Post-transcriptional mechanisms of centrosome regulation

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Project Summary Centrosome deregulation is the leading cause of heritable microcephaly, a congenital birth defect typically associated with intellectual disabilities and developmental delay. Centrosome dysfunction is also considered a key driver and prognostic marker of cancer. Yet, mechanisms underlying centrosome regulation remain incompletely understood. Centrosomes undergo cell cycle-dependent changes in composition and organization to modulate their activity as microtubule-organizing centers, and these oscillations contribute to the diversity of centrosome functions. One dynamic constituent of centrosomes is mRNA, yet the functional role of mRNA localized to centrosomes remains poorly understood. In this proposal, we examine whether mRNA contributes to centrosome regulation and functions. In Aim 1, we define mechanisms of mRNA localization to centrosomes. In Aim 2, we uncover the regulatory contributions of two conserved RNA-binding proteins. Aim 3 examines the function of mRNA localized to centrosomes. The completion of this work will address long- standing questions about the role of mRNA localized to centrosomes within a genetically tractable model. This work will contribute to our understanding of centrosome regulation, aspects of which are deregulated in cases of microcephaly and cancer.