染色体不稳定性（CIN）是恶性肿瘤发生的主要原因。Aurora-A 和BRCA2调节细胞有丝分裂，其异常表达促进细胞染色体非整倍性或多倍性，诱导染色体不稳定性和肿瘤发生，但其作用机制十分不清。本课题组在前期研究中发现过量的Aurora-A 与BRCA2结合并抑制BRCA2在胞质分裂中间体的表达和定位，诱导细胞胞质分裂异常和细胞多核性增加，导致染色体多倍性/非整倍性和肿瘤形成。我们推测Aurora-A很可能在细胞有丝分裂末期，通过磷酸化和促泛素化降解作用调节BRCA2 蛋白表达，因而调控染色体不稳定性和肿瘤发生。本课题拟以卵巢癌为模型，从分子、细胞、动物和人体组织水平分别研究Aurora-A磷酸化和促泛素化降解BRCA2的作用位点和机制，并揭示其对细胞染色体不稳定性和卵巢癌发生、发展的调节规律。本课题的实施有望为Aurora-A相关卵巢癌的有效诊断和靶向治疗提供一定的理论依据和临床应用基础。

Chromosomal instability (CIN) is the major driver in development of malignancy. Both Aurora-A and BRCA2 regulate cell mitosis, but their abnormal expression promotes cell chromosomal aneuploidy or polyploidy, which causes chromosomal instability and tumorigenesis, but the underlying mechanism is unclear. Our previous study revealed that Aurora-A binds to BRCA2 and inhibits the expression and localization of BRCA2 at midbody during cytokinesis, which induces abnormal cytokinesis and increases cell multinuclearity, resulting in chromosomal polyploidy and ovarian tumorigenesis. Thus, we hypothesize that Aurora-A may regulate the expression of BRCA2 through phosphorylation and ubiquitination-mediated degradation at the end of cell mitosis to control chromosomal instability and tumorigenesis. This project is designed to use ovarian cancer as a model, at the different levels in molecules, cells, animals, and human tissues, to investigate the effective sites and mechanism of BRCA2 phosporylation and ubiquitnation-mediated degradation driven by Aurora-A, from which to reveal the regulatory mechanism of chromosomal instability and ovarian cancer formation and development. The fulfillment of this project may provide theoretical evidences and clinical applications for effective diagnosis and targeted therapy of Aurora-A-associated ovarian cancer.