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Title page for ETD etd-09032011-100056


Type of Document Dissertation
Author Nam, Edward Adam
URN etd-09032011-100056
Title Phospho-regulation of the DNA Damage Response Kinase ATR
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Albert Reynolds Committee Chair
David Cortez Committee Member
Ellen Fanning Committee Member
Graham Carpenter Committee Member
Sandra Zinkel Committee Member
Keywords
  • replication stress
  • DNA-PK
  • ATR
  • ATM
  • DNA damage
Date of Defense 2011-08-26
Availability unrestricted
Abstract
Understanding how cells maintain genome integrity is necessary to gain insight into the pathology of cancer and to identify therapeutic targets and biomarkers. The DNA damage response kinase ATR is essential for the maintenance of the cellular genome. In this dissertation, I hypothesize that ATR is phosphorylated in response to DNA damage. I also characterize a novel ATR inhibitor and explore its efficacy as an anti-cancer agent. I discover that ATR is phosphorylated on T1989 in response to DNA damage and marks an activated kinase. T1989 phosphorylation is not critical for ATR function. As a proximal marker for ATR activity, T1989 phosphorylation has significant potential as a biomarker. I also identify a novel regulatory region in ATR that separates the essential function of ATR from its G2 checkpoint activity. Finally, I demonstrate that an ATR inhibitor sensitizes cells to replication stress, suggesting ATR inhibition may be a good therapeutic strategy to pursue.
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