One of the key aims of cancer research is to understand how cells detect and repair double-strand breaks (DSBs) in DNA. DSBs are important because they are a major source of genome instability that is a hallmark of cancer. Moreover, many of the most widely used and effective anti-cancer therapies use targeted irradiation or chemotherapeutics to create DSBs, which preferentially kill cancer cells. The Mre11-Rad50-Nbs1 (MRN) protein complex, its repair cofactor Ctp1/CtIP/Sae2, and its checkpoint signaling cofactor Tel1/ATM, have evolutionary conserved functions that are crucial for detecting and repairing DSBs, and for activating the DNA damage checkpoint that arrests cell division. Fission yeast mutants lacking MRN or Ctp1 are unable to repair DSBs, and therefore display genomic instability and are acutely sensitive to clastogens. Human genetic diseases that partially impair the functions of these proteins cause genome instability syndromes. Notably, hypomorphic mutations in human Nbs1 cause microcephaly, developmental abnormalities, immunodeficiency, radiation sensitivity and cancer predisposition. Recent studies revealed that Nbs1 functions as a molecular tether that links Ctp1 and Tel1 to the Mre11-Rad50 complex. In this project, we propose to use genetic, cell biological and in vivo assays to characterize the functional interactions between the MRN complex and Ctp1 at DSBs formed by replication fork collapse. These studies will improve the conceptual understanding of how mutations in human Nbs1 cause cancer, and in doing so enhance opportunities for developing new strategies for cancer prevention and treatment.

Public Health Relevance

The Mre11-Rad50-Nbs1 protein complex, Ctp1 (CtIP) and Tel1 (ATM) protect genome integrity and prevent cancer causing mutations by detecting, signaling and repairing DNA double-strand breaks. This project will define the functional interactions amongst these proteins, and thereby identify new potential anti- cancer strategies. !

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077325-16
Application #
8627558
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Pelroy, Richard
Project Start
1998-04-20
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
16
Fiscal Year
2014
Total Cost
$379,684
Indirect Cost
$179,323
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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