Most, if not all tumor cells harbor signs of genomic instability, which can contribute to their development. DNA repair combats genomic instability and thus, is a powerful tumor suppressor mechanism. Inherited mutations in genes encoding for repair factors are associated with significant increases in cancer susceptibility, establishing tha failure to repair DNA damage causes or facilitates tumor development. Nonetheless, DNA damaging therapies are amongst the most widely used and most successful cancer therapies. The inherent genomic instability of cancer cells makes them more vulnerable to a high damage burden. This can be exploited in the clinic by targeting specific DNA repair modules that are uniquely essential for tumor cells. We will build a map of protein-protein interactions for repair factors common to multiple repair pathways. We will identify protein-protein interactions, which are specifically enhanced or reduced following treatment with DNA topoisomerase inhibitors and DNA crosslinkers. These differentially regulated modules will identify potential vulnerabilities in the DNA repair networks of cancer cells and will open the possibility for precise, targeted therapies.

Public Health Relevance

The proposed research is highly relevant to public health. Elucidating how DNA repair modules operate as a network is critical to our understanding of cancer development and therapies. A wide variety of DNA repair defects cause genomic instability and subsequent tumor development. Furthermore, the most effective cancer therapies are DNA damaging therapies: radiation therapy and several classes of chemotherapies. Our proposed studies will identify specific vulnerabilities within the DNA repair network of cancer cells, which will be exploited to design more effective and more precise therapies for cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
1R35CA197606-01
Application #
8955897
Study Section
Special Emphasis Panel (ZCA1-GRB-S (M1))
Program Officer
Pelroy, Richard
Project Start
2015-08-01
Project End
2022-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$492,802
Indirect Cost
$184,801
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Aparicio, Tomas; Gautier, Jean (2016) BRCA1-CtIP interaction in the repair of DNA double-strand breaks. Mol Cell Oncol 3:e1169343
Aparicio, Tomas; Baer, Richard; Gottesman, Max et al. (2016) MRN, CtIP, and BRCA1 mediate repair of topoisomerase II-DNA adducts. J Cell Biol 212:399-408