Insights into the Metabolic Regulation of Growth and Proliferation in Saccharomyces Cerevisiae
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Cells needs to gauge their capacity to grow based on nutrient availability, and adopt different metabolic strategies for optimal growth and survival. We have investigated the molecular mechanism of how growth decisions are made based on metabolic status and how metabolic enzymes are regulated by nutrient availability. In the first part of this study, we report that acetyl-CoA is the downstream metabolite of carbon sources that represents a critical metabolic signal for growth and proliferation. Upon entry into growth, intracellular acetyl-CoA levels increase substantially and consequently induce the Gcn5p/SAGA-catalyzed acetylation of histones at genes important vi for growth, thereby enabling their rapid transcription and commitment to growth. Acetyl-CoA functions as a carbon-source rheostat that signals the initiation of the cellular growth program by promoting the acetylation of histones specifically at growth genes. In the second part of the study, we report the dynamic modification of ribosome biogenesis transcription factor Ifh1p regulated by different metabolic cues. Ribosome biogenesis requires an enormous commitment of energy and resources in growing cells. We show that Ifh1p is dynamically acetylated and phosphorylated as a function of the growth state of cells. Ifh1p is acetylated at numerous sites in its N-terminal region by Gcn5p and deacetylated by NAD+-dependent deacetylases of the sirtuin family. Acetylation of Ifh1p is responsive to intracellular acetyl-CoA levels and serves to regulate the stability of Ifh1p. The phosphorylation of Ifh1p is mediated by Protein Kinase A and is dependent on TORC1 signaling. Instead of modulating overall rates of RP gene transcription or growth, these nutrient-responsive modifications of Ifh1p play a more prominent role in the regulation of cellular replicative lifespan. Finally, we report the different roles of acetyl-CoA synthetases Acs1p and Acs2p in yeast metabolism. While Acs2p is important for rapid growth in glucose medium, Acs1p has unique roles in more challenging growth conditions. It is important for yeast metabolic cycling and is recruited to foci structure near mitochondria that might be involved in shuttling acetyl-CoA into the mitochondria during hypoxia.