Abstract
BackgroundThe unfolded protein response (UPR) is a eukaryotic signaling pathway, from the endoplasmic reticulum (ER) to the nucleus. Protein misfolding in the ER triggers the UPR. Accumulating evidence links the UPR in diverse aspects of cellular homeostasis. The UPR responds to the overall protein synthesis capacity and metabolic fluxes of the cell. Because the coupling of metabolism with cell division governs when cells start dividing, here we examined the role of UPR signaling in the timing of initiation of cell division and cell cycle progression, in the yeast Saccharomyces cerevisiae.Methodology/Principal FindingsWe report that cells lacking the ER-resident stress sensor Ire1p, which cannot trigger the UPR, nonetheless completed the G1/S transition on time. Furthermore, loss of UPR signaling neither affected the nutrient and growth rate dependence of the G1/S transition, nor the metabolic oscillations that yeast cells display in defined steady-state conditions. Remarkably, however, loss of UPR signaling led to hypersensitivity to genotoxic stress and a ten-fold increase in chromosome loss.Conclusions/SignificanceTaken together, our results strongly suggest that UPR signaling is not necessary for the normal coupling of metabolism with cell division, but it has a role in genome maintenance. These results add to previous work that linked the UPR with cytokinesis in yeast. UPR signaling is conserved in all eukaryotes, and it malfunctions in a variety of diseases, including cancer. Therefore, our findings may be relevant to other systems, including humans.
Highlights
In eukaryotes, proteins have to assume their native folding states, as they traffic through the endoplasmic reticulum (ER)
Conclusions/Significance: Taken together, our results strongly suggest that unfolded protein response (UPR) signaling is not necessary for the normal coupling of metabolism with cell division, but it has a role in genome maintenance
A role for the secretory pathway in cell division is almost selfevident in S. cerevisiae, since bud formation and cell surface growth depend on secretory processes
Summary
Proteins have to assume their native folding states, as they traffic through the endoplasmic reticulum (ER). Accumulation of unfolded proteins in the ER triggers the unfolded protein response (UPR). The UPR is triggered by acute stress, and by physiological situations, such as altered redox status, glucose limitation, or altered protein synthesis rates [4]. Yeast cells growing in nitrogen-rich media are not anabolically restricted, and protein synthesis outpaces protein folding in the ER resulting in the accumulation of unfolded polypeptides [5,6]. The unfolded protein response (UPR) is a eukaryotic signaling pathway, from the endoplasmic reticulum (ER) to the nucleus. Because the coupling of metabolism with cell division governs when cells start dividing, here we examined the role of UPR signaling in the timing of initiation of cell division and cell cycle progression, in the yeast Saccharomyces cerevisiae
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