Studies from my laboratory during the past two decades have focused on the characterization of the molecular functions and biochemical properties of factors and chromatin modifications associated with the elongating form of RNA polymerase II (Pol II), and how their translocations and mutations are associated with the pathogenesis of childhood leukemia and other forms of cancer. Our hope is that our molecular studies of transcriptional elongation control during normal development and during cancer will advance our understanding of the molecular mechanisms of rearrangement-based leukemia and other forms of human cancer for the treatment of these malignancies. To this end, our biochemical studies during the current funding cycle demonstrated that the Super Elongation Complex, PAF1 complex, and histone H3K79 methylation machinery are central for the regulation of pause/release by Pol II. We now plan to molecularly define the basis of this process and to also identify other cellular factors within our genome functioning with SEC, PAF1, and the H3K79 demethylases to regulate transcription elongation by Pol II. We will take advantage of a variety of biochemical, molecular, and genetic tools in multiple model systems to address these aims, which should (i) be instrumental for our understanding of the diverse roles of RNA Polymerase II elongation factors in the regulation of gene expression and in development and differentiation; and (ii) have a fundamental impact on our understanding of the mutations and translocations of this family of factors in human cancer. This information has the potential of proving helpful to investigators attempting to design rational approaches for the treatment of cancer.
Relevance: The focus of this application is on the role of transcriptional elongation control in the regulation of gene expression and how misregulation of this process is associated with different forms of human cancer. The RNA polymerase II elongation factors have been demonstrated to be mutated in different forms of cancer, therefore, the molecular information obtained in this renewal application about the biochemical, molecular, and enzymatic properties of RNA polymerase II elongation factors will be instrumental in the development of targeted therapeutics.
