Regulation of RNA Polymerase II transcription by the phosphatase Rtr1

磷酸酶 Rtr1 对 RNA 聚合酶 II 转录的调节

基本信息

批准号：
9532451
负责人：
AMBER L. MOSLEY
金额：
$ 9.8万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9532451
关键词：
Address Binding Binding Proteins C-terminal Cells Chromatin Chromatin Structure Code Complex Coupled Coupling DNA DNA Sequence Alteration Data Defect Disease Disease Progression Down-Regulation ENG gene Elongation Factor Event Excision Frequencies Gene Expression Genes Genetic Recombination Genetic Transcription Genome Stability Genomic Instability Goals Histone H3 Histones Human Hybrids Intercistronic Region Link Lysine Maintenance Malignant Neoplasms Mediating Messenger RNA Methylation Modification Pathogenesis Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Post-Translational Protein Processing Process Protein Binding Domain Protein Dephosphorylation Protein phosphatase Proteins Proteomics RNA RNA Polymerase II RNA Processing RNA polymerase II largest subunit Recruitment Activity Regulation Role Serine Site-Directed Mutagenesis Terminator Regions Testing Transcription Elongation Virus Diseases Work Yeasts cleavage factor combat genetic regulatory protein histone methyltransferase histone modification human disease in vitro Assay in vivo mRNA Precursor mRNA Stability nervous system disorder novel prevent protein complex restoration termination factor therapeutic target transcription termination

项目摘要

DESCRIPTION (provided by applicant): Proper regulation of RNA Polymerase II (RNAPII) transcription is required for proper gene expression levels and the maintenance of overall genome stability. The regulation of RNAPII is altered in the pathogenesis of many human diseases including cancer, neurological disorders, and viral infection. In order to combat changes in RNAPII transcription during the course of disease progression, the basic mechanisms that underlie the regulation of RNAPII must be understood. We have identified a novel regulator of RNAPII, an atypical protein phosphatase known as Rtr1 that is conserved from yeast to humans. We have shown that Rtr1 is required for dephosphorylation of a specific serine in a conserved domain in RNAPII known as the CTD. However, the mechanisms that require CTD dephosphorylation during transcription are not understood. In order to determine the precise role of Rtr1 during RNAPII transcription, we will focus on three specific questions: (1) Is Rtr1-dependent CTD dephosphorylation required for recruitment of the mRNA 3' end processing machinery? (2) Does Rtr1-dependent dephosphorylation stimulate the release of phospho-CTD binding proteins? and (3) Does Rtr1 regulate the phosphorylation status of other protein complexes involved in the regulation of RNAPII transcription elongation and termination? By addressing these key questions, we will increase our understanding of the fundamental process of RNAPII transcription which will allow us to define how defects in this process cause human disease.

描述（由申请人提供）：适当的基因表达水平和维持整体基因组稳定性需要对 RNA 聚合酶 II (RNAPII) 转录进行适当的调节。 RNAPII 的调节在许多人类疾病的发病机制中发生改变，包括癌症、神经系统疾病和病毒感染。为了对抗疾病进展过程中 RNAPII 转录的变化，必须了解 RNAPII 调节的基本机制。我们发现了一种新的 RNAPII 调节因子，这是一种被称为 Rtr1 的非典型蛋白磷酸酶，从酵母到人类都是保守的。我们已经证明，Rtr1 是 RNAPII 中称为 CTD 的保守结构域中特定丝氨酸去磷酸化所必需的。然而，转录过程中需要 CTD 去磷酸化的机制尚不清楚。为了确定 Rtr1 在 RNAPII 转录过程中的精确作用，我们将重点关注三个具体问题：（1）招募 mRNA 3' 末端加工机制是否需要 Rtr1 依赖性 CTD 去磷酸化？ (2) Rtr1 依赖性去磷酸化是否会刺激磷酸-CTD 结合蛋白的释放？ (3) Rtr1 是否调节参与 RNAPII 转录延伸和终止调节的其他蛋白复合物的磷酸化状态？通过解决这些关键问题，我们将加深对 RNAPII 转录基本过程的理解，这将使我们能够确定该过程中的缺陷如何导致人类疾病。