BRCA1 or BRCA2 mutations increase the risk of several cancers, including breast, ovarian, prostate, and pancreatic cancers. Cells with dysfunctional BRCA1 or BRCA2 gene expression suffer defects in performance of double strand break (DSB) repair mechanisms including homologous recombination (HR) and non- homologous DNA end joining (NHEJ). Cancer treatments exploit this characteristic, the best example of which is the PARP inhibitors (PARPi), which show ?synthetic lethality? with BRCA1 or BRCA2 deficiency due to HR repair defects in BRCA1 or BRCA2-deficient cancer cells. However, resistance to PARPi is a major clinical problem in BRCA-mutated cancers. Unexpectedly, loss of the DNA repair protein 53BP1 renders BRCA1- deficient cancer cells resistant to PARPi and radiation treatment, indicating that loss of 53BP1 expression is at least one scenario by which therapeutic resistance may arise in BRCA-mutated cancers. We and others reported recently that mechanistically, 53BP1 acts as an adaptor protein and controls two downstream sub-pathways, one mediated by PTIP and Artemis and the other mediated by RIF1 and MAD2L2, to coordinate pathologic DSB repair pathway choices in BRCA1-deficient cells. However, the direct upstream regulator(s) of 53BP1 function in DNA repair and cellular response to PARPi and/or irradiation in BRCA-mutated cancers remain unknown. Our recent studies have uncovered several 53BP1-binding proteins that regulates 53BP1 stability, modulates 53BP1 access to DSBs and functions in DNA repair through post-translational modification of 53BP1. Thus, our overall hypothesis is that previously unrecognized 53BP1 repair pathways confer PARPi resistance that can be targeted therapeutically in BRCA-mutated cancers. To address this hypothesis, we propose 3 specific aims:
Aim 1 : Determine the mechanism underlying TIRR regulation of 53BP1 at DSBs.
Aim 2 : Determine the role(s) of NUDT16 in 53BP1 regulation and in DNA repair pathways.
Aim 3 : Reveal the functional significance of HDGFRP3 in damage-induced 53BP1 localization, and DNA repair. Knowledge such as this is essential in identifying those patients with BRCA-mutated cancers who will most benefit from PARPi-based therapies.

Public Health Relevance

Cancers with BRCA mutations, such as breast and other cancers, are treated with PARPi inhibitors or irradiation that kills cancer cells with the mutation because the treatment interferes with DNA repair. Unfortunately, cancer cell resistance to PARPi has emerged as a vexing problem. We have found previously unrecognized DNA repair pathways that confer PARPi resistance and here will further investigate them as therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA222195-01A1
Application #
9659469
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2018-12-01
Project End
2023-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195