Regulating the regulators: the post-translational code of class I HDAC1 and HDAC2

Abstract

Class I histone deacetylases (HDACs) are cellular enzymes expressed in many tissues and play crucial roles in differentiation, proliferation, and cancer. HDAC1 and HDAC2 in particular are highly homologous proteins that show redundant or specific roles in different cell types or in response to different stimuli and signaling pathways. The molecular details of this dual regulation are largely unknown. HDAC1 and HDAC2 are not only protein modifiers, but are in turn regulated by post-translational modifications (PTMs): phosphorylation, acetylation, ubiquitination, SUMOylation, nitrosylation, and carbonylation. Some of these PTMs occur and crosstalk specifically on HDAC1 or HDAC2, creating a rational "code" for a differential, context-related regulation. The global comprehension of this PTM code is central for dissecting the role of single HDAC1 and HDAC2 in physiology and pathology.

Figure 1

Schematic representation of the PTMs spatial distribution of HDAC1 and HDAC2. (a) Organization of the functional domains of HDAC1 and HDAC2, as described in [43]. Numbers indicate the corresponding amino acidic (aa) positions. Percentages of identity were calculated by BLAST alignment of HDAC1 (CAG46518.1) and HDAC2 (AAH31055.2) protein sequences. (b) and (c) Visual comparison of the different PTMs occurring on HDAC1 and HDAC2 in the C-terminal (B) and central (C) domains. Different PTMs are illustrated by different colors and letters: P (yellow): phosphorylation, A (green): acetylation, U (blue): ubiquitination, S (red): SUMOylation, N (orange): nitrosylation, and C (lilac): carbonylation. The amino acidic sites of modification are indicated by the number of their position in the protein sequence: S: serine, K: lysine, Y: tyrosine, C: cysteine, and CBP: CBP histone acetyltransferase. When the precise position of a modified residue is not known, the amino acidic site is followed by an x. The question mark (?) is used when the precise amino acidic site has not been formally identified. The amino acids at the boundaries of the two domains are reported.

Figure 2

Schematic illustration of the crosstalk between different PTMs on HDAC2 in response to oxidative or nitric stress stimuli. Oxidative or nitric stimuli evoke a complex response in terms of PTMs on HDAC2 that results in a specific biological output [54, 55, 73, 74]. Different PTMs are illustrated by different colors and letters : P (yellow): phosphorylation, A (green): acetylation, U (blue): ubiquitination, and N (orange): nitrosylation. The modification enzymes, when known, are also reported: CKII: casein kinase II, and CBP: CBP histone acetyltransferase. When a mechanistic relation between two different PTMs events is not known, the question mark (?) has been used.