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Spatial organization of mRNA regulation and metabolic activity


Organization of biological processes is a central principle of cell biology. However, until recently, the context of this organization has largely centered on membrane-bound organelles and their internal biochemistry. Recent discoveries of intracellular structures that organize biochemical processes such as P bodies, purinosomes, and self-assembling metabolic enzymes suggests there is much to be uncovered in the studies of cytoplasmic organization. This thesis focuses on two mechanisms for organizing the cytoplasm: one involving the spatial regulation of key mRNA processing events in early development and the other involving polymerization of metabolic enzymes and the role it plays in connecting metabolic regulation to broader areas of cell biology. The spatial regulation of mRNA processing events is largely dependent on the role of the mRNA-associated ribonucleoprotein (RNP) complex that functions to regulate transcript translation and stability. We focus on one such RNP, Cup, that has been previously described as a translational repressor for oskar mRNA, the transcript that is critical for anterior-posterior patterning in Drosophila development. Here, we identify that Cup is also required for oskar mRNA stability. Conversely, we will also show a novel pathway for mRNA degradation. Previous studies have identified the role of the Pan gu kinase complex in activating the translation of the mRNA degradation machinery at the maternal-to-zygotic transition, where maternally loaded transcripts are degraded as a precursor to zygotic transcriptional control. We identify a parallel pathway that acts in concert to destabilize these maternal transcripts through ubiquitin-mediated degradation of the associated RNPs. Switching to a different mechanism of cytoplasmic organization, we will reveal the self-assembling property of the metabolic enzyme PRPP synthetase (PRPS), the enzyme responsible for synthesizing the substrate for nucleotide biosynthesis. We will also show the defects in cellular actin organization associated with the mutations in PRPS leading to a disease-state. Furthermore, we will identify that the inhibitor of PRPS associates with the polymerized form of PRPS and also with the actin cytoskeleton; this suggests a novel method of regulation and possible mechanism behind PRPS diseases.

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