在人类非整倍性细胞中抵消转录负担和蛋白质毒性应激需要增加的RNA和蛋白质降解。
Increased RNA and Protein Degradation Is Required for Counteracting Transcriptional Burden and Proteotoxic Stress in Human Aneuploid Cells
影响因子:33.30000
分区:医学1区 Top / 肿瘤学1区
发表日期:2024 Dec 02
作者:
Marica Rosaria Ippolito, Johanna Zerbib, Yonatan Eliezer, Eli Reuveni, Sonia Viganò, Giuseppina De Feudis, Eldad D Shulman, Anouk Savir Kadmon, Rachel Slutsky, Tiangen Chang, Emma M Campagnolo, Silvia Taglietti, Simone Scorzoni, Sara Gianotti, Sara Martin, Julia Muenzner, Michael Mülleder, Nir Rozenblum, Carmela Rubolino, Tal Ben-Yishay, Kathrin Laue, Yael Cohen-Sharir, Ilaria Vigorito, Francesco Nicassio, Eytan Ruppin, Markus Ralser, Francisca Vazquez, Stefano Santaguida, Uri Ben-David
摘要
非整倍性导致蛋白质复合物的化学计量失衡，从而危及细胞适应性。因此，非整倍体细胞需要通过调节其RNA和蛋白质水平来补偿DNA水平不平衡的水平，但是潜在的分子机制仍然未知。在这项研究中，我们解剖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降解的扰动更为敏感。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，从而使它们对蛋白酶体抑制更加敏感。在数百种人类癌细胞系和原发性肿瘤中概括了这些发现，非整倍性水平与多发性骨髓瘤对蛋白酶体抑制剂的患者的反应显着相关。因此，非整倍体细胞优先取决于基因表达过程中的几个关键淋巴结，从而在非整倍体细胞中产生临床可行的脆弱性。意义：非整倍性是癌症的标志，与预后不良和药物反应较差有关。我们揭示了含有额外染色体的细胞通过改变其RNA和蛋白质代谢来补偿其不平衡的DNA含量，从而使它们对RNA和蛋白质降解的扰动更敏感。请参阅Bakhoum的相关评论，p。 2315。
Abstract
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. In this study, we dissected multiple diploid versus 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 patients with multiple myeloma 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. Significance: Aneuploidy is a hallmark of cancer that is associated with poor prognosis and worse drug response. We reveal that cells with extra chromosomes compensate for their imbalanced DNA content by altering their RNA and protein metabolism, rendering them more sensitive to perturbation of RNA and protein degradation. See related commentary by Bakhoum, p. 2315.