Protein Acetylation

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Pathway Description:

Protein acetylation plays a crucial role in regulating chromatin structure and transcriptional activity. Many transcriptional coactivators possess intrinsic acetylase activity, while transcriptional corepressors are associated with deacetylase activity. Acetylation complexes (such as CBP/p300 and PCAF) or deacetylation complexes (such as Sin3, NuRD, NcoR and SMRT) are recruited to DNA-bound transcription factors (TFs) in response to signaling pathways. Histone hyperacetylation by histone acetyltransferases (HATs, also called KATs for lysine acetyltransferases) is associated with transcriptional activation, whereas histone deacetylation by histone deacetylases (HDACs or KDACs) is associated with transcriptional repression. Histone acetylation stimulates transcription by remodeling higher order chromatin structure, weakening histone-DNA interactions, and providing binding sites for transcriptional activation complexes containing proteins that possess bromodomains, which bind acetylated lysine. Histone deacetylation represses transcription through an inverse mechanism involving the assembly of compact higher order chromatin and the exclusion of bromodomain-containing transcription activation complexes. Histone hypoacetylation is a hallmark of silent heterochromatin. Site-specific acetylation of a growing number of non-histone proteins, including p53 and E2F, has been shown to regulate their activity, localization, specific interactions as well as stability/degradation, therefore controlling a variety of cellular processes, such as transcription, proliferation, apoptosis and differentiation. It is becoming clear that crosstalk between acetylation and other modifications, such as methylation and phosphorylation in histone and non-histone proteins, plays a critical role in the final output signals. Some modifications are required in a combinatorial order to exert an effect, while others are mutually exclusive. In this context, the different putative combinations likely work to diversify cellular signaling networks, providing a much broader way to modulate responses. At an organismal level, acetylation plays an important role in immunity, circadian rhythm and memory formation. Protein acetylation is becoming a favorable target in drug design for numerous disease conditions. However, most of the available activators and inhibitors are as yet broad and non-specific. Recent studies have provided detailed analysis on the function and structure of the different KATs and KDACs, therefore we could expect the development of better and more specific modulators in the near future.

Selected Reviews:

• Cunliffe VT (2008) Eloquent silence: developmental functions of Class I histone deacetylases. Curr. Opin. Genet. Dev. 18(5), 404–10.
• Dali-Youcef N, Lagouge M, Froelich S, Koehl C, Schoonjans K, Auwerx J (2007) Sirtuins: the 'magnificent seven', function, metabolism and longevity. Ann. Med. 39(5), 335–45.
• Guarente L (2007) Sirtuins in aging and disease. Cold Spring Harb. Symp. Quant. Biol. 72, 483–8.
• Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat. Rev. Genet. 10(1), 32–42.
• Mostoslavsky R (2008) DNA repair, insulin signaling and sirtuins: at the crossroads between cancer and aging. Front. Biosci. 13, 6966–90.
• Olsson A, Manzl C, Strasser A, Villunger A (2007) How important are post-translational modifications in p53 for selectivity in target-gene transcription and tumour suppression? Cell Death Differ. 14(9), 1561–75.
• Spange S, Wagner T, Heinzel T, Krämer OH (2009) Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int. J. Biochem. Cell Biol. 41(1), 185–98.
• Tyteca S, Legube G, Trouche D (2006) To die or not to die: a HAT trick. Mol. Cell 24(6), 807–8.
• Yang XJ, Seto E (2007) HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26(37), 5310–8.
• Yang XJ, Seto E (2008) Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol. Cell 31(4), 449–61.