Understanding the role of phosphorylation in RNA polymerase II transcription

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.