The response to single-gene duplication implicates translation as a key vulnerability in aneuploid yeast.

IF 4 2区 生物学 Q1 GENETICS & HEREDITY
PLoS Genetics Pub Date : 2024-10-25 eCollection Date: 2024-10-01 DOI:10.1371/journal.pgen.1011454
H Auguste Dutcher, James Hose, Hollis Howe, Julie Rojas, Audrey P Gasch
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Abstract

Aneuploidy produces myriad consequences in health and disease, yet models of the deleterious effects of chromosome amplification are still widely debated. To distinguish the molecular determinants of aneuploidy stress, we measured the effects of duplicating individual genes in cells with different chromosome duplications, in wild-type cells (SSD1+) and cells sensitized to aneuploidy by deletion of RNA-binding protein Ssd1 (ssd1Δ). We identified gene duplications that are nearly neutral in wild-type euploid cells but significantly deleterious in euploids lacking SSD1 or in SSD1+ aneuploid cells with different chromosome duplications. Several of the most deleterious genes are linked to translation. In contrast, duplication of other genes benefits multiple ssd1Δ aneuploids over controls, and this group is enriched for translational effectors. Furthermore, both wild-type and especially ssd1Δ aneuploids with different chromosome amplifications show increased sensitivity to translational inhibitor nourseothricin. We used comparative modeling of aneuploid growth defects, based on the cumulative fitness costs measured for single-gene duplication. Our results present a model in which the deleterious effects of aneuploidy emerge from an interaction between the cumulative burden of many amplified genes on a chromosome and a subset of duplicated genes that become toxic in that context. These findings provide a perspective on the dual impact of individual genes and overall genomic burden, offering new avenues for understanding aneuploidy and its cellular consequences.

对单个基因复制的反应表明,翻译是非整倍体酵母的一个关键弱点。
非整倍体在健康和疾病中产生无数后果,但染色体扩增的有害影响模型仍存在广泛争议。为了区分非整倍体压力的分子决定因素,我们在野生型细胞(SSD1+)和因缺失 RNA 结合蛋白 Ssd1(ssd1Δ)而对非整倍体敏感的细胞中,测量了不同染色体重复的细胞中单个基因重复的影响。我们发现了在野生型非整倍体细胞中几乎是中性的基因重复,但在缺乏 SSD1 的非整倍体细胞或具有不同染色体重复的 SSD1+ 非整倍体细胞中却具有显著的有害性。其中几个最有害的基因与翻译有关。相反,与对照组相比,其他基因的重复对多个ssd1Δ非整倍体有益,而且这组基因富含翻译效应因子。此外,野生型特别是染色体扩增不同的ssd1Δ非整倍体对翻译抑制剂诺苏霉素的敏感性都有所提高。我们根据单基因重复测得的累积健康成本,建立了非整倍体生长缺陷的比较模型。我们的研究结果提出了一个模型,在这个模型中,非整倍体的有害影响来自染色体上许多扩增基因的累积负担与在此背景下变得有毒的重复基因亚群之间的相互作用。这些发现提供了一个视角来看待单个基因和整体基因组负担的双重影响,为理解非整倍体及其细胞后果提供了新的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Genetics
PLoS Genetics GENETICS & HEREDITY-
自引率
2.20%
发文量
438
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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