HDAC5, a Key Component in Temporal Regulation of p53-Mediated Transactivation in Response to Genotoxic Stress

Abstract

Despite being one of the most well-studied transcription factors, the temporal regulation of p53-mediated transcription is not very well understood. Recent data suggest that target specificity of p53-mediated transactivation is achieved by posttranslational modifications of p53. K120 acetylation is a modification critical for recruitment of p53 to proapoptotic targets. Our data reveal that histone deacetylase 5 (HDAC5) binds to p53 and abrogates K120 acetylation, resulting in preferential recruitment of p53 to proarrest and antioxidant targets at early phases of stress. However, upon prolonged genotoxic stress, HDAC5 undergoes nuclear export. Concomitantly, p53 is acetylated at the K120 residue and selectively transactivates proapoptotic target genes, leading to onset of apoptosis. Furthermore, upon genotoxic stress in mice where HDAC5 expression is downregulated, the onset of apoptosis is accelerated in the highly vulnerable tissues. These findings suggest that HDAC5 is a key determinant of p53-mediated cell fate decisions in response to genotoxic stress.

Structural Basis for p53 Lys120-Acetylation-Dependent DNA-Binding Mode

“…Similar effect was found in a mouse knock-in model carrying the K117R mutation (analogous to K120 in human) [28]. The biochemical processes that regulate Lys120 acetylation-as well as deacetylationhave been studied by several groups [24,27,[29][30][31][32], but less is known about the molecular mechanism downstream of Lys120 acetylation and how this acetylation event directly affects the transcriptional activity of p53 and its interaction with the DNA.…”

Acetylation of p53 Protein at Lysine 120 Up-regulates Apaf-1 Protein and Sensitizes the Mitochondrial Apoptotic Pathway

“…Importantly, it is also possible that HDAC1 and HDAC5 might mediate distinct biological contexts to drive Lys-120 deacetylation of p53. Indeed, in a previous study that supports a dominant role of HDAC5 (38), a rather different stimulus (DNA damage) was used to trigger p53 activation.…”

Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma

“…12 Although 3600 acetylation sites at lysine residues have been identified on 1750 proteins in human cells, 13 and despite extensive searching to identify enzymatic substrates of class IIa HDACs, the substrates of class IIa HDACs have to date been identified primarily by overexpression experiments. [14][15][16] Specifically, recent studies show that class IIa HDACs have minimal enzymatic role compared with class I and class IIb 17 and mainly act as transcriptional suppressors of development and differentiation 18 by interacting with other proteins via nonenzymatic domains and/or recruiting other enzymatically active HDACs, such as HDAC3-NCoR/SMART. 19 In cancer cells, class IIa HDACs interact with transcriptional factors: HDAC4 with PLZFRARa in acute promyelocytic leukemia cells; 20 and HDAC4 with hypoxia-inducible factor-1α in renal carcinoma cells.…”