The yeast genome becomes unstable during stress, which often results in adaptive aneuploidy, allowing rapid activation of protective mechanisms that restore cellular homeostasis. In this study, we performed a genetic screen in Saccharomyces cerevisiae to identify genome adaptations that confer resistance to tunicamycin-induced endoplasmic reticulum (ER) stress. Whole-genome sequencing of tunicamycin-resistant mutants revealed that ER stress resistance correlated significantly with gains of chromosomes II and XIII. We found that chromosome duplications allow adaptation of yeast cells to ER stress independently of the unfolded protein response, and that the gain of an extra copy of chromosome II alone is sufficient to induce protection from tunicamycin. Moreover, the protective effect of disomic chromosomes can be recapitulated by overexpression of several genes located on chromosome II. Among these genes, overexpression of UDP-N-acetylglucosamine-1-P transferase (ALG7), a subunit of the 20S proteasome (PRE7), and YBR085C-A induced tunicamycin resistance in wild-type cells, whereas deletion of all three genes completely reversed the tunicamycin-resistance phenotype. Together, our data demonstrate that aneuploidy plays a critical role in adaptation to ER stress by increasing the copy number of ER stress protective genes. While aneuploidy itself leads to proteotoxic stress, the gene-specific effects of chromosome II aneuploidy counteract the negative effect resulting in improved protein folding.

酵母基因组在应激过程中变得不稳定，这通常会导致适应性非整倍性，从而允许快速激活恢复细胞稳态的保护机制。在这项研究中，我们对酿酒酵母进行了遗传筛选，以确定能够抵抗衣霉素诱导的内质网（ER）应激的基因组适应性。衣霉素抗性突变体的全基因组测序表明，内质网应激抗性与 II 号和 XIII 号染色体的获得显着相关。我们发现，染色体复制允许酵母细胞适应内质网应激，而与未折叠的蛋白质反应无关，并且仅获得额外的 II 号染色体拷贝就足以诱导免受衣霉素的保护。此外，二体染色体的保护作用可以通过位于 II 号染色体上的几个基因的过度表达来概括。在这些基因中，UDP- N-乙酰葡糖胺-1-P转移酶（ALG7）、20S蛋白酶体（PRE7）的亚基和YBR085C-A的过表达会诱导野生型细胞对衣霉素耐药，而所有三个基因的完全缺失逆转衣霉素耐药表型。总之，我们的数据表明，非整倍体通过增加内质网应激保护基因的拷贝数，在适应内质网应激方面发挥着关键作用。虽然非整倍性本身会导致蛋白质毒性应激，但 II 号染色体非整倍性的基因特异性效应抵消了导致蛋白质折叠改善的负面影响。