Cell growth and quiescence in eukaryotic cells is controlled by an evolutionarily conserved network of signaling pathways. Signal transduction networks operate to modulate a wide range of cellular processes and physiological properties when cells exit proliferative growth and initiate a quiescent state. How signaling networks function to respond to diverse signals that result in cell cycle exit and establishment of a quiescent state is poorly understood. Here, we studied the function of signaling pathways in quiescent cells using global genetic interaction mapping in the model eukaryotic cell, Saccharomyces cerevisiae (budding yeast). We performed pooled analysis of genotypes using molecular barcode sequencing (Bar-seq) to test the role of ~4,000 gene deletion mutants and ~12,000 pairwise interactions between all non-essential genes and the protein kinase genes TOR1, RIM15, and PHO85 in three different nutrient-restricted conditions in both proliferative and quiescent cells. We detect up to 10-fold more genetic interactions in quiescent cells than proliferative cells. We find that both individual gene effects and genetic interaction profiles vary depending on the specific pro-quiescence signal. The master regulator of quiescence, RIM15, shows distinct genetic interaction profiles in response to different starvation signals. However, vacuole-related functions show consistent genetic interactions with RIM15 in response to different starvation signals, suggesting that RIM15 integrates diverse signals to maintain protein homeostasis in quiescent cells. Our study expands genome-wide genetic interaction profiling to additional conditions, and phenotypes, and highlights the conditional dependence of epistasis.

中文翻译：

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调节激酶的遗传相互作用谱在环境条件和细胞状态之间有所不同。


真核细胞中的细胞生长和静止是由进化上保守的信号通路网络控制的。当细胞退出增殖生长并启动静止状态时，信号转导网络可调节广泛的细胞过程和生理特性。人们对信号网络如何响应导致细胞周期退出和静止状态建立的各种信号的功能知之甚少。在这里，我们使用模型真核细胞酿酒酵母（芽殖酵母）中的全局遗传相互作用图谱研究了静止细胞中信号通路的功能。我们使用分子条形码测序 (Bar-seq) 对基因型进行了汇总分析，以测试约 4,000 个基因缺失突变体的作用以及所有非必需基因与蛋白激酶基因 TOR1、RIM15 和 PHO85 之间约 12,000 个成对相互作用在三个不同的细胞中的作用。增殖细胞和静止细胞的营养限制条件。我们在静止细胞中检测到的遗传相互作用比增殖细胞多 10 倍。我们发现个体基因效应和遗传相互作用谱都根据特定的促静止信号而变化。静止的主调节因子 RIM15 在响应不同的饥饿信号时表现出不同的遗传相互作用特征。然而，液泡相关功能显示出与 RIM15 响应不同饥饿信号时一致的遗传相互作用，表明 RIM15 整合了不同的信号以维持静止细胞中的蛋白质稳态。我们的研究将全基因组遗传相互作用分析扩展到其他条件和表型，并强调了上位性的条件依赖性。