Histone acetyltransferase KAT5 is an enzyme that in humans is encoded by the KAT5gene.[5][6] 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.[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]
^ abMattera 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 1 November 2024). hdl:2042/38522.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
^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. PMID16341205. S2CID25051471.
^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. PMID21273583.
^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. PMID20026813.
^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
Doyon Y, Côté J (Apr 2004). "The highly conserved and multifunctional NuA4 HAT complex". Current Opinion in Genetics & Development. 14 (2): 147–54. doi:10.1016/j.gde.2004.02.009. PMID15196461.
Sapountzi V, Logan IR, Robson CN (2006). "Cellular functions of TIP60". The International Journal of Biochemistry & Cell Biology. 38 (9): 1496–509. doi:10.1016/j.biocel.2006.03.003. PMID16698308.
Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Creaven M, Hans F, Mutskov V, Col E, Caron C, Dimitrov S, Khochbin S (Jul 1999). "Control of the histone-acetyltransferase activity of Tip60 by the HIV-1 transactivator protein, Tat". Biochemistry. 38 (27): 8826–30. doi:10.1021/bi9907274. PMID10393559.
Sliva D, Zhu YX, Tsai S, Kamine J, Yang YC (Sep 1999). "Tip60 interacts with human interleukin-9 receptor alpha-chain". Biochemical and Biophysical Research Communications. 263 (1): 149–55. doi:10.1006/bbrc.1999.1083. PMID10486269.
Ran Q, Pereira-Smith OM (Nov 2000). "Identification of an alternatively spliced form of the Tat interactive protein (Tip60), Tip60(beta)". Gene. 258 (1–2): 141–6. doi:10.1016/S0378-1119(00)00410-8. PMID11111051.
Cao X, Südhof TC (Jul 2001). "A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60". Science. 293 (5527): 115–20. doi:10.1126/science.1058783. PMID11441186. S2CID43920642.
