Biology:KAT5

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Histone acetyltransferase KAT5 is an enzyme that in humans is encoded by the KAT5 gene.[1][2] It is also commonly identified as TIP60.

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.[2]

Structure

The structure of KAT5 includes an acetyl CoA binding domain and a zinc finger in the MYST domain, and a CHROMO domain.[3] Excess acetyl CoA is necessary for acetylation of histones. The zinc finger domain has been shown to aid in the acetylation process as well.[4] The CHROMO domain aids in KAT5 ability to bind chromatin, which is important for DNA repair.[5]

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.[6] 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.[7][8] 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.[9] 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.[10] 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.[7] 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.[11] 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.[3]

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.[12]

Studies have also shown that KAT5 augmented the ability of chemotherapy to stop tumor growth, demonstrating its potential for use in combination therapy.[14]

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.[16] Additionally, KAT5 reacts with human papillomavirus (HPV), the virus responsible for cervical cancer.[17]

Other proteins that KAT5 promotes may lead to cancer as well. For example, overexpressed E2F1, a transcriptional factor, is implicated in melanoma progression.[18] 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.[19]

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.[20]

Interactions

HTATIP has been shown to interact with:

References

  1. ↑ "Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator". Virology 216 (2): 357–66. Feb 1996. doi:10.1006/viro.1996.0071. PMID 8607265. 
  2. ↑ 2.0 2.1 "Entrez Gene: HTATIP HIV-1 Tat interacting protein, 60kDa". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10524. 
  3. ↑ 3.0 3.1 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. 
  4. ↑ "Tip60 histone acetyltransferase acts as a negative regulator of Notch1 signaling by means of acetylation". Molecular and Cellular Biology 27 (18): 6506–19. Sep 2007. doi:10.1128/MCB.01515-06. PMID 17636029. 
  5. ↑ "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. Nov 1995. doi:10.1093/nar/23.21.4229. PMID 7501439. 
  6. ↑ Lee, Frank. "Gene Transcription: Histone Acetylation, DNA Methylation and Epigenetics". Molecular Biology Web Book. Web Books Publishing. http://www.web-books.com/MoBio/Free/Ch4G.htm. 
  7. ↑ 7.0 7.1 7.2 "Activation of a Tip60/E2F1/ERCC1 network in human lung adenocarcinoma cells exposed to cisplatin". Carcinogenesis 33 (2): 320–5. Feb 2012. doi:10.1093/carcin/bgr292. PMID 22159227. 
  8. ↑ "The c-MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60". Molecular and Cellular Biology 24 (24): 10826–34. Dec 2004. doi:10.1128/MCB.24.24.10826-10834.2004. PMID 15572685. 
  9. ↑ "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. Sep 2005. doi:10.1073/pnas.0504211102. PMID 16141325. Bibcode: 2005PNAS..10213182S. 
  10. ↑ "Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks". Nature Cell Biology 8 (1): 91–9. Jan 2006. doi:10.1038/ncb1343. PMID 16341205. 
  11. ↑ "Tip60 acetyltransferase activity is controlled by phosphorylation". The Journal of Biological Chemistry 278 (7): 4713–8. Feb 2003. doi:10.1074/jbc.M211811200. PMID 12468530. https://hal.archives-ouvertes.fr/hal-00380484/document. 
  12. ↑ 12.0 12.1 "Role of Tip60 in human melanoma cell migration, metastasis, and patient survival". The Journal of Investigative Dermatology 132 (11): 2632–41. Nov 2012. doi:10.1038/jid.2012.193. PMID 22673729. 
  13. ↑ "Interplay between chromatin-modifying enzymes controls colon cancer progression through Wnt signaling". Human Molecular Genetics 23 (8): 2120–31. Apr 2014. doi:10.1093/hmg/ddt604. PMID 24287617. 
  14. ↑ 14.0 14.1 14.2 Ravichandran, Priyadarshini; Ginsburg, Daniel (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. 
  15. ↑ "TIP60 as a potential marker for the malignancy of gastric cancer". Anticancer Research 31 (1): 77–9. Jan 2011. PMID 21273583. 
  16. ↑ "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. Jul 2005. doi:10.1128/MCB.25.14.6178-6198.2005. PMID 15988028. 
  17. ↑ "The acetyltransferase Tip60 is a critical regulator of the differentiation-dependent amplification of human papillomaviruses". Journal of Virology 89 (8): 4668–75. Apr 2015. doi:10.1128/JVI.03455-14. PMID 25673709. 
  18. ↑ "E2F1 in melanoma progression and metastasis". Journal of the National Cancer Institute 102 (2): 127–33. Jan 2010. doi:10.1093/jnci/djp458. PMID 20026813. 
  19. ↑ "Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator". Virology 216 (2): 357–66. Feb 1996. doi:10.1006/viro.1996.0071. PMID 8607265. 
  20. ↑ Li, Zhiquan; Rasmussen, Lene Juel (2020-10-19). "TIP60 in Aging and Neurodegeneration" (in en). Ageing Research Reviews 64: 101195. doi:10.1016/j.arr.2020.101195. ISSN 1568-1637. PMID 33091598. http://www.sciencedirect.com/science/article/pii/S1568163720303305. 
  21. ↑ "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. Jul 2002. doi:10.1074/jbc.M203423200. PMID 11994312. 
  22. ↑ "The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators". Oncogene 18 (22): 3316–23. Jun 1999. doi:10.1038/sj.onc.1202717. PMID 10362352. 
  23. ↑ "Tip60 inhibits activation of CREB protein by protein kinase A". Biochemical and Biophysical Research Communications 269 (3): 758–66. Mar 2000. doi:10.1006/bbrc.2000.2358. PMID 10720489. 
  24. ↑ "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. Aug 2003. doi:10.1042/BJ20030087. PMID 12737628. 
  25. ↑ "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. May 2001. doi:10.1074/jbc.C000909200. PMID 11262386. 
  26. ↑ "Tip60 is required for DNA interstrand cross-link repair in the Fanconi anemia pathway". The Journal of Biological Chemistry 283 (15): 9844–51. Apr 2008. doi:10.1074/jbc.M709076200. PMID 18263878. 
  27. ↑ "Tip60 is a co-repressor for STAT3". The Journal of Biological Chemistry 278 (13): 11197–204. Mar 2003. doi:10.1074/jbc.M210816200. PMID 12551922. 
  28. ↑ "Tip60 is targeted to proteasome-mediated degradation by Mdm2 and accumulates after UV irradiation". The EMBO Journal 21 (7): 1704–12. Apr 2002. doi:10.1093/emboj/21.7.1704. PMID 11927554. 
  29. ↑ "MYC recruits the TIP60 histone acetyltransferase complex to chromatin". EMBO Reports 4 (6): 575–80. Jun 2003. doi:10.1038/sj.embor.embor861. PMID 12776177. 
  30. ↑ "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. Jul 2001. doi:10.1128/MCB.21.14.4470-4481.2001. PMID 11416127. 
  31. ↑ 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

Further reading

External links

  • Overview of all the structural information available in the PDB for UniProt: Q92993 (Histone acetyltransferase KAT5) at the PDBe-KB.



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