• Login
    View Item 
    •   Home
    • Graduate Theses, Dissertations and Projects
    • Queen's Graduate Theses and Dissertations
    • View Item
    •   Home
    • Graduate Theses, Dissertations and Projects
    • Queen's Graduate Theses and Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    The interaction between Rad9 and Tousled-like kinase 1 in the cell cycle and the DNA damage response

    Thumbnail
    View/Open
    Kelly_Ryan_P_201312_PhD.pdf (5.324Mb)
    Date
    2013-12-24
    Author
    Kelly, Ryan
    Metadata
    Show full item record
    Abstract
    Genomic integrity is preserved by checkpoints, which are signal transduction pathways that serve to delay cell cycle progression in the presence of DNA damage or replication stress. The heterotrimeric Rad9-Rad1-Hus1 (9-1-1) complex is a proliferating cell nuclear antigen (PCNA)-like clamp that is loaded onto DNA at structures resulting from damage, and is important for initiating and maintaining checkpoint signaling. Rad9 possesses a C-terminal tail unrelated to PCNA that is phosphorylated constitutively and in response to cell cycle position and DNA damage. Previous studies have identified tousled-like kinase 1 (TLK1) as a kinase that may modify Rad9. This thesis establishes that Rad9 is indeed phosphorylated in a TLK-dependent manner in vitro and in vivo, and that T355 within the C-terminal tail is the primary targeted residue. Phosphorylation of Rad9 at T355 is quickly reduced upon exposure to ionizing radiation before returning to baseline later in the damage response. In addition, TLK1 and Rad9 were shown to interact constitutively, and this interaction is enhanced in chromatin-bound Rad9 at later stages of the damage response. Furthermore, this thesis demonstrates that TLK1 is required for progression through S-phase in normally cycling cells, and that depletion of TLK1 results in a prolonged G2/M arrest upon exposure to ionizing radiation, a phenotype that is mimicked by over-expression of a Rad9-T355A mutant. Given that TLK1 is transiently inactivated upon phosphorylation by Chk1 in response to DNA damage, this work proposes that TLK1 and Chk1 act in concert to modulate the phosphorylation status of Rad9, which in turn plays a role in regulating the DNA damage response.
    URI for this record
    http://hdl.handle.net/1974/8536
    Collections
    • Queen's Graduate Theses and Dissertations
    • Biochemistry Graduate Theses (July 2007 - Sept 2016)
    Request an alternative format
    If you require this document in an alternate, accessible format, please contact the Queen's Adaptive Technology Centre

    DSpace software copyright © 2002-2015  DuraSpace
    Contact Us
    Theme by 
    Atmire NV
     

     

    Browse

    All of QSpaceCommunities & CollectionsPublished DatesAuthorsTitlesSubjectsTypesThis CollectionPublished DatesAuthorsTitlesSubjectsTypes

    My Account

    LoginRegister

    Statistics

    View Usage StatisticsView Google Analytics Statistics

    DSpace software copyright © 2002-2015  DuraSpace
    Contact Us
    Theme by 
    Atmire NV