Coupling of Protein Synthesis with Cell Division

蛋白质合成决定着细胞是否分裂、分裂的速度以及分裂的次数。然而，蛋白质合成是如何 与细胞分裂的分子联系尚不清楚。我们将使用发芽酵母作为模型系统来回答 这一问题是因为酵母具有适合于遗传和生化研究的独特性质。在 上一期，我们确定了参与蛋白质合成机制的转录本， 核糖体，在翻译的过程中，在同步分裂的细胞中维持着生理的 蛋白质合成与它们的分裂的耦合。我们将利用这些发现来解决长期- 细胞分裂所需蛋白质合成的长期问题。在目标1中，我们将确定如何 翻译调控脂肪生成对核形态的影响。我们建议进行实验来测试 脂类合成的翻译控制与脂转移蛋白一起影响特定部位的观点 控制细胞周期中细胞核的形态。我们还将测量 在细胞分裂过程中，细胞核内脂质水平的变化。在目标2中，我们将确定 一碳代谢途径在细胞周期中改变，并对翻译控制做出反应。我们的数据 指出酶在以叶酸为基础的一碳代谢中的关键作用。我们会 确定蛋白质合成如何控制一碳代谢酶的表达。我们会 还要测量一碳代谢途径的不同代谢物输入和输出如何 在细胞周期的不同时间点分配。总体而言，我们提出的研究将揭示 细胞生长、蛋白质合成和细胞分裂之间的联系，使新的治疗干预成为可能 增殖性疾病。

Protein synthesis governs if, how fast, and how many times cells divide. Yet how protein synthesis is linked molecularly with cell division is unknown. We will use budding yeast as a model system to answer this problem because yeast has unique properties suited for genetic and biochemical studies. In the previous period, we identified transcripts that engage with the protein synthesis machinery, the ribosomes, in the process of translation in synchronously dividing cells that maintained the physiological coupling of protein synthesis with their division. We will leverage these findings to tackle the long- standing problem of protein synthesis requirements for cell division. In Aim 1, we will identify how translational control of lipogenesis impinges on nuclear morphology. We propose experiments to test the idea that translational control of lipid synthesis, together with lipid-transfer proteins, impact specific parts of lipid metabolism, to control the morphology of the nucleus in the cell cycle. We will also measure the changing levels of lipids in the nucleus during cell division. In Aim 2, we will determine how outputs of one-carbon metabolic pathways change in the cell cycle and respond to translational control. Our data point to the critical roles of enzymes that are part of the folate-based, one-carbon metabolism. We will identify how protein synthesis controls the expression of enzymes of one-carbon metabolism. We will also measure how the different metabolite inputs and outputs of one-carbon metabolic pathways are allocated at distinct points in the cell cycle. Overall, the research we propose will reveal fundamental links between cell growth, protein synthesis, and cell division, enabling novel therapeutic interventions in proliferative diseases.