David H. Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.
Department of Genome Sciences, University of Washington, Seattle, WA 98195.
Proc Natl Acad Sci U S A. 2020 Jul 21;117(29):17031-17040. doi: 10.1073/pnas.2005648117. Epub 2020 Jul 6.
Aneuploidy, a condition characterized by whole chromosome gains and losses, is often associated with significant cellular stress and decreased fitness. However, how cells respond to the aneuploid state has remained controversial. In aneuploid budding yeast, two opposing gene-expression patterns have been reported: the "environmental stress response" (ESR) and the "common aneuploidy gene-expression" (CAGE) signature, in which many ESR genes are oppositely regulated. Here, we investigate this controversy. We show that the CAGE signature is not an aneuploidy-specific gene-expression signature but the result of normalizing the gene-expression profile of actively proliferating aneuploid cells to that of euploid cells grown into stationary phase. Because growth into stationary phase is among the strongest inducers of the ESR, the ESR in aneuploid cells was masked when stationary phase euploid cells were used for normalization in transcriptomic studies. When exponentially growing euploid cells are used in gene-expression comparisons with aneuploid cells, the CAGE signature is no longer evident in aneuploid cells. Instead, aneuploid cells exhibit the ESR. We further show that the ESR causes selective ribosome loss in aneuploid cells, providing an explanation for the decreased cellular density of aneuploid cells. We conclude that aneuploid budding yeast cells mount the ESR, rather than the CAGE signature, in response to aneuploidy-induced cellular stresses, resulting in selective ribosome loss. We propose that the ESR serves two purposes in aneuploid cells: protecting cells from aneuploidy-induced cellular stresses and preventing excessive cellular enlargement during slowed cell cycles by down-regulating translation capacity.
非整倍体，一种以整条染色体增益和缺失为特征的状态，通常与显著的细胞应激和适应性降低有关。然而，细胞如何应对非整倍体状态一直存在争议。在非整倍体出芽酵母中，已经报道了两种相反的基因表达模式：“环境应激反应”（ESR）和“常见非整倍体基因表达”（CAGE）特征，其中许多 ESR 基因受到相反的调控。在这里，我们研究了这个争议。我们表明，CAGE 特征不是非整倍体特异性的基因表达特征，而是将活跃增殖的非整倍体细胞的基因表达谱归一化为进入静止期的整倍体细胞的结果。由于进入静止期是 ESR 最强的诱导因素之一，因此在转录组研究中，当使用处于静止期的整倍体细胞进行归一化时，ESR 被掩盖了。当使用指数生长期的整倍体细胞与非整倍体细胞进行基因表达比较时，CAGE 特征在非整倍体细胞中不再明显。相反，非整倍体细胞表现出 ESR。我们进一步表明，ESR 导致非整倍体细胞中核糖体选择性丢失，这为非整倍体细胞密度降低提供了解释。我们得出结论，非整倍体出芽酵母细胞在应对非整倍体诱导的细胞应激时会引发 ESR，而不是 CAGE 特征，从而导致核糖体选择性丢失。我们提出，ESR 在非整倍体细胞中具有两个目的：保护细胞免受非整倍体诱导的细胞应激，并通过下调翻译能力来防止细胞周期减慢时细胞过度增大。
