The current model for DNA damage checkpoint initiation suggests that ssDNA, formed by 5' to 3' resection of DNA double strand breaks (DSBs), generates a signal that recruits and activates checkpoint signaling proteins. However, ssDNA formation is suppressed in the G1 checkpoint. In addition, this model does not explain why it is necessary for checkpoint proteins to bind adjacently to modified chromatin ten kilobases away from DSBs. Indeed, data published within the past decade have revealed a crucial role for chromatin modification in the DNA damage checkpoint response. Recent data show that chromatin modifications are necessary for recruitment and activation of yeast Rad9 and Crb2 as well as metazoan checkpoint adaptor proteins MDC1 and 53BP1. This thesis examines the role of chromatin modifications and DNA resection in immediate DNA damage checkpoint signaling. First, I determined that Rad9 chromatin association is necessary but not sufficient for checkpoint signaling and arrest in the telomere uncapping response. Next, I demonstrated that checkpoint signaling takes place in mutants deficient in long-range DNA resection or in mutants that fail to recruit checkpoint signaling proteins to ssDNA/RPA complexes. These studies contribute to the field by characterizing the contribution of Rad9 chromatin association and DNA resection to checkpoint signaling. I hope that in determining the mechanism of action for these events, they will contribute to the development of therapeutics used to sensitize tumors to radiation therapy.
|Advisor:||Kron, Stephen J.|
|Commitee:||Meredith, Stephen C., Storb, Ursula, Turner, Jerrold R.|
|School:||The University of Chicago|
|School Location:||United States -- Illinois|
|Source:||DAI-B 70/08, Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics|
|Keywords:||Chromatin, DNA damage response, Double strand breaks, ssDNA|
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