Noncanonical Post-Transcriptional Roles for SR Proteins During MicroRNA Biogenesis

All biological processes are under regulatory control for efficient and proper homeostatic function. Dysregulation of these mechanisms results in consequences that the cell must overcome. RNA binding proteins (RBPs) are a broad class of proteins that control RNAs. They regulate all aspects of an RNA’s lifecycle. The fate of RNA is dependent on interactions with its partnered RBPs. My thesis will be focused around a well characterized group of RBPs belonging to the SR protein family. Many RBPs are first characterized based on their roles in regulation of mRNAs. However, there are many different species of RNAs created in the cell that are maintained by RBPs. MicroRNAs (miRNAs) are short non-coding RNAs that function as regulators of mRNAs. Although the main enzymes that create miRNAs have been revealed, there are still many questions as to how their synthesis is is regulated during each step of biogenesis. In my dissertation I will show that traditionally characterized regulators of mRNA gene expression, the SR protein family members SRSF1 and SRSF3, have critical roles in miRNA biogenesis. Using a combination of in vivo and in vitro approaches we discover that these proteins bind to specific locations outside of the miRNA hairpin, a key feature required for miRNA biogenesis. This interaction promotes a structural conformation that enhances initial cleavage of miRNAs by allowing for better accessibility of the hairpin by the Microprocessor. My work expands the scope of post-transcriptional regulation by SR proteins by defining their roles during miRNA biogenesis