16. Protein Acetylation
 

16.1. Protein Acetylation and Deacetylation

 

Post-translational modification (PTM) occurs after translation of proteins and results in proteins experiencing chemical variations. These PMTs include methylation, acetylation, glycosylation, ubiquitination and phosphorylation (Xia C et al., 2020).

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As acetyl donor (such as acetyl-CoA) transmits acetyl groups to the proteins that go through catalysis by acetyltransferase, then the key machinery of the protein acetylation occurs (Drazic A et al., 2016) (Xia C et al., 2020).

 

Acetylation includes histone acetylation or non-histone acetylation and largely takes place on lysine residue (Verdin E and Ott M., 2015 as cited in Xia C et al., 2020) (Xia C et al., 2020). 

 

At present, there are three well established types of acetylation: Nα-acetylation, Nε-acetylation and O-acetylation (Lee T Y et al., 2010 as cited in Xia C et al., 2020) (Xia C et al., 2020).

 

Eighty five percent of human protein modification occurs as a result of Nα-acetylation, which is an irretrievable process and takes place through adding of an acetyl group to the α-amino group of the N-terminal amino acid (Hollebeke J et al., 2012 as cited in Xia C et al., 2020) (Xia C et al., 2020). 

 

Nε-acetylation, on the other hand, occurs when an acetyl group is inserted in the ε-amino group of the lysine residue, which is a mutable procedure (Thao S et al., 2010) (Xia C et al., 2020).

 

O-acetylation takes place when an acetyl group is inserted in the tyrosine/ serine/ threonine of a hydroxyl group (Yang X J and Gregoire S, 2007) (Xia C et al., 2020).

 

Role of Acetylation in Histone

 

Vincent Allfrey first discovered lysine acetylation in Histone in 1964, which is associated with having a regulatory role in gene transcription (Allfrey V G et al., 1964) (Verdon L et al., 2005 as cited in Xia C et al., 2020) (Xia C et al., 2020).

 

There are two main basic amino acids, lysine and arginine, that are found in a large quantity in histones, which make histones have a positive charge. Therefore, as histone is acetylated, then it loses its positive charge and consequently the binding of DNA to histone will be loosened and gene transcription will be expedited (Allfrey V G et al., 1964) (Xia C et al., 2020).

 

There are also huge quantity of proteins, which facilitate acetylation and deacetylation, such as histone acetyltransferase (HAT) and histone deacetylases (HDACs), which were correspondingly retitled to lysine acetyltransferases (KATs) and lysine deacetylases (KDACs)(Allis C D et al., 2007 as cited in Xia C et al., 2020) (Li P et al., 2020) (Xia C et al., 2020).

 

It was found that the level of substrate RNA could be controlled through acetylation, which in turn can affect the enzymatic function of nucleases (Song Le et al., 2016) (Xia C et al., 2020). This demonstrates that organisms can obtain self-regulation of cells via nucleases (Xia C et al., 2020).

 

One of the key gene transcription regulators is protein acetylation (Sterner D E and Berger S L., 2000) (Xia C et al., 2020) and it is involved in controlling more than 100 non histone proteins, consisting of transcription factors (TFs), transcriptional coactivators and nuclear receptors (Narita T et al., 2019 as cited in Xia C et al., 2020) (Xia C et al., 2020).  Furthermore, HATs are usually acting as transcriptional co-activators and are located in the nucleus (Ruhlmann F et al., 2019) (Xia C et al., 2020).

 

Protein acetylation usually leads to protein degradation and can also regulate a number of signaling pathways and influence the cell cycle (Xia C et al., 2020).

 

Protein Acetylation and Deacetylation Reference

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1.        Allfrey, V. G., Faulkner, R. & Mirsky, A. E. ACETYLATION AND METHYLATION OF HISTONES AND THEIR POSSIBLE ROLE IN THE REGULATION OF RNA SYNTHESIS. Proc. Natl. Acad. Sci. 51, 786–794 (1964).

2.        Allis, C. D. et al. New Nomenclature for Chromatin-Modifying Enzymes. Cell 131, 633–636 (2007).

3.        Drazic, A., Myklebust, L. M., Ree, R. & Arnesen, T. The world of protein acetylation. Biochim. Biophys. Acta - Proteins Proteomics 1864, 1372–1401 (2016).

4.        Hollebeke, J., Van Damme, P. & Gevaert, K. N-terminal acetylation and other functions of Nα-acetyltransferases. Biol. Chem. 393, 291–298 (2012).

5.        Lee, T.-Y. et al. N-Ace: Using solvent accessibility and physicochemical properties to identify protein N-acetylation sites. J. Comput. Chem. 31, 2759–2771 (2010).

6.        Li, P., Ge, J. & Li, H. Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease. Nat. Rev. Cardiol. 17, 96–115 (2020).

7.        Narita, T., Weinert, B. T. & Choudhary, C. Functions and mechanisms of non-histone protein acetylation. Nat. Rev. Mol. Cell Biol. 20, 156–174 (2019).

8.        Rühlmann, F. et al. The prognostic capacities of CBP and p300 in locally advanced rectal cancer. World J. Surg. Oncol. 17, 224 (2019).

9.        Thao, S., Chen, C.-S., Zhu, H. & Escalante-Semerena, J. C. Nε−Lysine Acetylation of a Bacterial Transcription Factor Inhibits Its DNA-Binding Activity. PLoS One 5, e15123 (2010).

10.     Verdin, E. & Ott, M. 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nat. Rev. Mol. Cell Biol. 16, 258–264 (2015).

11.     Verdone, L., Caserta, M. & Mauro, E. Di. Role of histone acetylation in the control of gene expression. Biochem. Cell Biol. 83, 344–353 (2005).

12.     Xia, C., Tao, Y., Li, M., Che, T. & Qu, J. Protein acetylation and deacetylation: An important regulatory modification in gene transcription (Review). Exp. Ther. Med. (2020). doi:10.3892/etm.2020.9073

13.     Yang, X. & Grégoire, S. Metabolism, cytoskeleton and cellular signalling in the grip of protein N ϵ ‐ and O‐acetylation. EMBO Rep. 8, 556–562 (2007).

 

16.2. Acetylation and Deacetylation of Histone

 

The protein acetylation investigation started with histones (Xia C et al., 2020).

 

The overhaul of DNA replication forks occurs as histone acetylation takes place (Xia C et al., 2020).

 

Acetylation of H4 on four lysine residues 5,8,12 and 16 occurs as a landmark of Nε-acetylation, which in turn is caused by nucleosome acetyltransferase of H4 (NuA4) involvement in this process (Xia C et al., 2020). These alterations will have an effect on the structural alteration of chromatin and assist the overhauls of fragmented DNA replication forks (Dhar S et al., 2017) (Xia C et al., 2020).

 

SWI1 assists histone H4 acetylation through enhancing the stability of NuA4 expression (Xia C et al., 2020). A deficit of SWI1 leads to a decrease in histone H4 acetylation due to inducing an inequilibrium in chromatin modification related protein vid21. Vid21 is found to be a monitoring subunit of NuA4 (Noguchi C et al., 2019) (Xia C et al., 2020).

 

It is known that the alteration in levels of SIRT6 leads to a rise in the level of H3K56ac from small to elevated cell mass. Also, as lactic acid level increases, then it causes a boost in H3K56ac level (Xia C et al., 2020).

 

It is also reported that there may be a relation between acetylation and repair after DNA damage as the level of H3K56ac rises in the cells with low acetylation soon after DNA damage. However, this process follows the opposite pattern as the level of H3K56ac declines in the cells when there is an elevated level of acetylation right after DNA damage (Vadla R et al., 2020) (Xia C et al., 2020).

 

Furthermore, according to Xia C et al., 2020, “histone acetyltransferase Gcn5p is a catalytic subunit of nuclear HAT” (Xia C et al., 2020). Histone acetylation of H3 and H4 occurs at specific lysines, which is on N-ε acetylation at particular lysines in the N-terminal domains. This, in turn, results in the progression of the cell growth, which is facilitated by catalysis performed by Gcn5P. These outcomes infer that this type of acetylation is vital for normal cell cycle advancement (Koprinarova M et al., 2010 as cited in Xia C et al., 2020) (Xia C et al., 2020).

 

Acetylation and Deacetylation of Histone Reference

 

1.        Dhar, S., Gursoy-Yuzugullu, O., Parasuram, R. & Price, B. D. The tale of a tail: histone H4 acetylation and the repair of DNA breaks. Philos. Trans. R. Soc. B Biol. Sci. 372, 20160284 (2017).

2.        Koprinarova, M., Schnekenburger, M. & Diederich, M. Role of Histone Acetylation in Cell Cycle Regulation. Curr. Top. Med. Chem. 16, 732–744 (2015).

3.        Noguchi, C. et al. The NuA4 acetyltransferase and histone H4 acetylation promote replication recovery after topoisomerase I-poisoning. Epigenetics Chromatin 12, 24 (2019).

4.        Vadla, R., Chatterjee, N. & Haldar, D. Cellular environment controls the dynamics of histone H3 lysine 56 acetylation in response to DNA damage in mammalian cells. J. Biosci. 45, 19 (2020).

5.        Xia, C., Tao, Y., Li, M., Che, T. & Qu, J. Protein acetylation and deacetylation: An important regulatory modification in gene transcription (Review). Exp. Ther. Med. (2020). doi:10.3892/etm.2020.9073

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16.3. Acetylation and Deacetylation of Non-Histone Protein

 

Non-histone protein acetylation is known to have a major role in regulatory activities e.g., non-histone proteins such as p53 and TFs can also be acetylated (Kim E et al., 2016) (Xia C et al., 2020). These non-histone proteins are usually playing roles in a number of physiological procedures such as gene transcription and protein folding (Wapenaar H and Dekker F J., 2016) (Xia C et al., 2020). 

 

P53 as a tumor suppressor is responsible for controlling the tumor formation and can be acetylated by the P300/CBT family as a method for Nε-acetylation (Xia C et al., 2020).

 

In this method, acetylation of p53 by P300/CBT family occurs at the C-terminal lysine of p53 and promotes the explicit DNA binding sites on p53 (Glozak M A et al., 2005 as cited in Xia C et al., 2020) (Xia C et al., 2020). The binding of p53 promoter by p300/CBT family, when DNA is impaired, augments the p53 stability through a rise in the transcriptional functionality of its gene (Suzuki M et al., 2018) (Xia C et al., 2020).

 

The other role of p300/CBT is causing the inhibition of E3 ubiquitin-protein ligase murine double minute 2 (MDM2) in order to control p53 (Xia C et al., 2020). MDM2 also inactivates p53 acetylation initiated by p300/CBT and promotes p53 degradation after its deacetylation (Ito A et al., 2001) (Xia C et al., 2020). Therefore, p53 acetylation is also correlated with controlling apoptosis (Xia C et al., 2020).

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It is important to know that p300 is an essential TF, which controls the transcriptional function of p53 through acetylation and plays a role in transformation of the cell from G1 to S phase (Iyer N G et al., 2007) (Shi D et al., 2016) (Xia C et al., 2020).

 

HDAC2, as a coreprossor, plays a role in the regulation of the target genes and is responsible for deacetylating p53 C-terminal lysine (Xia C et al., 2020).

 

It is known that stability of p53 is increased if the main lysine residues on p53 remain largely acetylated as a result of activities of KDAC inhibitors (KDACIs) (Brandl A et al., 2012 as cited in Xia C et al., 2020) (Xia C et al., 2020). Furthermore, KDACIs, through MDM2 and CHIP ligase, plays a role in the induction of mutant p53 degradation, when it inactivates HDAC6. This process is suggested to be the mutant p53 terminating machinery (Li D et al., 2011) (Xia C et al., 2020).

 

Acetylation and Deacetylation of Non-Histone Protein Reference

 

1.        Brandl, A. et al. Dynamically regulated sumoylation of HDAC2 controls p53 deacetylation and restricts apoptosis following genotoxic stress. J. Mol. Cell Biol. 4, 284–293 (2012).

2.        Glozak, M. A., Sengupta, N., Zhang, X. & Seto, E. Acetylation and deacetylation of non-histone proteins. Gene363, 15–23 (2005).

3.        Ito, A. et al. p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J. 20, 1331–1340 (2001).

4.        Iyer, N. G. et al. p300 is required for orderly G1/S transition in human cancer cells. Oncogene 26, 21–29 (2007).

5.        Kim, E. et al. Histone and Non-Histone Targets of Dietary Deacetylase Inhibitors. Curr. Top. Med. Chem. 16, 714–731 (2015).

6.        Li, D., Marchenko, N. D. & Moll, U. M. SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell Death Differ. 18, 1904–1913 (2011).

7.        Shi, D., Dai, C., Qin, J. & Gu, W. Negative regulation of the p300-p53 interplay by DDX24. Oncogene 35, 528–536 (2016).

8.        Suzuki, M., Ikeda, A. & Bartlett, J. D. Sirt1 overexpression suppresses fluoride-induced p53 acetylation to alleviate fluoride toxicity in ameloblasts responsible for enamel formation. Arch. Toxicol. 92, 1283–1293 (2018).

9.        Wapenaar, H. & Dekker, F. J. Histone acetyltransferases: challenges in targeting bi-substrate enzymes. Clin. Epigenetics 8, 59 (2016).

10.     Xia, C., Tao, Y., Li, M., Che, T. & Qu, J. Protein acetylation and deacetylation: An important regulatory modification in gene transcription (Review). Exp. Ther. Med. (2020). doi:10.3892/etm.2020.9073