MECHANISMS OF YEAST TRANSCRIPTIONAL REGULATORS

描述（改编自研究者摘要）： 这个建议是要从精确的分子角度来理解， 在S. Tup 1/Ssn 6阻遏物抑制酿酒酵母的表达 复杂. 该建议分为三个基本部分：（1） Tup 1/Ssn 6转录抑制机制的确定 以及鉴定进行该过程所需的其他蛋白质;（2） 以Tup 1/Ssn 6为实验系统，开发了一种通用的 用于理解两种常见蛋白质基序的模型，WD 40重复序列和TPR; 和（3）酵母中整个Tup 1/Ssn 6调控网络的描述， 包括所有利用Tup 1/Ssn 6的DNA结合蛋白， 由每个DNA结合蛋白控制的一整套基因。 该提案 还涵盖了实验室的一个新的研究方向，CHD 1的探索， 一种高度保守的酵母蛋白，可能在 染色质结构及其与转录的关系。 实验方法强调使用纯化的蛋白质， 生化实验来推断分子机制。 遗传方法 也被用来测试从生物化学中发展出来的模型。 研究和探索工具。 最后是DNA芯片和噬菌体展示 在具体情况下也利用技术。 鉴于基因调控蛋白的高度保守性， 在所有真核生物中，通用转录因子似乎很可能 本书所述的酵母蛋白质的许多原理， 建议将适用于其他设置。 基本了解 细胞特化背后的分子事件不仅提供了 框架来理解过程如何失败，但也提供了 基质和知识来设计治疗策略， 干预

DESCRIPTION (adapted from investigator's abstract): The long-term goal of this proposal is to understand, in precise molecular terms, how expression of a large set of genes in S. cerevisiae is repressed by Tup1/Ssn6 repressor complex. The proposal is divided into three basic parts: (1) the determination of the mechanism of transcriptional repression by Tup1/Ssn6 and the identification of additional proteins required to carry it out; (2) the development, using Tup1/Ssn6 as the experimental system, of a general model for understanding two common protein motifs, the WD40 repeat and TPR; and (3) a description of the entire Tup1/Ssn6 regulatory network in yeast, including all the DNA-binding proteins that utilize Tup1/Ssn6 and the complete set of genes controlled by each DNA-binding protein. The proposal also covers a new research direction in the lab, an exploration of CHD1, a highly conserved yeast protein that likely serves an important function in chromatin structure and its relation to transcription. The experimental approaches emphasize the use of purified proteins and biochemical experiments to deduce molecular mechanisms. Genetic approaches in yeast are also utilized to test models developed from the biochemical studies and as exploratory tools. Finally DNA chip and phage display technologies are also utilized in specific cases. Given the high degree of conservation of gene regulatory proteins and general transcription factors among all eucaryotes, it seems likely that many of the principles developed for the yeast proteins covered in this proposal will apply in other settings. A basic understanding of the molecular events underlying cell specialization provides not only a framework for understanding how the process can fail, but also provides the substrates and knowledge to design therapeutic strategies based on intervention.