Cellular quiescence in budding yeast

Abstract

Cellular quiescence, the temporary and reversible exit from proliferative growth, is the predominant state of all cells. However, our understanding of the biological processes and molecular mechanisms that underlie cell quiescence remains incomplete. As with the mitotic cell cycle, budding and fission yeast are preeminent model systems for studying cellular quiescence owing to their rich experimental toolboxes and the evolutionary conservation across eukaryotes of pathways and processes that control quiescence. Here, we review current knowledge of cell quiescence in budding yeast and how it pertains to cellular quiescence in other organisms, including multicellular animals. Quiescence entails large-scale remodeling of virtually every cellular process, organelle, gene expression, and metabolic state that is executed dynamically as cells undergo the initiation, maintenance, and exit from quiescence. We review these major transitions, our current understanding of their molecular bases, and highlight unresolved questions. We summarize the primary methods employed for quiescence studies in yeast and discuss their relative merits. Understanding cell quiescence has important consequences for human disease as quiescent single-celled microbes are notoriously difficult to kill and quiescent human cells play important roles in diseases such as cancer. We argue that research on cellular quiescence will be accelerated through the adoption of common criteria, and methods, for defining cell quiescence. An integrated approach to studying cell quiescence, and a focus on the behavior of individual cells, will yield new insights into the pathways and processes that underlie cell quiescence leading to a more complete understanding of the life cycle of cells. TAKE AWAY: Quiescent cells are viable cells that have reversibly exited the cell cycle Quiescence is induced in response to a variety of nutrient starvation signals Quiescence is executed dynamically through three phases: initiation, maintenance, and exit Quiescence entails large-scale remodeling of gene expression, organelles, and metabolism Single-cell approaches are required to address heterogeneity among quiescent cells.

Figure 1.. The mitotic cell cycle and quiescence.

Quiescent cells have exited the cell division cycle but maintain the capacity to resume growth and re-enter the mitotic cell in response to the appropriate signals. This reversible state is in contrast to terminally differentiated, or senescent cells, which cannot recommence the cell division cycle. In budding yeast, most quiescent cells exit the cell cycle in G1 and thus typically present as unbudded cells. However, in some cases yeast cells can initiate quiescence from other cell cycle stages.

Figure 2.. Alternative fates of haploid and diploid yeast cells in response to nutrient starvations.

S. cerevisiae can differentiate to form quiescent cells in haploid (1) or diploid (2) cells, or sporulate to form four haploid spores (3). Green and red represent the ploidy of cells.

Figure 3.. Contrasting properties of quiescent and proliferative cells.

Quiescent yeast cells are characterized by a combination of factors including altered cell morphology and remodeling of multiple cellular processes. Key features that distinguish proliferative and quiescent cells, with an indication of whether they are upregulated (up arrow) or downregulated (down arrow), are summarized.

Figure 4.. Conserved signaling pathways regulate cellular quiescence in budding yeast.

Different nutritional starvation signals (carbon, nitrogen, phosphorus) are sensed and transmitted via distinct signaling pathways. These pathways converge on regulation of the protein kinase, RIM15, which is considered the master regulator of quiescence. Regulation of protein homeostasis is a major downstream target of these pathways. Red arrow indicates global up-regulation and green arrow indicates an overall down-regulation.