Maintenance of genomic stability is critical for the well-being of organisms. The genome of a cell is under constant attack from exogenous and endogenous DNA damaging factors such as radiation, carcinogens and reactive radicals. To maintain genomic stability, cells have developed an elaborate DNA damage response (DDR) system, which is responsible for sensing DNA damage, halting the ongoing cell cycle, and repairing the damaged DNA. Failure in the DDR pathway leads to genomic instability, which is one of the driving forces of tumorigenesis. Many human genetic cancer predisposition syndromes are linked to defective DDR. For example, mutations in the BRCA1 gene are found in about 50% of familial breast cancer cases. Since individual tumors often have unique defects in the DDR pathway, insight into the basic mechanisms by which cells repair different DNA lesions can also guide individualized therapy. A promising example is the use of PARP inhibitors in cancers with BRCA1 and BRCA2 mutations. On the other hand, many studies suggest that overexpression of DNA repair factors contributes to resistance to chemotherapy. Therefore, studying this pathway has important implications in cancer pathogenesis and cancer therapy. Preliminary data within this proposal showed for the first time that the deubiquitinase, USP13, regulates homologous recombination mediated DNA repair. Mechanically, USP13 interacts with RAP80 and deubiquitinates RAP80, which in turn facilitates the recruitment of RAP80-BRCA1 complex to double strand breaks and promotes homologous recombination. Depleting or inhibiting USP13 sensitizes ovarian cancer cells but not the normal ovarian epithelial cells to cisplatin and PARP inhibitor. The central hypothesis of the proposal is that USP13 is a new factor in DNA repair. USP13 regulates DNA damage response and HR repair by deubiquitinating RAP80. Overexpression of USP13 contributes to chemotherapeutic resistance by enhancing DNA repair. These experiments will reveal a novel function of USP13 in DNA repair and response to chemotherapy. In addition, it will reveal a new therapeutic target in sensitizing ovarian cancer cells, especially those overexpressing USP13, by targeting the USP13-RAP80-BRCA1 pathway.
The Specific Aims are the following: 1. Investigate the regulation of RAP80 by USP13. 2. Study the regulation of USP13 by DDR signaling. 3. Investigate the role of USP13 in chemoresistance.
Ovarian cancer is the most common cause of cancer deaths for gynecologic tumors in the United States. Recent clinical trials showed that PARP inhibitors and platinum-based therapy are effective in treating ovarian cancer patients with mutations in the BRCA1/2 genes, but are not effective for patients without such mutations. How to make ovarian cancers respond to therapy for these patients without BRCA mutations is a very important unanswered question. This project clarifies a specific enzyme, USP13, as a novel potential therapeutic target for ovarian cancers with wild type BRCA1. Furthermore, combined treatment with USP13 inhibitor Spautin-1 and PARP inhibitor might be a novel treatment strategy to effectively treat ovarian cancers.
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