The International Journal of Biochemistry & Cell Biology
ReviewAcetylation of non-histone proteins modulates cellular signalling at multiple levels
Section snippets
Histone acetylation
Eukaryotic DNA, histones and histone-like proteins are assembled into nucleosomes. Histones, the main protein component of chromatin, not merely play a role in packaging DNA. The tails and the globular domains of histones can be modified by acetylation, phosphorylation, methylation, ubiquitination, sumoylation, and less commonly by citrullination and ADP-ribosylation. These posttranslational modifications can alter DNA-histone interactions or the binding of proteins, such as transcription
HDACs and SIRTs
HATs catalyse the transfer of an acetyl group from acetyl-CoA to the ɛ-NH2 group of the amino acid side chain of lysine residues. Acetylation of lysine residues at the ɛ-NH2 is highly dynamic. The first deacetylase activity was identified back in the 1960s (Inoue and Fujimoto, 1969), soon after the discovery of histone acetylation and its potential role in the regulation of gene expression (Allfrey et al., 1964, Phillips, 1963). Since histones were the first identified targets of deacetylases,
HATs
Since the discovery of the first HAT enzyme, the yeast Hat1 (Kleff et al., 1995), a lot of attention has been drawn to these enzymes. HATs are evolutionarily conserved from yeast to man and form multiple subunit complexes (Kimura et al., 2005). Unlike HDACs, HATs are more diverse in structure and function (Yang, 2004). In mammals, over 30 HATs display distinct substrate specificities for histones and non-histone proteins. HATs do not acetylate lysine moieties randomly. Crystal structure
Non-histone targets of HDACs and HATs—the acetylome
Lysine side chains can be acetylated, methylated (mono-, di- or trimethylation), ubiquitinated (mono- or polyubiquitination), sumoylated and ADP-ribosylated (Merrick and Duraisingh, 2007). These rivalling and reversible posttranslational modifications are regulated by a complex interplay of different enzymes. Reversible acetylation of lysine ɛ-amino groups crucially modulates protein function und cellular networks (Fig. 1). In eukaryotic cells, acetylation is among the most common covalent
Acetylation regulates multiple processes from gene expression to protein activity
Acetylation can affect signalling pathways and thereby alter cell fate and function. mRNA splicing, mRNA transport, mRNA integrity, translation, protein activity, protein localisation, protein stability and interactions are regulated by acetylation. Hence, acetylation can interfere with every step of regulatory processes from signalling to transcription to protein degradation.
Conclusion
Aberrant lysine acetylation has been reported in malignant cells (Yang, 2004), and HATs and HDACs are closely linked to severe diseases such as cancer, neurodegeneration, cardiovascular disorders, inflammatory lung diseases, as well as to ageing (Blander and Guarente, 2004, Carrozza et al., 2003, Heinzel and Krämer, 2007, Ito et al., 2007, McKinsey and Olson, 2004, Saha and Pahan, 2006). The previous view that HDACi modulate gene expression mainly by histone acetylation appears to be too
Acknowledgements
We apologise to authors whose research articles could not be cited due to space limitations. This work was supported by the Deutsche Forschungsgemeinschaft (DFG).
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