BRCA1既是乳腺癌发生易感基因，又是其放射敏感性的关键调控基因。DNA解螺旋酶WRN，在DNA复制和损伤修复中发挥重要功能。我们前期工作表明，WRN能和BRCA1直接相互作用，影响DNA损伤修复复合体Rad51-ssDNA的稳定性和乳腺癌细胞放射敏感性。在此基础上，本课题将进一步探讨：1）确定和BRCA1直接相互作用的WRN具体功能结构域，及与该结构域相互作用的BRCA1关键磷酸化位点；2）探索辐照后WRN-BRCA1调控Rad51-ssDNA复合体动态解聚效应及分子机制；3）辐照后，WRN-BRCA1调控Rad51-ssDNA核蛋白丝解聚的分子事件和染色体基因组不稳定性的关联性；4）在动物水平检测WRN、BRCA1相互作用及对乳腺癌放射敏感性的影响。这些研究的开展，将进一步阐明BRCA1和WRN相互作用及调控辐射敏感性的机制，并为放射增敏的靶向药物开发及乳腺癌综合治疗提供新思路。

BRCA1, multiple functions in breast cancer susceptibility and DNA damage and repair, plays key roles in homologous recombination repair pathway. WRN as a helicase involves in DNA replication and genome stability. My previous data showed that WRN cooperated with BRCA1 influencing breast cancer cells radiosensitivity. Based on our preliminary data, we will further explore the function of WRN-BRCA1 in regulating Rad51-ssDNA filament dynamic equilibrium in IR induced DSBs in S phase in breast cancer. 1) How does WRN cooperate with BRCA1 in response irradiation stress and which BRCA1 phosphorylation site activates in this process? 2) What’s the mechanism of WRN-BRCA1 in regulating Rad51-ssDNA complex forming and dissolving and in response DNA damage repair? 3) Clarify the function that WRN-BRCA1 keeps the genome stability after breast cancer cells irradiation damage. This investigation will explore and develop the molecular mechanism for WRN-BRCA1 in HR pathway through Rad51-ssDNA depolymerization in breast cancer cell irradiation damage. It will also support the design for breast cancer radiosensitivity drug in clinical therapy through blocking the WRN-BRCA1 signal pathway.