Coordination of nutrient availability and ribosome biogenesis in Saccharomyces cerevisiae

All levels of organisms from bacteria to humans are driven to grow for the purpose of dividing and reproducing with the underlining goal of survival as a species. The fundamental challenge for the organisms is then to aptly assess their growth potential and adjust their growth rate based on the availability of nutrient sources. Rapid alteration of growth program is especially important to microorganisms, such as yeast, that naturally inhabit widely fluctuating nutritional environments. Cell growth is essentially the accumulation of mass. The syntheses of metabolites and macromolecules that provide the increase in biomass are performed by proteins, which in turn are synthesized by ribosomes via cellular processes that consume tremendous amount of cellular energy. Therefore, the cell's ability and decision to grow are intimately tied to the production of ribosomes, which together are tightly coordinated to nutrient availability. Not surprisingly, the cell utilizes complex, interlocking networks of signaling pathways to couple ribosome biosynthesis to nutrient status.;In Saccharomyces cerevisiae, glucose signaling is primarily transmitted by the Ras/PKA signaling pathway, and nitrogen signaling predominantly by the TORC1 signaling pathway. Either nutrient deprivation or inhibition of signaling pathways results in immediate and robust repression of genes required for ribosome biogenesis (Ribi) and genes encoding ribosomal proteins (RP). Although the enrichment of PAC and RRPE sequence elements in the promoters of Ribi genes have been identified, the transcription factors that communicate nutrient signals as relayed by upstream signaling pathways to regulate the expression of Ribi genes have remained unknown.;The recent discovery of three transcription factors---Dot6/Tod6 and Stb3---to bind PAC and RRPE motifs, respectively, finally made possible defining the signaling pathway from nutrient availability to ribosome biogenesis. By examining the role of Dot6 and Tod6 in nutrient control of Ribi gene expression in vivo, I show that PAC sites function as Dot6/Tod6 dependent repressor elements in vivo. Moreover, Dot6 and Tod6 mediate different nutrient signals, with Tod6 responsible for efficient repression of Ribi genes following inhibition of the nitrogen sensitive TORC1 pathway and Dot6 for repression following inhibition of the carbon sensitive PKA signaling pathway. Consistently, Dot6 and Tod6 are required for efficient repression of Ribi gene repression immediately following nutrient deprivation and for successful adaptation to nutrient limitation. Thus, these results establish Dot6/Tod6 as a direct link between nutrient availability, Ribi gene regulation and growth control.;Cells respond to fluctuating nutrient status by altering their transcriptional, metabolic and developmental programs. However, the causality in this response is unclear. I provide evidence here that the growth rate-specific transcriptional pattern is determined by what the cell perceives as its nutritional environment rather than the actual availability of nutrients or their metabolic products.