Lysine Deacetylase (KDAC) Regulatory Pathways: an Alternative Approach to Selective Modulation

Abstract

Protein lysine deacetylases (KDACs), including the classic Zn2+-dependent histone deacetylases (HDACs) and the nicotinamide adenine dinucleotide (NAD+)-requiring sirtuins, are enzymes that play critical roles in numerous biological processes, particularly the epigenetic regulation of global gene expression programs in response to internal and external cues. Dysregulation of KDACs is characteristic of several human diseases, including chronic metabolic, neurodegenerative, and cardiovascular diseases and many cancers. This has led to the development of KDAC modulators, two of which (HDAC inhibitors vorinostat and romidepsin) have been approved for the treatment of cutaneous Tcell lymphoma. By their nature, existing KDAC modulators are relatively nonspecific, leading to pan-KDAC changes and undesired side effects. Given that KDACs are regulated at many levels, including transcriptional, posttranslational, subcellular localization, and through their complexation with other proteins, it should be possible to affect specific KDAC activity through manipulation of endogenous signaling pathways. In this Minireview, we discuss our present knowledge of the cellular controls of KDAC activity and examples of their pharmacologic regulation.

Reconstitution of Mammalian Enzymatic Deacylation Reactions in Live Bacteria Using Native Acylated Substrates

“…Specifically, we considered Lys9-acetylated histone 3 (H3 AcK9)- and Lys310-acetylated RelA (RelA AcK310)-derived peptides, with the acetylated proteins being known substrates of several KDACs. 7 , 41 − 44 Indeed, acetylation plays an important role in the regulation of these proteins. Histone 3 K9-acetylation is recognized as a major epigenetic PTM that has been linked to various cellular processes and diseases, such as telomere maintenance, neural differentiation, and nonalcoholic fatty liver disease, among others.…”

Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1

“…Autocatalytic modifications of proteins are common and have been primarily described for kinases (30), acetyltransferases (31), and also for phosphatases (32) but not for deacetylases. An involvement of acetylation/deacetylation in the regulation of enzymatic activity of this class of proteins has mostly remained enigmatic, although acetylation of several protein deacetylases has been reported previously (33). So far, the only example for a regulatory acetylation of a protein deacetylase is the inhibition of HDAC6 tubulin deacetylase activity by p300-mediated acetylation but the reversibility of this modification was not studied (34).…”

The multifaceted influence of histone deacetylases on DNA damage signalling and DNA repair

“…Lysine deacetylases either depend on Zn 2+ , such as class I histone deacetylases (HDACs), comprising HDAC1, 2, 3 and 8, class IIA, comprising HDAC4, 5, 7 and 9, class IIB, comprising HDAC6 and 10 and the class IV enzyme HDAC11, or they depend on NAD + , a characteristic of the class III sirtuin like deacetylases SIRT1-7 (1). They remove acetyl-marks from lysines of histones and non-histone proteins and thereby contribute to widely diverse biological processes such as epigenetic regulation of gene expression, protein stability, enzyme and transcription factor activity and protein–protein interactions (1). Due to the numeral targets of these lysine deacetylases, they have been shown to play roles in apoptosis (2), differentiation (3) and DNA repair (4), to name a few.…”

“…The role of nuclear SIRTs in regulating BER via TDG substrate specificity and APE1 and WRN enzymatic activity is telling as these deacetylases are NAD + dependent (1). As stated, the activation of PARP1 during BER leads to the depletion of NAD + due to the PARylation at the sites of damage.…”