KAT5

Last updated
KAT5
Protein HTATIP PDB 2ou2.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases KAT5 , ESA1, HTATIP, HTATIP1, PLIP, TIP, TIP60, ZC2HC5, cPLA2, lysine acetyltransferase 5, NEDFASB
External IDs OMIM: 601409; MGI: 1932051; HomoloGene: 100661; GeneCards: KAT5; OMA:KAT5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10524

81601

Ensembl

ENSG00000172977

ENSMUSG00000024926

UniProt

Q92993

Q8CHK4

RefSeq (mRNA)

NM_001206833
NM_006388
NM_182709
NM_182710

RefSeq (protein)

NP_001193762
NP_006379
NP_874368
NP_874369

Location (UCSC) Chr 11: 65.71 – 65.72 Mb Chr 19: 5.65 – 5.66 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Histone acetyltransferase KAT5 is an enzyme that in humans is encoded by the KAT5 gene. [5] [6] It is also commonly identified as TIP60.

Contents

The protein encoded by this gene belongs to the MYST family of histone acetyl transferases (HATs) and was originally isolated as an HIV-1 TAT-interactive protein. HATs play important roles in regulating chromatin remodeling, transcription and other nuclear processes by acetylating histone and nonhistone proteins. This protein is a histone acetylase that has a role in DNA repair and apoptosis and is thought to play an important role in signal transduction. Alternative splicing of this gene results in multiple transcript variants. [6]

Structure

The structure of KAT5 includes an acetyl CoA binding domain and a zinc finger in the MYST domain, and a CHROMO domain. [7]

Excess acetyl CoA is necessary for acetylation of histones. The zinc finger domain has been shown to aid in the acetylation process as well. [8]

The CHROMO domain aids in KAT5 ability to bind chromatin, which is important for DNA repair. [9]

Function

KAT5 enzyme is known for acetylating histones in the nucleosome, which alters binding with DNA. Acetylation neutralizes the positive charge on histones, decreasing binding affinity of negatively charged DNA. [10] This in turn decreases steric hindrance of DNA and increases interaction of transcription factors and other proteins. Three key functions of KAT5 are its ability to regulate transcription, DNA repair, and apoptosis.

Transcription

Transcription factors such as E2F proteins and c-Myc can regulate the expression of proteins, particularly those involved with the cell cycle. [11] [12] KAT5 acetylates histones on genes of these transcription factors, which promote their activity.

DNA repair

KAT5 is an important enzyme for repairing DNA and returning cellular function to normal through its regulation of ataxia telangiectasia mutant (ATM) protein kinase. [13] ATM protein kinase phosphorylates and therefore activates proteins involved in DNA repair. However, to be functional, ATM protein kinase must be acetylated by the KAT5 protein. Lack of KAT5 suppresses ATM protein kinase activity and reduces the ability of a cell to correct its DNA.

KAT5 also works later in the DNA repair process, as it serves as a cofactor for TRRAP. [14] TRRAP enhances DNA remodeling by binding to chromatin near broken double stranded DNA sequences. KAT5 aids this recognition.

Apoptosis

P53 is well known for causing cell apoptosis after DNA damage. Acetylation of p53 by KAT5 induces this cell death. [11] Therefore, lack of KAT5 allows cells with damaged DNA to avoid apoptosis and continue dividing.

Regulation

KAT5 catalytic activity is regulated by the phosphorylation of its histones during the G2/M phase of the cell cycle. [15] Phosphorylation of KAT5 serines 86 and 90 reduces its activity. Therefore, cancer cells with uncontrolled growth and improper G2/M checkpoints lack KAT5 regulation by cyclin dependent kinase (CDK) phosphorylation.

Clinical relevance

KAT5 has many clinically significant implications that make it a useful target for diagnostic or therapeutic approaches. Most notably, KAT5 helps to regulate cancers, HIV, and neurodegenerative diseases. [7]

Cancer

As mentioned above, KAT5 helps to repair DNA and upregualte tumor suppressors such as p53. Therefore, many cancers are marked by a reduction of KAT5 mRNA. KAT5 also is linked to metastasis and malignancy. [16]

Studies have also shown that KAT5 augmented the ability of chemotherapy to stop tumor growth, demonstrating its potential for use in combination therapy. [18]

However, KAT5 isn't always anti-cancer. It can enhance the activity of proteins for viruses that cause cancer such as human T-cell lymphotropic virus type-1 (HTLV), which may result in leukemia and lymphoma. [20] Additionally, KAT5 reacts with human papillomavirus (HPV), the virus responsible for cervical cancer. [21]

Other proteins that KAT5 promotes may lead to cancer as well. For example, overexpressed E2F1, a transcriptional factor, is implicated in melanoma progression. [22] More research needs to be performed to clearly elucidate the overall role KAT5 has in cancer.

HIV

KAT5 binds to HIV-1 Tat transactivator and helps to promote HIV replication. [23]

Aging and Neurodegeneration

TIP60 regulates diverse cellular pathways including autophagy, DNA repair, neuronal survival, learning/memory, sleep/wake patterns, and protein turnover, all of which contribute to cellular homeostasis and organismal health so as to counteract aging and neurodegeneration. [24]

Interactions

HTATIP has been shown to interact with:

Related Research Articles

<span class="mw-page-title-main">Histone acetyltransferase</span> Enzymes that catalyze acyl group transfer from acetyl-CoA to histones

Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.

<span class="mw-page-title-main">Histone deacetylase</span> Class of enzymes important in regulating DNA transcription

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.

<span class="mw-page-title-main">EP300</span> Protein-coding gene in the species Homo sapiens

Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 also known as EP300 or p300 is an enzyme that, in humans, is encoded by the EP300 gene. It functions as histone acetyltransferase that regulates transcription of genes via chromatin remodeling by allowing histone proteins to wrap DNA less tightly. This enzyme plays an essential role in regulating cell growth and division, prompting cells to mature and assume specialized functions (differentiate), and preventing the growth of cancerous tumors. The p300 protein appears to be critical for normal development before and after birth.

<span class="mw-page-title-main">Transcription factor Sp1</span> Protein-coding gene in the species Homo sapiens

Transcription factor Sp1, also known as specificity protein 1* is a protein that in humans is encoded by the SP1 gene.

<span class="mw-page-title-main">Coactivator (genetics)</span> Class of proteins involved in regulation of transcription

A coactivator is a type of transcriptional coregulator that binds to an activator to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.

<span class="mw-page-title-main">PCAF</span> Protein-coding gene in the species Homo sapiens

P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53.

<span class="mw-page-title-main">CREB-binding protein</span> Nuclear protein that binds to CREB

CREB-binding protein, also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the CREBBP gene in humans, located on chromosome 16p13.3. CBP has intrinsic acetyltransferase functions; it is able to add acetyl groups to both transcription factors as well as histone lysines, the latter of which has been shown to alter chromatin structure making genes more accessible for transcription. This relatively unique acetyltransferase activity is also seen in another transcription enzyme, EP300 (p300). Together, they are known as the p300-CBP coactivator family and are known to associate with more than 16,000 genes in humans; however, while these proteins share many structural features, emerging evidence suggests that these two co-activators may promote transcription of genes with different biological functions.

<span class="mw-page-title-main">Histone acetylation and deacetylation</span> Biological processes used in gene regulation

Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">Transformation/transcription domain-associated protein</span> Protein-coding gene in the species Homo sapiens

Transformation/transcription domain-associated protein, also known as TRRAP, is a protein that in humans is encoded by the TRRAP gene. TRRAP belongs to the phosphatidylinositol 3-kinase-related kinase protein family.

<span class="mw-page-title-main">KAT2A</span> Protein-coding gene in the species Homo sapiens

Histone acetyltransferase KAT2A is an enzyme that in humans is encoded by the KAT2A gene.

<span class="mw-page-title-main">TAF10</span> Protein-coding gene in the species Homo sapiens

Transcription initiation factor TFIID subunit 10 is a protein that in humans is encoded by the TAF10 gene.

<span class="mw-page-title-main">HIST2H4A</span> Protein-coding gene in the species Homo sapiens

Histone H4 is a protein that in humans is encoded by the HIST2H4A gene.

<span class="mw-page-title-main">HIST2H2AC</span> Protein-coding gene in the species Homo sapiens

Histone H2A type 2-C is a protein that in humans is encoded by the HIST2H2AC gene.

<span class="mw-page-title-main">KAT7 (gene)</span> Protein-coding gene in the species Homo sapiens

Histone acetyltransferase KAT7 is an enzyme that in humans is encoded by the KAT7 gene. It specifically acetylates H4 histones at the lysine12 residue (H4K12) and is necessary for origin licensing and DNA replication. KAT7 associates with origins of replication during G1 phase of the cell cycle through complexing with CDT1. Geminin is thought to inhibit the acetyltransferase activity of KAT7 when KAT7 and CDT1 are complexed together.

<span class="mw-page-title-main">HIST1H3C</span> Protein-coding gene in the species Homo sapiens

Histone H3.1 is a protein that in humans is encoded by the HIST1H3C gene.

<span class="mw-page-title-main">KAT8</span> Protein-coding gene in the species Homo sapiens

K(lysine) acetyltransferase 8 (KAT8) is an enzyme that in humans is encoded by the KAT8 gene.

<span class="mw-page-title-main">JADE1</span> Protein-coding gene in the species Homo sapiens

JADE1 is a protein that in humans is encoded by the JADE1 gene.

While the cellular and molecular mechanisms of learning and memory have long been a central focus of neuroscience, it is only in recent years that attention has turned to the epigenetic mechanisms behind the dynamic changes in gene transcription responsible for memory formation and maintenance. Epigenetic gene regulation often involves the physical marking of DNA or associated proteins to cause or allow long-lasting changes in gene activity. Epigenetic mechanisms such as DNA methylation and histone modifications have been shown to play an important role in learning and memory.

The NuA4 histone acetyltransferase complex is a protein complex that has histone acetylase activity on chromatin, as well as ATPase, DNA helicase and structural DNA binding activities. The complex is thought to be involved in double-strand DNA break repair. Subunits of the human complex include HTATIP/TIP60, TRRAP, RUVBL1, RUVBL2, beta-actin and BAF53/ACTL6A. In yeast, the complex has 13 subunits, including the catalytic subunit Esa1.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000172977 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024926 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Kamine J, Elangovan B, Subramanian T, Coleman D, Chinnadurai G (Feb 1996). "Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator". Virology. 216 (2): 357–66. doi: 10.1006/viro.1996.0071 . PMID   8607265.
  6. 1 2 "Entrez Gene: HTATIP HIV-1 Tat interacting protein, 60kDa". Archived from the original on 2024-04-27. Retrieved 2024-04-27.
  7. 1 2 Mattera L (2011). "HTATIP (HIV-1 Tat interacting protein, 60kDa)". Atlas of Genetics and Cytogenetics in Oncology and Haematology (3). doi: 10.4267/2042/38522 (inactive 2024-04-11). hdl:2042/38522.{{cite journal}}: CS1 maint: DOI inactive as of April 2024 (link)
  8. ↑ Kim MY, Ann EJ, Kim JY, Mo JS, Park JH, Kim SY, Seo MS, Park HS (Sep 2007). "Tip60 histone acetyltransferase acts as a negative regulator of Notch1 signaling by means of acetylation". Molecular and Cellular Biology. 27 (18): 6506–19. doi:10.1128/MCB.01515-06. PMC   2099611 . PMID   17636029.
  9. ↑ Koonin EV, Zhou S, Lucchesi JC (Nov 1995). "The chromo superfamily: new members, duplication of the chromo domain and possible role in delivering transcription regulators to chromatin". Nucleic Acids Research. 23 (21): 4229–33. doi:10.1093/nar/23.21.4229. PMC   307373 . PMID   7501439.
  10. ↑ Lee F. "Gene Transcription: Histone Acetylation, DNA Methylation and Epigenetics". Molecular Biology Web Book. Web Books Publishing. Archived from the original on 2015-05-04. Retrieved 2015-05-06.
  11. 1 2 3 Van Den Broeck A, Nissou D, Brambilla E, Eymin B, Gazzeri S (Feb 2012). "Activation of a Tip60/E2F1/ERCC1 network in human lung adenocarcinoma cells exposed to cisplatin". Carcinogenesis. 33 (2): 320–5. doi: 10.1093/carcin/bgr292 . PMID   22159227.
  12. ↑ Patel JH, Du Y, Ard PG, Phillips C, Carella B, Chen CJ, Rakowski C, Chatterjee C, Lieberman PM, Lane WS, Blobel GA, McMahon SB (Dec 2004). "The c-MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60". Molecular and Cellular Biology. 24 (24): 10826–34. doi:10.1128/MCB.24.24.10826-10834.2004. PMC   533976 . PMID   15572685.
  13. ↑ Sun Y, Jiang X, Chen S, Fernandes N, Price BD (Sep 2005). "A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM". Proceedings of the National Academy of Sciences of the United States of America. 102 (37): 13182–7. Bibcode:2005PNAS..10213182S. doi: 10.1073/pnas.0504211102 . PMC   1197271 . PMID   16141325.
  14. ↑ Murr R, Loizou JI, Yang YG, Cuenin C, Li H, Wang ZQ, Herceg Z (Jan 2006). "Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks". Nature Cell Biology. 8 (1): 91–9. doi:10.1038/ncb1343. PMID   16341205. S2CID   25051471.
  15. ↑ Lemercier C, Legube G, Caron C, Louwagie M, Garin J, Trouche D, Khochbin S (Feb 2003). "Tip60 acetyltransferase activity is controlled by phosphorylation". The Journal of Biological Chemistry. 278 (7): 4713–8. doi: 10.1074/jbc.M211811200 . PMID   12468530. S2CID   8276821. Archived from the original on 2022-01-11. Retrieved 2024-04-27.
  16. 1 2 Chen G, Cheng Y, Tang Y, Martinka M, Li G (Nov 2012). "Role of Tip60 in human melanoma cell migration, metastasis, and patient survival". The Journal of Investigative Dermatology. 132 (11): 2632–41. doi: 10.1038/jid.2012.193 . PMID   22673729.
  17. ↑ Chevillard-Briet M, Quaranta M, Grézy A, Mattera L, Courilleau C, Philippe M, Mercier P, Corpet D, Lough J, Ueda T, Fukunaga R, Trouche D, Escaffit F (Apr 2014). "Interplay between chromatin-modifying enzymes controls colon cancer progression through Wnt signaling". Human Molecular Genetics. 23 (8): 2120–31. doi: 10.1093/hmg/ddt604 . PMID   24287617.
  18. 1 2 3 Ravichandran P, Ginsburg D (April 2015). "Tip60 Overexpression Exacerbates Chemotherapeutic Drug Treatment in Breast, Pancreatic, and Lung Cancer Cell Lines". The FASEB Journal. 29 (S1): Supplement 725.21. doi: 10.1096/fasebj.29.1_supplement.725.21 .
  19. ↑ Sakuraba K, Yokomizo K, Shirahata A, Goto T, Saito M, Ishibashi K, Kigawa G, Nemoto H, Hibi K (Jan 2011). "TIP60 as a potential marker for the malignancy of gastric cancer". Anticancer Research. 31 (1): 77–9. PMID   21273583.
  20. ↑ Awasthi S, Sharma A, Wong K, Zhang J, Matlock EF, Rogers L, Motloch P, Takemoto S, Taguchi H, Cole MD, Lüscher B, Dittrich O, Tagami H, Nakatani Y, McGee M, Girard AM, Gaughan L, Robson CN, Monnat RJ, Harrod R (Jul 2005). "A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions". Molecular and Cellular Biology. 25 (14): 6178–98. doi:10.1128/MCB.25.14.6178-6198.2005. PMC   1168837 . PMID   15988028.
  21. ↑ Hong S, Dutta A, Laimins LA (Apr 2015). "The acetyltransferase Tip60 is a critical regulator of the differentiation-dependent amplification of human papillomaviruses". Journal of Virology. 89 (8): 4668–75. doi:10.1128/JVI.03455-14. PMC   4442364 . PMID   25673709.
  22. ↑ Alla V, Engelmann D, Niemetz A, Pahnke J, Schmidt A, Kunz M, Emmrich S, Steder M, Koczan D, Pützer BM (Jan 2010). "E2F1 in melanoma progression and metastasis". Journal of the National Cancer Institute. 102 (2): 127–33. doi:10.1093/jnci/djp458. PMID   20026813.
  23. ↑ Kamine J, Elangovan B, Subramanian T, Coleman D, Chinnadurai G (Feb 1996). "Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator". Virology. 216 (2): 357–66. doi: 10.1006/viro.1996.0071 . PMID   8607265.
  24. ↑ Li Z, Rasmussen LJ (2020-10-19). "TIP60 in Aging and Neurodegeneration". Ageing Research Reviews. 64: 101195. doi:10.1016/j.arr.2020.101195. ISSN   1568-1637. PMID   33091598. S2CID   224775578. Archived from the original on 2023-03-04. Retrieved 2024-04-27.
  25. ↑ Gaughan L, Logan IR, Cook S, Neal DE, Robson CN (Jul 2002). "Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor". The Journal of Biological Chemistry. 277 (29): 25904–13. doi: 10.1074/jbc.M203423200 . PMID   11994312. S2CID   9930504.
  26. ↑ Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG, Scheidereit C, Leutz A (Jun 1999). "The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators". Oncogene. 18 (22): 3316–23. doi: 10.1038/sj.onc.1202717 . PMID   10362352. S2CID   2356435.
  27. ↑ Gavaravarapu S, Kamine J (Mar 2000). "Tip60 inhibits activation of CREB protein by protein kinase A". Biochemical and Biophysical Research Communications. 269 (3): 758–66. doi: 10.1006/bbrc.2000.2358 . PMID   10720489.
  28. ↑ Nordentoft I, Jørgensen P (Aug 2003). "The acetyltransferase 60 kDa trans-acting regulatory protein of HIV type 1-interacting protein (Tip60) interacts with the translocation E26 transforming-specific leukaemia gene (TEL) and functions as a transcriptional co-repressor". The Biochemical Journal. 374 (Pt 1): 165–73. doi:10.1042/BJ20030087. PMC   1223570 . PMID   12737628.
  29. ↑ Lee HJ, Chun M, Kandror KV (May 2001). "Tip60 and HDAC7 interact with the endothelin receptor a and may be involved in downstream signaling". The Journal of Biological Chemistry. 276 (20): 16597–600. doi: 10.1074/jbc.C000909200 . PMID   11262386. S2CID   38498534.
  30. ↑ Hejna J, Holtorf M, Hines J, Mathewson L, Hemphill A, Al-Dhalimy M, Olson SB, Moses RE (Apr 2008). "Tip60 is required for DNA interstrand cross-link repair in the Fanconi anemia pathway". The Journal of Biological Chemistry. 283 (15): 9844–51. doi: 10.1074/jbc.M709076200 . PMC   2398728 . PMID   18263878.
  31. ↑ Xiao H, Chung J, Kao HY, Yang YC (Mar 2003). "Tip60 is a co-repressor for STAT3". The Journal of Biological Chemistry. 278 (13): 11197–204. doi: 10.1074/jbc.M210816200 . PMID   12551922. S2CID   6317335.
  32. ↑ Legube G, Linares LK, Lemercier C, Scheffner M, Khochbin S, Trouche D (Apr 2002). "Tip60 is targeted to proteasome-mediated degradation by Mdm2 and accumulates after UV irradiation". The EMBO Journal. 21 (7): 1704–12. doi:10.1093/emboj/21.7.1704. PMC   125958 . PMID   11927554.
  33. ↑ Frank SR, Parisi T, Taubert S, Fernandez P, Fuchs M, Chan HM, Livingston DM, Amati B (Jun 2003). "MYC recruits the TIP60 histone acetyltransferase complex to chromatin". EMBO Reports. 4 (6): 575–80. doi:10.1038/sj.embor.embor861. PMC   1319201 . PMID   12776177.
  34. ↑ Sheridan AM, Force T, Yoon HJ, O'Leary E, Choukroun G, Taheri MR, Bonventre JV (Jul 2001). "PLIP, a novel splice variant of Tip60, interacts with group IV cytosolic phospholipase A(2), induces apoptosis, and potentiates prostaglandin production". Molecular and Cellular Biology. 21 (14): 4470–81. doi:10.1128/MCB.21.14.4470-4481.2001. PMC   87107 . PMID   11416127.
  35. ↑ Bakshi, K., Ranjitha, B., Dubey, S. et al. Novel complex of HAT protein TIP60 and nuclear receptor PXR promotes cell migration and adhesion. Sci Rep 7, 3635 (2017). https://doi.org/10.1038/s41598-017-03783-w

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