Understanding the role of phosphorylation in RNA polymerase II transcription

了解磷酸化在 RNA 聚合酶 II 转录中的作用

• 批准号: BB/Y004590/1
• 负责人: Lidia Vasilieva
• 金额: $ 70.44万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY004590%2F1
• 关键词: Understanding; role; phosphorylation; RNA; polymerase

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.

细胞必须将 DNA 编码的信息转化为编码蛋白质的信使 mRNA，这是通过一种称为 RNA 聚合酶 II (Pol II) 的酶的作用来实现的。这个过程称为转录。 Pol II 转录的调节对于细胞功能至关重要。尽管人们付出了很多努力来了解转录是如何启动的，但对转录延伸和终止调节所涉及的机制却知之甚少。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，在人类疾病中，未能调节 Pol II 延伸的速度和及时终止会导致由于个体基因的异常表达而导致发病机制。我们最近发现，从修饰蛋白中去除磷酸基团的蛋白磷酸酶在调节 Pol II 延伸速度和促进 Pol II 转录终止方面发挥着核心作用。该项目旨在通过确定本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，来发现控制 Pol II 转录中磷酸酶调节和功能的基本机制。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开发，提高靶向特异性，并揭示转录失调如何导致疾病和衰老。