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    • Graduate School - MU Theses and Dissertations (MU)
    • Theses and Dissertations (MU)
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    • 2012 Dissertations (MU)
    • 2012 MU dissertations - Access restricted to MU
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    Characterization of the role of the DNA damage response pathway in parvoviral replication

    Adeyemi, Richard, 1982-
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    Date
    2012
    Format
    Thesis
    Metadata
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    Abstract
    [ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] We report that low multiplicity infection with the autonomous parvovirus minute virus of mice (MVM) results in the activation of a DNA damage response (DDR), characterized by the phosphorylation and recruitment of a number of DDR proteins to MVM replication centers. Replication of the virus is required for signaling. We show that ATM is the main transducer of the DDR. ATM inhibitors restrict MVM replication and ameliorate virus-induced cell cycle arrest, suggesting that DDR facilitates virus replication, perhaps in part by promoting cell cycle arrest. We also report that, although MVM leads to activated p53, p21 levels are reduced via a proteasome-mediated mechanism. This loss was sustained, as virus replicated in infected cells held at G2 phase. Addition of the cyclin-dependent kinase (CDK) inhibitor roscovitine after S-phase entry reduced MVM replication, suggesting that CDK activity was critical for continued viral replication and virus-induced reduction of p21 may thus be necessary to prevent inhibition of CDK. Finally we report the viral G2 arrest does not depend on the checkpoint kinases Chk1 and Chk2. Instead, remarkably, levels of the mitotic cyclin B1 were dramatically reduced in a proteasome-independent, but RNA-dependent, manner. This loss was shown to prevent infected cells from progressing into mitosis and potentially allows for continued viral replication in G2-arrested cells. MVM thus employs atypical mechanisms to carefully navigate and exploit the cellular DDR machinery during infection to enhance its replication in the host by creating a cellular environment conducive for sustained viral replication in arrested cells.
    URI
    https://hdl.handle.net/10355/15925
    https://doi.org/10.32469/10355/15925
    Degree
    Ph. D.
    Thesis Department
    Microbiology (Medicine) (MU)
    Rights
    Access is limited to the campus of the University of Missouri--Columbia.
    Collections
    • 2012 MU dissertations - Access restricted to MU
    • Molecular Microbiology and Immunology electronic theses and dissertations (MU)

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