Synthetic lethality between toxic amino acids, RTG-target genes and chaperones in Saccharomyces cerevisiae.

IF 2.2 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yeast Pub Date : 2024-09-01 Epub Date: 2024-07-30 DOI:10.1002/yea.3975
Marina E Druseikis, Shay Covo
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引用次数: 0

Abstract

The toxicity of non-proteinogenic amino acids has been known for decades. Numerous reports describe their antimicrobial/anticancer potential. However, these molecules are often toxic to the host as well; thus, a synthetic lethality approach that reduces the dose of these toxins while maintaining toxicity can be beneficial. Here we investigate synthetic lethality between toxic amino acids, the retrograde pathway, and molecular chaperones. In Saccharomyces cerevisiae, mitochondrial retrograde (RTG) pathway activation induces transcription of RTG-target genes to replenish alpha-ketoglutarate and its downstream product glutamate; both metabolites are required for arginine and lysine biosynthesis. We previously reported that tolerance of canavanine, a toxic arginine derivative, requires an intact RTG pathway, and low-dose canavanine exposure reduces the expression of RTG-target genes. Here we show that only a few of the examined chaperone mutants are sensitive to sublethal doses of canavanine. To predict synthetic lethality potential between RTG-target genes and chaperones, we measured the expression of RTG-target genes in canavanine-sensitive and canavanine-tolerant chaperone mutants. Most RTG-target genes were induced in all chaperone mutants starved for arginine; the same trend was not observed under lysine starvation. Canavanine exposure under arginine starvation attenuated and even reversed RTG-target-gene expression in the tested chaperone mutants. Importantly, under nearly all tested genetic and pharmacological conditions, the expression of IDH1 and/or IDH2 was induced. In agreement, idh1 and idh2 mutants are sensitive to canavanine and thialysine and show synthetic growth inhibition with chaperone mutants. Overall, we show that inhibiting molecular chaperones, RTG-target genes, or both can sensitize cells to low doses of toxic amino acids.

有毒氨基酸、RTG 目标基因和伴侣蛋白在酿酒酵母中的合成致死率。
非蛋白源氨基酸的毒性早已为人所知。许多报告都描述了它们的抗菌/抗癌潜力。然而,这些分子通常对宿主也有毒性;因此,在保持毒性的同时减少这些毒素剂量的合成致死方法可能是有益的。在这里,我们研究了有毒氨基酸、逆行途径和分子伴侣之间的合成致死率。在酿酒酵母(Saccharomyces cerevisiae)中,线粒体逆行(RTG)途径的激活会诱导 RTG 目标基因的转录,以补充α-酮戊二酸及其下游产物谷氨酸;精氨酸和赖氨酸的生物合成都需要这两种代谢物。我们以前曾报道,对毒性精氨酸衍生物卡那瓦宁的耐受性需要完整的 RTG 途径,低剂量卡那瓦宁暴露会降低 RTG 靶基因的表达。在这里,我们发现只有少数几个受检的伴侣突变体对亚致死剂量的卡那瓦宁敏感。为了预测 RTG 靶基因和伴侣蛋白之间的合成致死潜力,我们测量了对卡纳瓦宁敏感和对卡纳瓦宁耐受的伴侣蛋白突变体中 RTG 靶基因的表达。在精氨酸饥饿的所有伴侣蛋白突变体中,大多数 RTG 目标基因都被诱导;在赖氨酸饥饿的情况下,没有观察到相同的趋势。在精氨酸饥饿条件下,暴露于卡那凡宁可减轻甚至逆转受测伴侣突变体中 RTG 目标基因的表达。重要的是,在几乎所有测试的遗传和药理学条件下,IDH1 和/或 IDH2 的表达都被诱导。一致的是,idh1 和 idh2 突变体对卡纳瓦宁和硫柳碱敏感,并表现出与伴侣蛋白突变体的合成生长抑制。总之,我们的研究表明,抑制分子伴侣、RTG 目标基因或同时抑制这两种基因可使细胞对低剂量的有毒氨基酸敏感。
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
Yeast
Yeast 生物-生化与分子生物学
CiteScore
5.30
自引率
3.80%
发文量
55
审稿时长
3 months
期刊介绍: Yeast publishes original articles and reviews on the most significant developments of research with unicellular fungi, including innovative methods of broad applicability. It is essential reading for those wishing to keep up to date with this rapidly moving field of yeast biology. Topics covered include: biochemistry and molecular biology; biodiversity and taxonomy; biotechnology; cell and developmental biology; ecology and evolution; genetics and genomics; metabolism and physiology; pathobiology; synthetic and systems biology; tools and resources
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