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    Regulation of Ded1 Activity in Translation Initiation

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    Author
    Aryanpur, Peyman Paul
    Issue Date
    2019
    Advisor
    Bolger, Timothy A.
    
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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, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    DEAD-box RNA helicases are critical regulators of gene expression. The S. cerevisiae DEAD-box helicase Ded1 has long been used as a model to study the biochemical and biological functions of these enzymes. Here I present two paradigms of regulation for Ded1 activity: by the protein interaction with Gle1, and by the TORC1 signaling pathway. In the first study I help elucidate the mechanism of Gle1 regulation of Ded1 in translation initiation. We show that GLE1 expression suppresses the repressive effects of DED1 in vivo and Gle1 counteracts Ded1 in translation assays in vitro. Furthermore, both Ded1 and Gle1 affect the assembly of preinitiation complexes. Through mutation analysis and binding assays, we show that Gle1 inhibits Ded1 by reducing its affinity for RNA. Our results are consistent with a model wherein active Ded1 promotes translation but inactive or excess Ded1 leads to translation repression. In the second study I examine the role of Ded1 in the translational response to TORC1 inhibition and identify a novel function of Ded1 as a translation repressor. I show that C-terminal mutants of DED1 are defective in downregulating translation following TORC1 inhibition with rapamycin. Furthermore, following TORC1 inhibition, eIF4G1 normally dissociates from translation complexes and is degraded, and this process is attenuated in mutant cells. Mapping the functional requirements for Ded1 in this translational response indicates that Ded1 enzymatic activity and interaction with eIF4G1 are required, while homo-oligomerization may be dispensable. Our results are consistent with a model wherein, Ded1 stalls translation and specifically removes eIF4G1 from translation pre-initiation complexes, thus removing eIF4G1 from the translating mRNA pool and leading to the co-degradation of both proteins. Shared features among DED1 orthologs suggest that this role is conserved and may be implicated in pathologies such as oncogenesis.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Molecular & Cellular Biology
    Degree Grantor
    University of Arizona
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