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The metabolite acetyl-coenzyme A (acetyl-CoA) serves as an essential element for a wide range of cellular functions including adenosine triphosphate (ATP) production, lipid synthesis, and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa histone deacetylases (HDACs). Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.

Citation

Ryan Houston, Shiori Sekine, Michael J Calderon, Fayaz Seifuddin, Guanghui Wang, Hiroyuki Kawagishi, Daniela A Malide, Yuesheng Li, Marjan Gucek, Mehdi Pirooznia, Alissa J Nelson, Matthew P Stokes, Jacob Stewart-Ornstein, Steven J Mullett, Stacy G Wendell, Simon C Watkins, Toren Finkel, Yusuke Sekine. Acetylation-mediated remodeling of the nucleolus regulates cellular acetyl-CoA responses. PLoS biology. 2020 Nov;18(11):e3000981

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PMID: 33253182

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