Transcription Control by the Ubiquitin-Proteasome System

泛素-蛋白酶体系统的转录控制

• 批准号: 7413741
• 负责人: William Patrick Tansey
• 金额: $ 37.8万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7413741
• 关键词: ATP phosphohydrolase; Animal Model; Binding; Biochemical Genetics; Blushing; Chromatin; Chromatin Structure; Complement; DNA-Directed RNA Polymerase; Dimensions; Environment; Event; Foundations; Funding; Future; Gene Activation; Gene Expression Regulation; Gene Silencing; Genes; Genetic Transcription; Growth and Development function; Heart; Heterogeneous Nuclear RNA; Histone H2B; Histone H3; Histones; Homeostasis; Life; Ligase; Link; Lysine; Malignant Neoplasms; Mediating; Methylation; Mono-S; Nature; Nuclear; Nuclear Envelope; Numbers; Play; Polymerase; Process; Proteins; Proteolysis; RNA Polymerase II; RNA Processing; RNA polymerase II largest subunit; Recruitment Activity; Research; Role; Saccharomyces cerevisiae; System; Transcription Coactivator; Transcriptional Activation; Transcriptional Regulation; Ubiquitin; Ubiquitin-mediated Proteolysis Pathway; Work; Yeasts; base; cancer therapy; cell growth; density; human disease; improved; insight; mRNA Precursor; multicatalytic endopeptidase complex; novel; ubiquitin ligase

DESCRIPTION (provided by applicant): Transcriptional regulation and ubiquitin-mediated proteolysis are two processes that feature prominently in the control of cell growth and development. Consistent with their pivotal roles in maintaining cellular homeostasis, deregulation of both transcription and ubiquitin-mediated protein destruction lies at the heart of a variety of human diseases, including cancer. At first blush, these two processes have apparently very little in common-transcription is the first step in the life of any protein; proteolysis is the last. Despite the disparate nature of these processes, however, a growing body of evidence suggests that components of the ubiquitin-proteasome system are directly involved in the regulation of gene expression. The connection of these processes reveals a previously unanticipated level of transcriptional control that we are anxious to explore. This proposal defines a research strategy to investigate how ubiquitin-dependent processes regulate the activity of three key players in transcriptional regulation-transcriptional activators, RNA polymerase, and histones. These studies will be complemented with a highly-integrated analysis of the role of proteasome components in gene activation. To achieve this objective, we will employ a combination of genetic and biochemical approaches using the model organism Saccharomyces cerevisiae. We will study how ubiquitylation of the prototypical yeast activator Gal4 connects transcriptional activation to events required for co-transcriptional pre-messenger RNA processing. We will investigate how ubiquitylation of the largest subunit of RNA polymerase II regulates polymerase activity and subunit composition, and how ubiquitylation of histone H2B modulates histone dynamics and interaction of chromatin with the nuclear environment. And, finally, we will study how proteasome subunits are recruited to chromatin and their function in both gene activation and transcriptional silencing. Results of these studies will provide valuable insight into how transcription and the ubiquitin-proteasome systems intersect, and will serve as a paradigm for our understanding of this new dimension in transcriptional control. Importantly, our work will also provide an intellectual framework for understanding how these processes contribute to human disease, and offers the potential to identify ways to regulate aberrant transcription by modulating the activity of the ubiquitin system; a strategy that could very-well form the basis of improved cancer therapies.

描述（由申请人提供）：转录调节和泛素介导的蛋白水解是两个过程，在控制细胞生长和发育方面具有突出的特征。与它们在维持细胞稳态中的关键作用一致，转录和泛素介导的蛋白质破坏的放松管制是包括癌症在内的多种人类疾病的核心。乍一看，这两个过程显然几乎没有公共转录是任何蛋白质生命的第一步。蛋白水解是最后一个。尽管这些过程的性质不同，但越来越多的证据表明，泛素 - 蛋白酶体系统的组成部分直接参与基因表达的调节。这些过程的联系揭示了我们急于探索的先前意外的转录控制水平。该提案定义了一种研究策略，以研究泛素依赖性过程如何调节转录调节转录 - 转录激活剂RNA聚合酶和组蛋白的三个主要参与者的活性。这些研究将通过对蛋白酶体在基因激活中的作用的高度集成分析进行补充。为了实现这一目标，我们将使用模型有机体酿酒酵母采用遗传和生化方法的结合。我们将研究原型酵母活化剂GAL4的泛素化如何将转录激活与共转录预读预选前RNA处理所需的事件联系起来。我们将研究最大的RNA聚合酶II亚基的泛素化如何调节聚合酶活性和亚基组成，以及组蛋白H2B的泛素化如何调节染色质与核环境的组蛋白的相互作用和相互作用。最后，我们将研究如何将蛋白酶体亚基募集到染色质及其在基因激活和转录沉默中的功能。这些研究的结果将为转录和泛素 - 蛋白酶体系统相交的方式提供宝贵的见解，并将作为我们对转录控制中这一新维度的理解的范式。重要的是，我们的工作还将提供一个智力框架，以了解这些过程如何促进人类疾病，并通过调节泛素系统的活动来确定调节异常转录的潜力；一种可能非常孔的策略构成了改善癌症疗法的基础。