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    Molecular Mechanisms of Centriole Assembly

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    Author
    McLamarrah, Tiffany Ann
    Issue Date
    2016
    Keywords
    Centriole
    Plk4
    Cellular and Molecular Medicine
    Ana2
    Advisor
    Rogers, Gregory
    
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    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    Chromosomal Instability (CIN) occurs in over 90% of all sporadic tumors and manifests as whole chromosome loss or gain, gene deletions, amplifications, inversion, and translocations. CIN is not only a hallmark of cancer but promotes tumorigenesis. CIN is caused by errors during mitosis and one major CIN-promoting mechanism is centrosome over-duplication (amplification); another cancer hallmark. Centrosome amplification causes abnormal mitotic spindle assembly, directly promoting chromosome mis-segration with consequent aneuploidy and other forms of CIN. Central to controlling centrosome numbers and function are the Polo kinases, including Polo-like kinase 4 (Plk4). Plk4 is a component of centrosomes and recognized as the master-regulator of centrosome function and duplication. Plk4 is a mitotic kinase whose levels increase throughout S-phase and G2 to peak in mitosis. During late mitosis, Plk4 localizes to a spot on parent centrioles, licensing this single site for future daughter centriole assembly. Plk4 activity initiates the hierarchial recruiment of two conserved essential centriole proteins: Ana2, followed by the cartwheel protein Sas6. By analysis in a yeast-2-hybrid screen, we identified several novel interactions of centriole proteins, including the interaction of Ana2 and Plk4. Plk4 phosphorylates Ana2 to both positively and negatively regulate centriole duplication. Our preliminary data suggests that Plk4 recruits Ana2 by phosphorylating a protein on the outer centriole surface, generating a phospho-landing platform, and that this Plk4 target is Sas4 (CPAP in humans). Notably, the Sas4 pattern on centrioles is complex, forming both a ring and an asymmetric spot during mitotic progression. Like Sas4, Ana2 is a Plk4 substrate, and when mixed with purified Ana2, Sas4 stimulates Ana2 hyperphosphorylation in vitro. Thus, Plk4 influences centriole assembly on multiple platforms.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Cellular and Molecular Medicine
    Degree Grantor
    University of Arizona
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