400 HAT component knockdown was unique to ES cells, as negligible changes were observed following knockdown in mouse embryonic fibroblasts. p400 localized to the promoters of both silent and active genes in mouse ES cells, and this localization was dependent upon histone H3 lys4 trimethylation (H3K4me3). Genes misregulated in ES cells following knockdown of Tip60 or p400 were enriched for developmental regulators and significantly overlapped with genes misregulated in ES cells following knockdown of the transcription factor Nanog (607937). Depletion of Nanog reduced p400 binding to target promoters without affecting H3K4me3 levels. Fazzio et al. (2008) concluded that the Tip60-p400 HAT complex integrates signals from Nanog and H3K4me3 to regulate gene expression in ES cells.
Lin et al. (2012) reported that glycogen synthase kinase-3 (GSK3; 606784), when deinhibited by default in cells deprived of growth factors, activates acetyltransferase TIP60 through phosphorylating TIP60 serine at codon 86. This directly acetylates and stimulates the protein kinase ULK1 (603168), which is required for autophagy. Cells engineered to express TIP60(S86A) that cannot be phosphorylated by GSK3 could not undergo serum deprivation-induced autophagy. An acetylation-defective mutant of ULK1 failed to rescue autophagy in Ulk-null mouse embryonic fibroblasts. Cells used signaling from GSK3 to TIP60 and ULK1 to regulate autophagy when deprived of serum but not glucose. Lin et al. (2012) concluded that their findings uncovered an activating pathway that integrates protein phosphorylation and acetylation to connect growth factor deprivation to autophagy.
Using small interfering RNA-mediated knockdown studies in human osteosarcoma cells, Hu et al. (2013) showed that ZNF668 (617103) promoted TIP60-mediated H2AX lys5 acetylation and chromatin relaxation to facilitate homologous recombination-directed repair of double-strand breaks caused by ionizing radiation.
Obri et al. (2014) reported the identification and characterization of the human protein ANP32E (609611) as a chaperone specific for H2A.Z (142763) and showed that ANP32E is a member of the presumed H2A.Z histone-exchange complex p400/TIP60. ANP32E interacts with a short region of the docking domain of H2A.Z through a motif termed H2A.Z-interacting domain (ZID).
Role in Tumorigenesis
Gorrini et al. (2007) stated that the acetyltransferase Tip60 might influence tumorigenesis in multiple ways. For example, Tip60 is a coregulator of transcription factors that either promote or suppress tumorigenesis, such as Myc (190080) and p53 (191170). Also, Tip60 modulates DNA-damage response (DDR) signaling, and a DDR triggered by oncogenes can counteract tumor progression. Using Myc transgenic mice that were heterozygous for a Tip60 gene knockout allele, Gorrini et al. (2007) showed that Tip60 counteracts Myc-induced lymphomagenesis in a haploinsufficient manner and in a time window that is restricted to a pre- or early-tumor stage. Gorrini et al. (2007) further found that the human TIP60 gene is a frequent target for monoallelic loss in human lymphomas and head-and-neck and mammary carcinomas, with concomitant reduction in mRNA levels. Immunohistochemical analysis also demonstrated loss of nuclear TIP60 staining in mammary carcinomas. These events correlated with disease grade and frequently concurred with mutation of p53. Thus, in both mouse and human, TIP60 has a haploinsufficient tumor suppressor activity that is independent from--but not contradictory with--its role within the ARF-p53 pathway. Gorrini et al. (2007) suggested that this is because critical levels of TIP60 are required for mounting an oncogene-induced DDR in incipient tumor cells, the failure of which might synergize with p53 mutation towards tumor progression.
Independently, Ran and Pereira-Smith (2000) and Sheridan et al. (2001) determined that the KAT5 gene contains 14 exons. Ran and Pereira-Smith (2000) found that the KAT5 gene spans over 9 kb.
Kamine et al. (1996) reported that the promoter region of the KAT5 gene lacks a TATA box, but that it has a number of consensus binding sites for transcription factors, including SP1 (189906).
By genomic sequence analysis, Sheridan et al. (2001) mapped the KAT5 gene to chromosome 11q13.
In 3 unrelated patients with neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (NEDFASB; 619103), Humbert et al. (2020) identified 3 different de novo heterozygous missense mutations in the KAT5 gene: R53H (601409.0001), C369S (601409.0002), and S413A (601409.0003). The mutations were found by exome sequencing and the patients were ascertained through the GeneMatcher program. None of the mutations were present in the gnomAD database. In vitro functional expression studies showed that the mutations resulted in variably decreased histone acetyltransferase (HAT) activity compared to controls. The C369S variant showed the most dramatic effect, being unable to acetylate free histones and chromatin. The complexes containing R53H and S413A were mostly defective in their HAT activity toward chromatin, not free histones. The findings suggested haploinsufficiency; however, a dominant-negative effect could not be excluded. Transcriptome analysis of patient cells showed dysregulation of several genes involved in development, which the authors suggested led to the neurodevelopmental syndrome observed in the patients.
Hu et al. (2009) found that Tip60 +/- mice developed and reproduced normally, but Tip60 -/- embryos died at the blastocyst-gastrula transition.
The article by Kaidi and Jackson (2013) was retracted because the authors could not confirm the results described in some of the figures.
In a 30-year-old woman (patient 1) with neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (NEDFASB; 619103), Humbert et al. (2020) identified a de novo heterozygous c.158G-A transition (c.158G-A, NM_006388.3) in the KAT5 gene, resulting in an arg53-to-his (R53H) substitution at a conserved residue in the chromodomain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in cells transfected with the mutation showed that it resulted in decreased HAT activity compared to controls.
In a 13-year-old boy (patient 2) with neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (NEDFASB; 619103), Humbert et al. (2020) identified a de novo heterozygous c.1105T-A transversion (c.1105T-A, NM_006388.3) in the KAT5 gene, resulting in a cys369-to-ser (C369S) substitution at a conserved residue near the acetyl-CoA binding domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the mutation resulted in decreased HAT activity compared to controls.
In a 2-year-old boy (patient 3) with neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (NEDFASB; 619103), Humbert et al. (2020) identified a de novo heterozygous c.1237T-G transversion (c.1237T-G, NM_006388.3) in the KAT5 gene, resulting in a ser413-to-ala (S413A) substitution at a conserved residue in the acetyl-CoA binding domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the mutation resulted in decreased HAT activity compared to controls.
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