During the previous funding period, fundamental insights regarding the cell cycle checkpoint functions of the Mre11 complex were obtained. The complex's role as a sensor of DNA damage was firmly solidified through the elucidation of Rad50S hypermorphism in activation of the DNA damage signaling pathway, and was shown for the first time to influence apoptosis in addition to cell cycle checkpoints. The research program proposed here utilizes murine experimental systems to examine the response to ionizing radiation as well as intrinsic sources of DNA damage signaling. A major goal of these studies is to define the mechanisms of ATM regulation in response to ionizing radiation and endogenous clastogenic events. We have established mice in which the Mre11 complex's influences on apoptosis, tumor suppression, and the repair of ionizing radiation- induced DNA damage are genetically and mechanistically separable. The governing hypothesis of this proposal is that the response to DNA damage is sorted into those arms of the DNA damage response by the Mre11 complex. We further hypothesize that sorting of the response is effected by Mre11 complex functional interactions that are specific to particular contexts such as DNA replication or meiotic progression. Addressing these hypotheses will provide a foundation for understanding and improving responses to ionizing radiation in therapeutic settings.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059413-12
Application #
7737365
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Hagan, Ann A
Project Start
1999-05-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
12
Fiscal Year
2010
Total Cost
$589,516
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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