Yeast Ess1, a Conserved PPlase Essential for Mitosis

描述(申请者摘要)：长期目标是了解如何 脯氨酰异构酶(PPIase)控制着重要的细胞过程，如 转录和有丝分裂。这些酶催化顺式/反式异构化。 指在环状氨基酸之前的多肽键。这 构象变化被认为是蛋白质正确折叠的重要因素。 并控制他们的活动。PPIase存在于所有生物体中，并且是最好的 因为它们是免疫抑制和抗真菌药物的靶标而闻名。 然而，它们在细胞中的正常功能尚不清楚，因为大多数可能是 在它们各自的生物体中通过基因缺失而被移除而不被观察到 后果。然而，有一个例外，称为ESS1的PPIase是 在酿酒酵母中生长所需的。ESS1和它的人类 同源基因Pin 1与细胞周期调控有关。最近的发现表明 ESS1与羧基末端在物理上和基因上相互作用 RNA聚合酶II的结构域(CTD)，提示在细胞转录中发挥作用 周期基因。这项研究将利用Ess1的基本性质 以及酵母遗传学解释Ess1途径的能力。主要关注点 将理解ESSI在转录中的作用。具体地说，目标是 是：(1)定义ESS1基因和下列基因之间的遗传相互作用 已知对转录很重要，(2)发现其基因 转录依赖于Ess1，并通过它控制细胞周期进程 有丝分裂，(3)结合酵母遗传学和生物化学的应用来研究 Ess1如何绑定CTD，目标是确定Ess1如何控制RNA 聚合酶II的功能，最后，(4)检查Ess1对 致病真菌的毒性，最终目标是开发抗真菌药物 抑制Ess1功能的药物。

DESCRIPTION (APPLICANT'S ABSTRACT): The long-term goal is to understand how prolyl-isomerases (PPIases) control important cellular processes such as transcription and mitosis. These enzymes catalyze the cis/trans isomerization of the peptide bond that precedes the cyclic amino acid proline. This conformational change is thought to be important for proper folding of proteins and control of their activity. PPIases are found in all organisms, and are best known because they are the targets of immunosuppressive and antifungal drugs. However, their normal function in cells is not understood, since most can be removed by gene deletion in their respective organism without observable consequences. There is one exception, however, a PPIase called Ess 1 that is required for growth in the yeast, Saccharomyces cerevisiae. Ess 1 and its human homolog, Pin 1, are implicated in cell cycle confrol. Recent discoveries show that Ess 1 interacts physically and genetically with the carboxy-terminal domain (CTD) of RNA polymerase II, suggesting a role in transcription of cell cycle genes. This study will take advantage of the essential nature of Ess 1 and the power of yeast genetics to elucidate the Ess1 pathway. The main focus will be to understand the role of Essi in transcription. Specifically, the aims are: (1) to define genetic interactions between the ESS1 gene and genes that are known to be important for transcription, (2) to discover genes whose transcription depends on Ess1 and that control cell cycle progression through mitosis, (3) to combine the use of yeast genetics with biochemistry to study how Ess1 binds the CTD, with the goal of determining how Ess1 controls RNA polymerase II function, and finally, (4) to examine the importance of Ess1 for virulence in pathogenic fungi, with the eventual goal of developing antifungal drugs that inhibit Ess1 function.