ATM regulates many cellular processes including DNA damage responses and DNA double-strand break (DSB) repair in addition to responses involving oxidative stress and cell growth. Many of the processes ATM are associated with that are triggered by radiation have been described and characterized. However, the mechanisms involved in ATM's ability to balance growth and assess DNA damage (and other stresses) and help the cell decide between survival and death are relatively unknown. We have recently reported on the interesting observation that in response to radiation, ATM and prosurvival MEK/ERK signaling forms a feedback loop that regulates homologous recombination repair - ATM regulates ERK phosphorylation (and thus activation) whereas MEK/ERK is required for phosphorylation of ATM at serine-1981. Neither mechanism is presently known. Herein, we propose to determine the mechanisms of both these processes as well as the role of ATM and MEK/ERK signaling in regulating non-homologous end-joining (NHEJ), and, in particular, whether ATM and MEK/ERK signaling control DNA repair fidelity in this system. We will focus our studies on finding possible links between growth factor receptor and PI3K/AKT survival signaling and the ability to modulate the quality of NHEJ. A better understanding of these processes is important since there is little information available regarding the cell's ability to balance cellular growth with stress responses in cancer, in particular how it relates to DSB repair. This information might be utilized for improving cancer therapy.

Public Health Relevance

There is little information available regarding the cell's ability to balance cellular growth with stress responses in cancer, in particular how it relates to DNA repair. The dynamic interaction between growth and stress that is controlled by ATM is important and might be utilized for improving cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21ES016636-02S1
Application #
8073827
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Mcallister, Kimberly A
Project Start
2009-05-15
Project End
2010-08-31
Budget Start
2010-05-28
Budget End
2010-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$21,003
Indirect Cost
Name
Virginia Commonwealth University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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