Genetic screen identifies adaptive aneuploidy as a key mediator of ER stress resistance in yeast

Significance In eukaryotes, about one-third of all proteins are folded in the endoplasmic reticulum (ER). When protein folding demand exceeds capacity of the ER, the unfolded protein response (UPR) is activated to counteract ER stress. However, the mechanisms of adaptation to ER stress are not restricted to the UPR. Here, we report that gain of chromosome II in yeast allows adaptation of cells to protein misfolding. We narrowed down the effect of chromosome II duplication to three genes, which promote ER stress resistance independently of the UPR. Overexpression of these genes was sufficient to protect cells from ER stress and led to the elimination of aneuploidy. Thus, aneuploidy can serve as an important genome adaptation protecting cells against ER stress.