The role of a BRCA1 associated complex in DNA damage response and tumor suppression

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ABSTRACT The hereditary breast and ovarian cancer tumor suppressor protein BRCA1 plays critical roles in DNA repair, cell cycle checkpoint control, and maintenance of genomic stability. BRCA1 is recruited to DNA damage sites through a BRCA1-associated complex, the BRCA1-A complex in response to ionizing radiation. Abraxas is the central adaptor protein in the BRCA1-A complex and binds to BRCA1 BRCT domains in a phosphorylation-dependent manner. We have demonstrated that Abraxas plays an important role in suppressing tumor development in mice and that the interaction between Abraxas and BRCA1 is critical for Abraxas' function in repair of DNA and maintenance of genome stability, indicating that Abraxas is part of BRCA1 signaling in breast tumor suppression. Focusing on the role of Abraxas in ionizing radiation-induced double strand break repair and elucidating the regulatory mechanism for Abraxas's function will provide insights into the role of Abraxas as a novel tumor suppressor gene and will uncover novel mechanisms important for its tumor suppressor function. In this application, we will first investigate a novel mechanism regulating Abraxas-mediated BRCA1 accumulation at DNA double strand breaks through double-phosphorylation of the C-terminus of Abraxas in response to ionizing radiation. Second, we will examine the tumor-related somatic mutations of Abraxas and determine the regulatory mechanisms for the function of Abraxas in suppressing genomic instability and tumor development. Third, we will determine the role of Abraxas in breast tumor suppression by generating and examining mammary-specific Abraxas- deficient mouse models. Together, our study will determine the role of Abraxas as a tumor suppressor gene and the regulatory mechanisms for its tumor suppressor function. It will provide new insights into the causes and mechanisms of breast cancer and may lead to the discovery of new therapies for Abraxas-deficient breast cancer.