Many studies suggest that overexpression of DNA repair factors could contribute to resistance to radiochemotherapy. Therefore, studying this pathway has important implications in cancer pathogenesis and cancer therapy. We found that UCHL3, a deubiquitinase, is overexpressed in breast cancer. In addition, increased expression of UCHL3 correlates with poor prognosis for breast cancer patients. However, whether or not UCHL3 casually contributes to clinical phenotypes is unclear, because the cellular function of UCHL3 remains unclear. Here we show for the first time that UCHL3 is involved in DNA repair. We found that UCHL3 interacts Rad51 and deubiquitinates Rad51 without affecting Rad51 levels. UCHL3 itself is phosphorylated following DNA damage and is recruited to double strand breaks. In addition, UCHL3 is important for the recruitment of Rad51 to double strand breaks and homologous recombination. Downregulating UCHL3 sensitizes breast cancer cells to radiation and PARP inhibitors, while overexpressing UCHL3 renders breast cancer cells resistant to these treatments. Based on these Preliminary Data, we hypothesize that UCHL3 is a new factor in DNA repair. UCHL3 deubiquitinates Rad51 and promotes Rad51 function and homologous recombination. Increased UCHL3 contributes to resistance to radiation and chemotherapy by enhancing DNA repair. In this application, we will further explore how UCHL3 regulates Rad51 and how UCHL3 itself is regulated. We will also test the role of UCHL3 in radiochemoresistance using clinically relevant models.
Our Specific Aims are: 1. Investigate the regulation of Rad51 by UCHL3; 2. Study the regulation of UCHL3; 3. Investigate the role of UCHL3 in breast cancer therapy. Our studies will reveal a novel function of UCHL3 in DNA repair and response to radiation and chemotherapy. In addition, it will reveal a new therapeutic target in sensitizing breast cancer cells, especially those overexpressing UCHL3, by targeting the UCHL3-Rad51 pathway.
Defective DNA damage response pathway is linked to tumorigenesis. In addition, given that many cancer therapies involve DNA damage-inducing agent, a detailed understanding of the DNA damage response pathway and its status in cancer cells will help us to design targeted therapy for specific cancers and to overcome resistance to chemotherapy. We will explore novel regulatory mechanism of the DNA damage response pathway and use knowledge gained to study mechanisms of resistance to chemotherapy in patient- derived breast cancer models.
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