Regulation of RNA Polymerase II transcription by the phosphatase Rtr1

描述(由申请人提供)：对RNA聚合酶II(RNAPII)转录的适当调控是适当的基因表达水平和维持整体基因组稳定性所必需的。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调控的基本机制。我们已经确定了RNAPII的一个新的调节因子，RNAPII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中被称为CTD的保守结构域中特定丝氨酸去磷酸化所必需的。然而，在转录过程中需要CTD去磷酸化的机制还不清楚。为了确定Rtr1在RNAPII转录中的确切作用，我们将重点研究三个具体问题：(1)依赖Rtr1的CTD去磷酸化是否需要重新招募mRNA3‘端加工机制？(2)依赖Rtr1的去磷酸化是否刺激磷酸化-CTD结合蛋白的释放？以及(3)Rtr1是否调节与RNAPII转录延长和终止有关的其他蛋白质复合体的磷酸化状态？通过解决这些关键问题，我们将增加对RNAPII转录的基本过程的理解，这将使我们能够定义这一过程中的缺陷是如何导致人类疾病的。 公共卫生相关性：基因表达和基因组稳定性的变化是癌症等人类疾病的特征。在多种疾病状态下，由于RNAPII基因转录调控的改变而引起的基因表达和基因组稳定性的变化。我们的工作将确定在RNAPII转录过程中使用的新的调控机制，这些机制可以作为治疗人类疾病的靶点。

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. PUBLIC HEALTH RELEVANCE: Changes in gene expression and genome stability are hallmarks of human diseases such as cancer. In multiple disease states, changes in gene expression and genome stability and caused by altered regulation of RNAPII gene transcription. Our work will identify novel regulatory mechanisms that are employed during RNAPII transcription that could serve as therapeutic targets for the treatment of human disease.