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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-09032011-100056 |
| Date | 07 September 2011 |
| Creators | Nam, Edward Adam |
| Contributors | Ellen Fanning, Sandra Zinkel, Albert Reynolds, David Cortez, Graham Carpenter |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-09032011-100056/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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