Beyond the pol II CTD: the expanding roles of the pol II CTD modification enzymes (360G-Wellcome-210641_Z_18_Z)

The multiple Tyr1Ser2Pro3Thr4Ser5Pro6Ser7 repeats within the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II (pol II) undergo reversible phosphorylation during transcription of human protein-coding genes1. The pattern of CTD phosphorylation is controlled by CTD kinases and phosphatases through the transcription cycle, which ensures the sequential recruitment of transcription and RNA processing factors required for correct gene expression. It is now becoming clear that the CTD modification enzymes have multiple additional targets that may play key roles in transcription, RNA processing and even translation. The exact roles that these kinases and phosphatases play in the cell is therefore not yet well understood. The aim of the proposed research is to understand the precise role(s) that CTD kinases and phosphatases play in transcription and downstream processes through modification of the CTD and other factors, what molecular mechanisms are involved and how their activities are co-ordinated. Towards this goal, I will use state of the art technology to determine the direct effect of loss of CTD kinase or CTD phosphatase activity, identify the targets of the CTD kinases and phosphatases and characterize the molecular interactions underlying the functions of CTD kinases and phosphatases.