非整倍性会导致蛋白质复合物化学计量失衡，从而危及细胞健康。因此，非整倍体细胞需要通过调节 RNA 和蛋白质水平来补偿不平衡的 DNA 水平，但潜在的分子机制仍然未知。在这里，我们剖析了多个二倍体与非整倍体细胞模型。我们发现非整倍体细胞通过增加几种 RNA 降解途径来应对转录负担，因此对 RNA 降解的扰动更加敏感。在蛋白质水平上，非整倍体细胞通过减少蛋白质翻译和增加蛋白质降解来减轻蛋白质毒性应激，使它们对蛋白酶体抑制更加敏感。这些发现在数百个人类癌细胞系和原发性肿瘤中得到了概括，非整倍性水平与多发性骨髓瘤患者对蛋白酶体抑制剂的反应显着相关。因此，非整倍体细胞优先依赖于基因表达过程中的几个关键节点，从而在非整倍体细胞中产生临床上可操作的漏洞。

Aneuploidy results in a stoichiometric imbalance of protein complexes that jeopardizes cellular fitness. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, but the underlying molecular mechanisms remain unknown. Here, we dissected multiple diploid vs. aneuploid cell models. We found that aneuploid cells cope with transcriptional burden by increasing several RNA degradation pathways, and are consequently more sensitive to the perturbation of RNA degradation. At the protein level, aneuploid cells mitigate proteotoxic stress by reducing protein translation and increasing protein degradation, rendering them more sensitive to proteasome inhibition. These findings were recapitulated across hundreds of human cancer cell lines and primary tumors, and aneuploidy levels were significantly associated with the response of multiple myeloma patients to proteasome inhibitors. Aneuploid cells are therefore preferentially dependent on several key nodes along the gene expression process, creating clinically-actionable vulnerabilities in aneuploid cells.