BRCA1是一个重要的抑癌基因，在抑制乳腺癌的发生中起重要作用。BRCA1突变个体对乳腺癌和卵巢癌高度易感。当细胞DNA受到损伤时，BRCA1可以迅速被靶向募集到损伤部位，参与对DNA双链断裂（DSBs）的修复。BRCA1对DSBs的识别和募集依赖于DSBs处的K63连接的多聚泛素化链（K63Ub）。K63Ub修饰是一种重要的蛋白质修饰方式，可介导蛋白分子间的相互作用，在BRCA1介导的同源重组修复中发挥重要作用，但是目前对于它是如何调控和影响BRCA1的功能及其抑癌机理并不清楚。本研究拟分离和鉴定DNA损伤相关的K63Ub修饰蛋白，揭示DSBs部位K63Ub合成和降解的生化途径，运用基因敲低细胞模型，阐明K63Ub水平与BRCA1功能之间的关系。此研究对于分离新的乳腺癌易感基因,解析BRCA1抑癌网络组成和抑癌机理、以及乳腺癌的防治和抗癌药物研发等都具有重要意义。

BRCA1 is a key tumor suppressor which plays central roles in the suppression of breast and ovarian cancer. Clinical mutations of BRCA1 strongly predispose women to breast and ovarian cancer. Upon DNA damage, BRCA1 is promptly recruited to the site of DNA damage, where it participates and mediates homologous recombination repair ofDNA double strand-breaks (DSBs). The process of BRCA1 recruitment requires molecular recognition of K63-linked polyubiquitin chains (K63-Ub) at the site of DSBs. As an important type of protein modification, K63-linked polyubiquitination can mediate protein-protein interaction, playing critical roles in BRCA1-dependent,homologous recombinationdirected repair. The process and molecular basis on how K63-linked polyubiquitination is regulated at DSBs and its role in BRCA1-dependent DNA damage repair and tumor suppression are largely undefined. This proposal will aim to isolate and characterize these K63-Ub polyubiquitinated proteins that are associated with DNA damage repair, and to disclose the biochemical pathways for the synthesis as well as hydrolysis of K63-Ub at sites of DSBs. Moreover, siRNA or shRNA-based knockdown cell lines will be generated to investigate the possible correlation between the levels of K63-linked polyubiquitination and BRCA1-dependent homologous recombination in the suppression of breast cancer. This study will provide novel insights into BRCA1 biology and the mechanism underlying its tumor suppression。 It will also promote the identification of breast cancer susceptible genes,and have implications in the screening, diagnosis and treatment of breast cancer as well as in the development of anti-tumor drugs.