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kat5

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Official Full Name
K(lysine) acetyltransferase 5
Background
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. [provided by RefSeq, Jul 2008]
Synonyms
KAT5; K(lysine) acetyltransferase 5; TIP; ESA1; PLIP; TIP60; cPLA2; HTATIP; ZC2HC5; HTATIP1; histone acetyltransferase KAT5; K-acetyltransferase 5; cPLA2 interacting protein; cPLA(2)-interacting protein; 60 kDa Tat-interactive protein; Tat interacting protein, 60kDa; histone acetyltransferase HTATIP; HIV-1 Tat interactive protein, 60kDa; HIV 1 Tat interactive protein, 60kDa , HTATIP; K acetyltransferase 5; Tat interacting protein; 60kDa; lysine acetyltransferase 5

Recent Research

Lysine acetyltransferase (KAT) is an enzyme that catalyzes the transfer of acetyl groups from acetyl-CoA to the lysine ε-amino group on the protein substrate. KAT includes multiple families, and MYST (MOZ, Ybf2/Sas3, Sas2 and KAT5) is one of them. As an important member of the MYST family, KAT5 plays a vital role in gene transcriptional regulation, DNA damage response, cell cycle, autophagy, and tumorigenesis and metastasis. KAT5 contains an N-terminal chromatin domain and a C-terminal conserved MYST domain. Also included in the MYST domain is a Cys-Cys-His-His zinc finger structure with a nuclear receptor cassette (NR-box) at the C-terminus that interacts with nuclear receptors.

KAT5 is involved in the regulation of transcription factors

Some reports show that KAT5 is involved in the regulation of a variety of nuclear hormone receptors, such as androgen receptor, estrogen receptor, glucocorticoid receptor and retinoid related receptors. The androgen receptor (AR) is involved in the growth and development of the prostate, and KAT5 binds through its C-terminal NR-box Leu-XX-leu-leu (LXXLL) motif and nuclear receptor activation function-2 (AF-2) domain to activate the nuclear hormone receptor. KAT5 can also directly acetylate AR to enhance its transcriptional activity. Moreover, KAT5 also has effect on early adipocyte differentiation. PPARγ is mainly involved in adipocyte differentiation and plays an important role in lipid homeostasis and energy metabolism. KAT5 interacts with the AF1 domain of PPARγ to activate transcriptional activation and participate in the differentiation of early adipocytes.

C-myc is a member of the myc gene family. It plays an important role in regulating gene expression, promoting cell growth and apoptosis. KAT5 acts as a c-myc coactivator involved in gene transcription, it directly acetylates c-myc, increases its stability and transcriptional activity. The KAT5 complex can also be recruited to the chromosome by myc, causing acetylation of histone H3K9, H3K14, H3K18, H4K5, H4K12 and other lysine sites to enhance myc transcriptional activity. Furthermore, KAT5 also participates in the activation of atrial natriuretic promoter with serum response factor (SRF) and involves in the regulation of SRF-dependent expression of cardiovascular related genes.

In other aspects, KAT5 can act as a synergistic inhibitor of STAT3 by inhibiting the transcriptional activity of STAT3 by recruiting HDAC7, thus causing tumor cell growth arrest and apoptosis. KAT5 acts as a co-suppressor of the ZEB (Zinc finger E box binding protein) and binds to ZEB to inhibit gene transcription. In addition, KAT5 is also involved in the regulation of the NF-κB signaling pathway, and together with the β-catenin complex, synergistically regulates the expression of the tumor metastasis suppressor gene KAI1 (Figure 1).

KAT5 Figure 1. Model of KAT5 involvement in gene transcription

KAT5 participates in DNA damage repair

When DNA double-strand breaks, the histone H2AX first phosphorylates and forms a focal point at the breakpoint, and then recruits DNA repair related proteins such as Mre11-Rad50-Nbs1 complex (MRN) and ATM. It was found that KAT5 is important for the phosphorylation and homologous recombination of H2AX. It interacts with the MRN complex and aggregates into the DNA double-stranded damage site. TRRAP plays a bridging role in the interaction between KAT5 and MRN. KAT5 plays a direct role in the ATM activation process. When DNA is damaged, the acetyltransferase activity of KAT5 is activated. Then,KAT5 binds to the FATC domain of ATM to form a KAT5-ATM complex, acetylates the K3016 site of ATM and activates it. In turn, it induces ATM auto phosphorylation and initiates a series of downstream repair reactions.

KAT5 is also involved in the normal supply of intracellular dNTPs during DNA repair. In the low concentration state of dNTP, Ribonucleic acid reductase (RNR) is recruited to the DNA double-stranded damage site is a KAT5-dependent process. In the UV damage reaction, KAT5 can also undergo auto acetylation, which can enhance the binding ability of KAT5 to the substrate and enhance the activity of acetyltransferase. Recent studies have found that zinc finger protein 668 acts as a DNA repair regulator that interacts with KAT5. The knockdown of zinc finger protein 668 reduces the interaction of KAT5 with H2AX and affects radiation-induced H2AX hyperacetylation, which in turn affects staining. The loose state of the DNA affects the recruitment of DNA damage site repair proteins and homologous recombination repair.

KAT5 in DNA damage cell cycle, apoptosis, autophagy, glucose metabolism and stem cell regulation

It has been shown that p53 plays an important role in the regulation of KAT5-mediated apoptosis and cell cycle arrest. After DNA damage, the K120 site of p53 is rapidly acetylated by KAT5, and acetylated p53 specifically aggregates on the proapoptotic gene BAX and PUMA promoters, activates gene transcription and induces apoptosis. K120 acetylation loss specifically inhibits p53-mediated transcription of the apoptotic genes BAX and PUMA. Programmed cell death factor PDCD5 enhances KAT5 acetyltransferase activity, induces acetylation of K120 at p53, and promotes apoptosis-related gene expression. Besides, ING5, a coactivator of KAT5, is involved in the acetylation of the K120 locus of p53, which forms a complex with KAT5 and p53 and is involved in p53-mediated apoptosis under DNA damage.

However, KAT5 is not completely dependent on p53 during the apoptotic reaction. The knockdown of KAT5 can directly affect the activation of caspase 3, JNK phosphorylation and ATR pathway in cells, so that p53 is involved in the occurrence and regulation of apoptosis. It has been shown that KAT5 is involved in the regulation of autophagy. In the absence of growth factors, AKT is inhibited, which in turn activates GSK3 and phosphorylates the S86 site of KAT5, promoting KAT5 acetylation of ULK1 and affecting autophagy.

In addition, KAT5 plays an important role in the development of breast cancer. Twist is an important transcriptional activator of epithelial-mesenchymal transition. KAT5 can acetylate Twist's K73/K76 locus to interact with BET family member BRD4 combines and further activates expression of WNT5a, inhibition of WNT5a can reduce the invasiveness of breast cancer cells and the formation of tumor spheres.

Glycogen synthase (GSK-3) has been shown to phosphorylate the serine at position 86 of KAT5, which affects the K120 acetylation and PUMA expression of p53 and affects p53-mediated apoptosis. In addition, there are many other proteins involved in the regulation of apoptosis mediated KAT5, FANCD2 when localized in the nucleus to induce apoptosis. When lethal dose causes DNA damage, KAT5 can interact with Axin, inhibit the binding of Pirh2 and Axin, and form Axin- KAT5-HIPK2-p53 complex, which promotes p53 activation and induces apoptosis. Moreover, PCK1 (phosphoenolpyruvate carboxykinase) is an important regulatory kinase of the gluconeogenesis pathway. Recent studies have confirmed that KAT5 can regulate its kinase activity by acetylating the K514 site of PCK1, and then regulate gluconeogenesis by regulating key rate-limiting enzymes. Furthermore, KAT5 can maintain its dryness by regulating the expression of certain genes in stem cells. Diploid gene knockout KAT5 mice die early in the embryo, demonstrating the important role of KAT5 in stem cell function mainten.

References:

  1. Zhang H, et al. Function Research of Acetyltransferase Tip60 (KAT5). Progress in Biochemistry & Biophysics, 2015, 42(1):25-31.
  2. Ortegaatienza S, et al. ATM and KAT5 safeguard replicating chromatin against formaldehyde damage. Nucleic Acids Research, 2016, 44(1):198-209.
  3. Cregan S, et al. KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma. International Journal of Oncology, 2016, 48(3):1290-1296.
  4. Legube G, et al. Tip60 is targeted to proteasome-mediated degradation by Mdm2 and accumulates after UV irradiation. Embo Journal, 2014, 21(7):1704-1712.
  5. Gao C, et al. Rational design and validation of a Tip60 histone acetyltransferase inhibitor. Scientific Reports, 2014, 4(4):5372.