Grant: Project Grant

The flow of information from DNA to RNA to protein is fundamental to all cells in every living organism. The first step in this process-the synthesis of messenger RNA from a DNA template-is called transcription and is carried out by the enzyme RNA polymerase. Transcription occurs in multiple steps, each of which can be regulated by a diverse array of proteins. Defective regulation of transcription underlies many complex human diseases. The elongation phase of transcription, in which the RNA polymerase enzyme travels along the DNA template synthesizing RNA, is an important point of control that is abnormally regulated in heart disease and in a variety of cancers. How elongation is controlled at a molecular level remains poorly understood, and the central goal of the proposed research is to gain further knowledge of these molecular details so that they can be exploited for therapeutic benefit in human disease. Since the elongation process is fundamental to gene activation and is highly conserved in evolution, we use a simple unicellular organism (fission yeast) to model the elongation process and its control in human disease. The research focuses in particular on proteins that are functionally related to Cdk9, a master regulator protein for transcription elongation. Our research has uncovered novel functions for these proteins at unexpected locations on chromosomal DNA, as well as mechanisms that dynamically link elongation to other steps in the transcription process. Given the recent development of drugs that target elongation, further study of the molecular basis for these effects will provide important knowledge that may have important clinical implications.