Aneuploidy-induced proteotoxic stress can be effectively tolerated without dosage compensation, genetic mutations or stress responses

The protein homeostasis (proteostasis) network maintains balanced protein synthesis, folding, transport and degradation within a cell. Because failure to maintain proteostasis is associated with aging and disease, a concerted effort has been placed on studying how the proteostasis network responds to various stresses. Typically, this is accomplished using ectopic overexpression of well-characterized, model misfolded protein substrates; however, how cells tolerate large-scale, diverse burden to the proteostasis network is not understood. Aneuploidy, the state of imbalanced chromosome content, adversely affects the proteostasis network by dysregulating the expression of hundreds of proteins simultaneously. Using aneuploid yeast cells as a model, we address what compensatory adjustments enable cells to tolerate large-scale, diverse challenges to the proteostasis network. Here we show adapted aneuploid Saccharomyces cerevisiae strains that exhibit robust growth and enhanced stress tolerance associated with enhancement of translation, folding, and quality control systems without genetic changes or activation of canonical stress response pathways.