RNA polymerase II (Pol II) elongation control plays a major role in regulating transcription throughout development and differentiation of multi-cellular organisms. The process is characterized by the default action of negative elongation factors, including NELF and DSIF that halt transcription of initiated polymerases near promoters. These promoter-proximal paused polymerases are either released from the template by TTF2 or other termination factors or are allowed to enter productive elongation through the selective action of the positive elongation factor, P-TEFb. The cyclin dependent kinase activity of P-TEFb is regulated by reversible association with the 7SK snRNP mediated by HEXIM proteins. The main goal of this proposal is to further define the mechanisms utilized to control Pol II elongation and to enable efficient transcription through nucleosomes. We will use newly developed biochemical methods and global techniques to elucidate mechanisms enabling transcription through chromatin, the role of paused Pol II in maintaining promoter accessibility, and the role of cyclin dependent kinases and the PAF1 complex in elongation control. We will also determine how the key elongation control factor P-TEFb is regulated by the 7SK snRNP and examine the role of mRNA cap methylation in elongation control. The principle investigator is a professor at the University of Iowa and this project will be carried out in the excellent environment offered by his lab and the facilities in the University of Iowa, Carver College of Medicine. The studies proposed here should significantly increase our understanding of mechanisms controlling gene expression and this will be useful in explaining the dysregulation of transcription that occurs in cancer and the hijacking of elongation control machinery by the AIDs virus.
The goal of this project is to understand how gene expression is regulated by controlling RNA polymerase II elongation. Dysregulation of components of the elongation control machinery leads to developmental defects, cancer and active HIV infections. Our studies will provide the framework to understand and potentially treat these diseases.
|Price, David H (2018) Transient pausing by RNA polymerase II. Proc Natl Acad Sci U S A 115:4810-4812|