Understanding the role of phosphorylation in RNA polymerase II transcription

细胞必须将DNA编码的信息转化为蛋白质编码信使mRNA，这是通过一种叫做RNA聚合酶II （Pol II）的酶的作用来实现的。这个过程被称为转录。调控Pol II转录是细胞功能的核心。虽然很多努力都致力于了解转录是如何启动的，但调控转录延伸和终止的机制却知之甚少。这代表了我们对生物学理解的根本差距，阻碍了人类疾病治疗方法的有效开发，其中由于个体基因的异常表达，无法调节Pol II延伸速度和及时终止导致发病机制。我们最近发现，从修饰蛋白中去除磷酸基团的蛋白质磷酸酶在调节Pol II延伸速度和促进Pol II转录终止中起着核心作用。该项目旨在通过确定自身缺乏特异性的磷酸酶如何靶向并激活转录因子和Pol II的去磷酸化，从而发现控制Pol II转录中磷酸酶调控和功能的基本机制。这项工作产生的机制见解将揭示控制基因调控的普遍原理，指导未来治疗方法的发展，提高靶向性，并告知转录失调如何导致疾病和衰老。

Cells must convert information encoded in DNA into protein-coding messenger mRNA, which is achieved through the action of an enzyme called RNA polymerase II (Pol II). This process is called transcription. Regulation of Pol II transcription is central to cellular function. While a lot of efforts have been dedicated to understanding how transcription is initiated, mechanisms involved in regulating of transcription elongation and termination are poorly understood. This represents a fundamental gap in our understanding of biology, preventing efficient development of therapeutic approaches for human diseases where failure to regulate speed of Pol II elongation and timely termination results in pathogenesis due to abnormal expression of individual genes. We have recently discovered that protein phosphatases enzymes that remove phosphate group from modified proteins, play a central role in regulating Pol II elongation speed and promoting termination of Pol II transcription. This project aims to discover fundamental mechanisms that control regulation and function of the phosphatases in Pol II transcription by determining how phosphatases that on their own lack specificity are targeted to and activated for dephosphorylation of the transcription factors and Pol II. The mechanistic insights generated by this work will uncover universal principles that control gene regulation, guide development of future therapeutic approaches with improved specificity of targeting and inform on how dysregulated transcription could lead to disease and aging.