KAT5 (HIV-1 Tat interacting protein, 60kDa)

2007-10-01   Lise Mattera 

Dr Trouche Team, LBCMCP, UMR 5088 CNRS, 118 route de Narbonne, 31062 Toulouse cedex 9, France

Identity

HGNC
LOCATION
11q13.1
LOCUSID
ALIAS
ESA1,HTATIP,HTATIP1,NEDFASB,PLIP,TIP,TIP60,ZC2HC5,cPLA2
FUSION GENES

DNA/RNA

Atlas Image

Description

The HTATIP gene consists of 14 exons. 7,586 bases.

Transcription

The predominant mRNA transcribed from this gene is 2,229 bp long. This is actually the isoform 2 of HTATIP.
Two others isoforms generated by alternative splicing have been described:
  • Isoform 1 retains the alternatively spliced intron 1.
  • Isoform 3 lacks exon 5.
  • Pseudogene

    No pseudogene is currently known.

    Proteins

    Atlas Image

    Description

    The Tip60 protein (isoform 2) is 513 amino acids long and its molecular weight is about 60 kDa. It was cloned and characterized in 1996 thanks to its interaction with the HIV-1 transactivator Tat protein.
    Isoform 1 produces a 546 amino acids long protein.
    Isoform 3 produces a 461 amino acids long protein.
    A novel isoform, Tip55, encodes a novel splicing variant corresponding to 103 amino acids of the C-terminus.
    The domain architectures of human TIP60 is similar to yeast Esa1 protein and consist of a chromodomain and a MYST domain harboring a zinc finger and an Acetyl-CoA binding site.

    Expression

    Tip60 is ubiquitously expressed.
    In mouse adult tissues Tip60 is expressed in the following decreasing order of intensity: testis, heart, brain, kidney, liver, lung, with little to no expression in spleen and skeletal muscle .
    In human, Tip60 (Isoform 2) and PLIP (Isoform 3) are expressed in human heart, kidney and brain tissue.
    With a half-life of approximately 30 minutes, Tip60 is very unstable. In normal conditions, the proteasome pathway permits to maintain low protein levels. Tip60 is ubiquitinated and targeted to proteasome-mediated degradation by Mdm2 but also by p300-associated E4 ubiquitin ligase. Tip60 is stabilized after DNA damage, and accumulates in cells. Moreover, Tip60 is the target of several post-translational modifications such as phosphorylation on serine 86 and 90 by cdc2 but also acetylation by p300/CBP acetyltransferases. Acetylation by p300/CBP occurs in the zinc finger of Tip60 but consequences of this modification are currently not known. Finally, a recent report shows that Tip60 is sumoylated at lysines 430 and 451 via Ubc9.
    No data are available about regulation of the Tip60 promoter.

    Localisation

    Tip60 (Isoform 2) is nuclear. PLIP (Isoform 3) is nuclear but also cytoplasmic.

    Function

    Tip60 is a Histone Acetyltransferase (HAT), which belongs to the MYST family. It participates in a multimolecular complex: The Tip60 complex, which contains proteins such as p400, Tip49a and Tip49b . Within this complex, Tip60 exerts its HAT activity on nucleosomal histone H4. Tip60 is involved in various cellular mechanisms:
  • In transcription: Tip60 acts as a coactivator. Indeed, Tip60 is able to interact with transcription factors, such as E2F-1 or c-Myc. Tip60 can be recruited to Myc and E2F-1 target promoters and enhances Myc transactivation. It also acetylates histone H4 on several E2F responsive genes. Moreover Tip60 was found to be involved in nuclear receptor (NR) signaling and to be a NR-coregulator.
  • In apoptosis and cell cycle arrest: Tip60 can interact with and acetylate the tumor suppressor p53. It enhances p53 binding to pro-apoptotic target genes like PUMA, Bax or Fas. Moreover, Tip60 is also required for cell growth arrest via the p21-dependent pathway.
  • In DNA repair: Tip60 is involved in double strand breaks (DSB) repair. Interacting and acetylating ATM, Tip60 participates in DNA damage signaling. But, Tip60 is also involved directly in DSB repair since it is recruited, with TRRAP, to the DSB site. Tip60 interacts with the chromatin surrounding sites of DSBs and this recruitment is responsible for hyperacetylation of histone H4.
  • Homology

    Tip60 CHROMO domain has been identified by sequence homology with the Heterochromatin-associated protein 1 (HP1) chromodomain, which recognizes methylated lysines. It also harbors the MYST domain, which is highly conserved from yeast to human.
    Homologs in other species:
  • S. Cerevisae: Esa1
  • D. Melanogaster: DmeI/Tip60
  • M. musculus: Htatip
  • R. norvegicus: Htatip
    Predicted:
  • P.troglodytes: HTATIP
  • M.mulatta: HTATIP
  • Mutations

    Note

    No mutation in Tip60 protein has been currently described.

    Implicated in

    Entity name
    Acquired Immunodeficiency Syndrome (AIDS)
    Disease
    Tip60 interacts with the HIV-1 transactivator Tat and this interaction inhibits Tip60 HAT activity. Moreover, in Jurkat cells, Tat enhances Tip60 turnover since it uses the p300/CBP-associated E4-type ubiquitin-ligase activity to induce polyubiquitynation and degradation of Tip60. This targeting by Tat induces an impairment of Tip60-dependent apoptosis after DNA damage.
    Entity name
    Neurodegenerative diseases
    Disease
    In the nucleus of human H4 neuroglioma cells, TIP60 can interact with a free carboxyl-terminal intracellular fragment, APP-CT, which is generated by the cleavage of the Amyloid precursor protein APP by a gamma-secretase. This fragment induces apoptosis of neuroglioma and this cell death is enhanced when a wild type form of Tip60 is transfected. Thus Tip60 might play a role in Alzheimers disease neurodegeneration.
    Entity name
    Spinocerebellar ataxia type-1
    Disease
    TIP60 participates in a complex with ATXN1 and ROR-alpha in a conditional transgenic mouse model of Spinocerebellar ataxia type-1 (SCA1), one of the nine inherited polyglutamine neurodegenerative diseases.
    Entity name
    Cancers
    Disease
    Immunohistochemistry experiments have shown that Tip60 accumulates in the nucleus of hormone-refractory prostate cancer compared to prostate hyperplasia and primary prostate cancer.
    Entity name
    Lung cancer and colon cancer
    Disease
    Real time RT-PCR experiments have shown that Tip60 mRNA is under expressed in colon and lung carcinomas.
    Entity name
    Skin cancer
    Disease
    The expression levels of TIP60 protein, analyzed by western blot, were found to be greater in skin tumors as compared to adjacent non-tumor-bearing skin in a skin cancer mouse model (K6/ODC mouse). Additionally, the interaction between Tip60 and E2F1 is enhanced in these tumors.
    Entity name
    HTLV-1 induced leukemogenesis
    Disease
    Enhancement of c-Myc transforming activity by HTLV-1 p30II oncoprotein in HeLa cells requires TIP60 HAT activity.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    159880282005A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions.Awasthi S et al
    150420922004A large-scale RNAi screen in human cells identifies new components of the p53 pathway.Berns K et al
    103641961999Tip60 is a nuclear hormone receptor coactivator.Brady ME et al
    177048092008Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response.Cheng Z et al
    160010852005HIV-1 Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses.Col E et al
    103935591999Control of the histone-acetyltransferase activity of Tip60 by the HIV-1 transactivator protein, Tat.Creaven M et al
    127761772003MYC recruits the TIP60 histone acetyltransferase complex to chromatin.Frank SR et al
    115917002001Tip60 is a co-activator specific for class I nuclear hormone receptors.Gaughan L et al
    119943122002Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor.Gaughan L et al
    127174242003Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development.Halkidou K et al
    169121892006Tip60 protein isoforms and altered function in skin and tumors that overexpress ornithine decarboxylase.Hobbs CA et al
    109661082000Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis.Ikura T et al
    86072651996Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator.Kamine J et al
    165976242006Co-activation of atrial natriuretic factor promoter by Tip60 and serum response factor.Kim MS et al
    120321522002The gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells.Kinoshita A et al
    168652622006New p53 related genes in human tumors: significant downregulation in colon and lung carcinomas.LLeonart ME et al
    153107562004Role of the histone acetyl transferase Tip60 in the p53 pathway.Legube G et al
    128016432003Identification of a larger form of the histone acetyl transferase Tip60.Legube G et al
    124685302003Tip60 acetyltransferase activity is controlled by phosphorylation.Lemercier C et al
    120365952002Characterization and expression of the mouse tat interactive protein 60 kD (TIP60) gene.McAllister D et al
    163412052006Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks.Murr R et al
    111110512000Identification of an alternatively spliced form of the Tat interactive protein (Tip60), Tip60(beta).Ran Q et al
    171103302006RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice.Serra HG et al
    114161272001PLIP, a novel splice variant of Tip60, interacts with group IV cytosolic phospholipase A(2), induces apoptosis, and potentiates prostaglandin production.Sheridan AM et al
    161413252005A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM.Sun Y et al
    171891872006Acetylation of the p53 DNA-binding domain regulates apoptosis induction.Sykes SM et al
    171891862006Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis.Tang Y et al
    151218712004E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1.Taubert S et al
    166016862006Tip60 and p400 are both required for UV-induced apoptosis but play antagonistic roles in cell cycle progression.Tyteca S et al

    Other Information

    Locus ID:

    NCBI: 10524
    MIM: 601409
    HGNC: 5275
    Ensembl: ENSG00000172977

    Variants:

    dbSNP: 10524
    ClinVar: 10524
    TCGA: ENSG00000172977
    COSMIC: KAT5

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000172977ENST00000341318Q92993
    ENSG00000172977ENST00000352980Q92993
    ENSG00000172977ENST00000352980A0A024R5E8
    ENSG00000172977ENST00000377046Q92993
    ENSG00000172977ENST00000377046A0A024R597
    ENSG00000172977ENST00000528198E9PRM3
    ENSG00000172977ENST00000530446Q92993
    ENSG00000172977ENST00000530605H0YEP0
    ENSG00000172977ENST00000531880E9PRL6
    ENSG00000172977ENST00000533596H0YEG3
    ENSG00000172977ENST00000534104E9PRS1
    ENSG00000172977ENST00000534650E9PJI1
    ENSG00000172977ENST00000534681E9PMG8

    Expression (GTEx)

    0
    10
    20
    30
    40
    50
    60
    70

    Pathways

    PathwaySourceExternal ID
    HTLV-I infectionKEGGko05166
    HTLV-I infectionKEGGhsa05166
    Signal TransductionREACTOMER-HSA-162582
    Signaling by WntREACTOMER-HSA-195721
    TCF dependent signaling in response to WNTREACTOMER-HSA-201681
    Formation of the beta-catenin:TCF transactivating complexREACTOMER-HSA-201722
    Gene ExpressionREACTOMER-HSA-74160
    Generic Transcription PathwayREACTOMER-HSA-212436
    Transcriptional Regulation by TP53REACTOMER-HSA-3700989
    Cell CycleREACTOMER-HSA-1640170
    Cell Cycle CheckpointsREACTOMER-HSA-69620
    G2/M CheckpointsREACTOMER-HSA-69481
    G2/M DNA damage checkpointREACTOMER-HSA-69473
    DNA RepairREACTOMER-HSA-73894
    Cellular responses to stressREACTOMER-HSA-2262752
    Cellular SenescenceREACTOMER-HSA-2559583
    DNA Damage/Telomere Stress Induced SenescenceREACTOMER-HSA-2559586
    Chromatin organizationREACTOMER-HSA-4839726
    Chromatin modifying enzymesREACTOMER-HSA-3247509
    HATs acetylate histonesREACTOMER-HSA-3214847
    DNA Double-Strand Break RepairREACTOMER-HSA-5693532
    DNA Double Strand Break ResponseREACTOMER-HSA-5693606
    Sensing of DNA Double Strand BreaksREACTOMER-HSA-5693548
    Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksREACTOMER-HSA-5693565
    Homology Directed RepairREACTOMER-HSA-5693538
    HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
    Processing of DNA double-strand break endsREACTOMER-HSA-5693607
    HDR through Homologous Recombination (HRR)REACTOMER-HSA-5685942
    Homologous DNA Pairing and Strand ExchangeREACTOMER-HSA-5693579
    Presynaptic phase of homologous DNA pairing and strand exchangeREACTOMER-HSA-5693616
    Resolution of D-Loop StructuresREACTOMER-HSA-5693537
    Resolution of D-loop Structures through Holliday Junction IntermediatesREACTOMER-HSA-5693568
    Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)REACTOMER-HSA-5693554
    HDR through Single Strand Annealing (SSA)REACTOMER-HSA-5685938
    Nonhomologous End-Joining (NHEJ)REACTOMER-HSA-5693571
    Regulation of TP53 ActivityREACTOMER-HSA-5633007
    Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    171891862006Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis.283
    161413252005A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM.281
    163412052006Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks.231
    149662702004Structural and functional conservation of the NuA4 histone acetyltransferase complex from yeast to humans.230
    121509972002Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein.196
    197839832009Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60.193
    177093922007DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics.150
    127761772003MYC recruits the TIP60 histone acetyltransferase complex to chromatin.140
    177287592007Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response.126
    155726852004The c-MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60.125

    Citation

    Lise Mattera

    KAT5 (HIV-1 Tat interacting protein, 60kDa)

    Atlas Genet Cytogenet Oncol Haematol. 2007-10-01

    Online version: http://atlasgeneticsoncology.org/gene/40893/kat5