Mechanisms of RNA localization and centrosome regulation

PROJECT SUMMARY: Centrosomes are multifunctional organelles that organize the microtubule cytoskeleton required for mitotic spindle formation, enabling chromosome segregation and safeguarding genomic stability. During interphase, centrosomes also contribute to intracellular trafficking, cell polarity and migration, and ciliogenesis. Centrosomes undergo cell cycle-dependent oscillations in composition and organization to modulate their activity and diversity of functions. Prior to mitotic onset, centrosomes increase their microtubule-organizing activity through a process called centrosome maturation involving the recruitment of centrosomal proteins to the pericentriolar material. RNA is also recruited to centrosomes before mitotic entry. Our research contributes to an emerging model whereby local RNAs and on-site translational control influence centrosome activity. While RNA localization to centrosomes is conserved across metazoans, we still lack a complete understanding of which RNAs localize to centrosomes, how they get there, and their biological functions. The overarching goal of our research program is to investigate how posttranscriptional mechanisms instruct centrosome activity. The proposed work examines how local RNA directs centrosome function by determining the basis for cell cycle-dependent oscillations in RNA enrichment, conserved regulatory paradigms, and the unbiased discovery of novel regulators. To achieve these goals, we utilize genetically tractable models and multidisciplinary approaches. These studies will provide new insights into how centrosomes regulate their activities and may inform how centrosome dysfunction contributes to developmental disorders, neurodegeneration, and cancer.