This will be the first study to exploit the newly discovered function of the checkpoint clamp in homologous recombination repair. We have previously established that ATM- dependent phosphorylation of the checkpoint clamp protein Rad9 governs DNA repair pathways to prevent genomic instability during unperturbed cell cycle. We recently learned that BRCA1 (breast and ovarian cancer type 1) interacts with Rad9. We also identified DNA2 nucleases as Rad9 interacting proteins, and the interaction is enhanced by DNA damage. Based on our preliminary results, we hypothesis that the checkpoint clamp is involved in the double-strand break-end resection process. If we can identify the precise function of the checkpoint clamp in homologous recombination, then we will be well on the way to understanding how the checkpoint clamp regulates repair/replication proteins in order to maintain genomic stability. Understanding of DNA repair regulation, in turn, will likely hold the key to understanding what keeps the genome stable.

Public Health Relevance

In this application, we propose to study newly discovered connections between a cell cycle checkpoint protein and DNA repair proteins, focusing on the mechanisms of the double-strand end resection process. The results gained from this study will deepen our understanding of double-strand break repair regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM113253-05
Application #
9627981
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Willis, Kristine Amalee
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205