Reversible acetylation of HDAC8 regulates cell cycle.

HDAC8, a member of class I HDACs, plays a pivotal role in cell cycle regulation by deacetylating the cohesin subunit SMC3. While cyclins and CDKs are well-established cell cycle regulators, our knowledge of other regulators remains limited. Here we reveal the acetylation of K202 in HDAC8 as a key cell cycle regulator responsive to stress. K202 acetylation in HDAC8, primarily catalyzed by Tip60, restricts HDAC8 activity, leading to increased SMC3 acetylation and cell cycle arrest. Furthermore, cells expressing the mutant form of HDAC8 mimicking K202 acetylation display significant alterations in gene expression, potentially linked to changes in 3D genome structure, including enhanced chromatid loop interactions. K202 acetylation impairs cell cycle progression by disrupting the expression of cell cycle-related genes and sister chromatid cohesion, resulting in G2/M phase arrest. These findings indicate the reversible acetylation of HDAC8 as a cell cycle regulator, expanding our understanding of stress-responsive cell cycle dynamics. Synopsis: Reversible acetylation of HDAC8 regulates SMC3 acetylation during the cell cycle, thereby impacting three-dimensional genome architecture, gene expression, and sister chromatid cohesion. These findings identify HDAC8 acetylation as a regulator of cell cycle dynamics. Acetylation at lysine 202 of HDAC8 inhibits its enzymatic activity. The acetylation levels of HDAC8 fluctuate dynamically throughout the cell cycle and in response to external stress stimuli. Acetylation of HDAC8 modifies three-dimensional chromatin structure and promotes the formation of chromatin loops. Acetylation of HDAC8 results in defects in sister chromatid cohesion. Reversible acetylation of HDAC8 regulates SMC3 acetylation during the cell cycle, thereby impacting three-dimensional genome architecture, gene expression, and sister chromatid cohesion. These findings identify HDAC8 acetylation as a regulator of cell cycle dynamics. [ABSTRACT FROM AUTHOR]