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在细胞生长和发育的控制中具有显着特征的两个过程。与它们在维持细胞稳态中的关键作用相一致，转录和泛素介导的蛋白质破坏的失调是包括癌症在内的多种人类疾病的核心。乍一看，这两个过程显然没有什么共同之处——转录是任何蛋白质生命的第一步；转录是蛋白质生命的第一步。蛋白水解是最后一个。然而，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渴望探索的先前未预料到的转录控制水平。该提案定义了一项研究策略，以研究泛素依赖性过程如何调节转录调控中三个关键参与者（转录激活剂、RNA 聚合酶和组蛋白）的活性。这些研究将得到对蛋白酶体成分在基因激活中作用的高度整合分析的补充。为了实现这一目标，我们将使用模型生物酿酒酵母结合遗传和生化方法。我们将研究原型酵母激活剂 Gal4 的泛素化如何将转录激活与共转录前信使 RNA 加工所需的事件联系起来。我们将研究 RNA 聚合酶 II 最大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 的泛素化如何调节组蛋白动力学以及染色质与核环境的相互作用。最后，我们将研究蛋白酶体亚基如何被招募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如何交叉提供有价值的见解，并将作为我们理解转录控制这一新维度的范例。重要的是，我们的工作还将提供一个知识框架来理解这些过程如何导致人类疾病，并提供通过调节泛素系统的活性来识别调节异常转录的方法的潜力；这一策略很可能成为改进癌症治疗的基础。