Increasing evidence suggest that the integrity of the DNA damage-signaling pathway is essential for the maintenance of genomic stability and the prevention of neoplastic transformation. In the last two years, we and others have demonstrated that a BRCT-containing protein 53BP1 (p53-binding protein 1) participates early in the DNA damage-signaling pathway and is a direct substrate of ATM. To understand the role of 53BP1 in the DNA damage-signaling pathway and tumorigenesis, we recently generated 53BP1 knockout mice. Using 53BP1-deficient cells and mice, we will study the function of 53BP1 in the regulation of DNA damage checkpoints in Specific Aim 1. Our preliminary studies reveal that 53BP1 participates in cellular responses to ionizing radiation. We will examine whether loss of 53BP1 expression in cells leads to increased radiation sensitivity and defects in DNA damage checkpoints. We will also explore whether 53BP1 participates in the regulation of p53 and p53-dependent transcription following DNA damage. 53BP1 is phosphorylated by ATM and rapidly localizes to the sites of DNA breaks following ionizing radiation. We have identified the focus-localization region and the damage-induced phosphorylation sites on 53BP1.
In Specific Aim 2, we will examine the relationship between these two events. The functional significance of focus-localization and hyper-phosphorylation of 53BP1 will also be assessed.
In Specific Aim 3, we will explore the roles of 53BP1 in tumorigenesis. The potential roles of 53BP1 in the DNA damage-signaling pathway suggest that 53BP1 may be involved in tumorigenesis. We will determine whether 53BP1-deficient mice will develop spontaneous tumors or have high incidence of radiation- or double-strand breaks-induced tumor formation. Together, these studies will provide insights into the roles of 53BP1 in the DNA damage-signaling pathway and tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100109-02
Application #
6746842
Study Section
Radiation Study Section (RAD)
Program Officer
Pelroy, Richard
Project Start
2003-05-09
Project End
2006-04-30
Budget Start
2004-05-21
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$292,365
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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