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Shape And Copy Number Of Centriole Duplication

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Centrioles are microtubule-based, 9-fold symmetrical cylinder-like structures that duplicate exactly once per cell cycle. The 9-fold symmetry is defined by a geometric scaffold known as the cartwheel, upon which all centrioles are formed. Centriole duplication starts with cartwheel assembly at the proximal sidewall of the preexisting (mother) centriole and ends with a new (daughter) centriole that is orthogonally engaged to its mother. After duplication, reduplication of the mother centriole in the same cell cycle is strictly inhibited by centriole engagement. It remains poorly understood how the geometric shape of the cartwheel is invariantly specified, and how the engagement blocks reduplication of the mother centrioles, two key questions that my thesis aims to address. For the shape control, we showed that a template-based step is involved in centriole biogenesis. Specifically, HsSAS-6, a major cartwheel component, is first recruited to the proximal lumen of the mother centriole, where the organization of HsSAS-6 molecules is shaped into a cartwheel-like configuration. Luminal HsSAS-6 is then released in a process mediated by PLK4 and STIL, before relocalizing to the outside wall of the mother centriole at which the daughter centriole subsequently grows. After duplication, the lumen of the engaged mother centriole is blocked for recruiting more HsSAS-6 until disengagement occurs at the end of the cell cycle, correlating with the engagement-mediated block for reduplication. Our results thus suggest that preexisting centrioles may function as an external template to guide and ensure the 9-fold symmetric assembly of new centrioles. For the copy number control, we found that the cartwheel, which forms the identity of the daughter centriole, constitutes the engagement-induced block for reduplication. We showed that cartwheel maintenance in the engaged daughter centriole is essential for the steady reduplication block for mother centrioles, and that maintaining the stability of the cartwheel requires the same reaction between the kinase PLK4 and the substrate STIL that drives centriole assembly. Thus, our study indicates that the promotion and suppression of centriole duplication are catalytically coupled through PLK4 to ensure centriole homeostasis.

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2016

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cartwheel; centriole; centrosome; duplication; licensing; PLK4

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Cell & Developmental Biology

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Doctor of Philosophy

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Government Document

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Attribution-NonCommercial-NoDerivatives 4.0 International

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dissertation or thesis

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