抑癌基因BRCA1是DNA损伤修复的核心分子之一，女性BRCA1突变会导致其一生中有高达90%的风险患乳腺癌。作为新一类治疗BRCA1缺陷乳腺癌的化疗药物，PARP抑制剂近年来倍受研究者关注。然而人们对PARP抑制剂的化疗机制仍不了解，这大大阻碍了该药的临床转化与治疗效果。申请人的前期工作发现PARP的生物合成物PAR可通过BARD1-BRCTs结构域与BRCA1/BARD1复合体结合，介导了BRCA1快速募集到DNA损伤位点；抑制PARP则阻断了BRCA1的快速募集，首次建立了PARP与BRCA1的分子联系。本项目将利用Parp1敲除MEFs与BRCA1突变肿瘤移植小鼠等模型，应用分子生物学、生物化学等手段，探讨不同BRCA1突变乳腺癌对PARP抑制剂的敏感性，揭示PARP抑制剂的化疗机制，为BRCA1缺陷乳腺癌的个体化治疗提供精准靶点，以及设计新一类PARP抑制剂提供理论依据。

The tumor suppression gene BRCA1 plays crucial role in DNA damage response and DNA repair. Breast cancer cases are often attributed to germline mutations of BRCA1, conferring lifetime risks of up to 90 % in the mutation women carriers for developing breast cancer. PARP inhibitors are emerging anticancer drugs for the chemotherapy of BRCA1-deficient breast cancer, and are attracting much attention of oncologic scientists. However, the chemotherapy mechanism of PARP inhibitor is far from clear, which affects the outcome of clinical treatment if the wrong targets are selected. Our recent finding reveals that PAR synthesized by PARP binds the BRCTs domain of BARD1, which mediates the quick recruitment of BRCA1/BARD1 complex to DNA damage sites. Inhibition of PARP suppresses the quick recruitment of BRCA1/BARD1. Thus, that work for the first time uncovered the molecular link between PARP and BRCA1. In this current proposal, by using Parp1-/- knockout MEFs and xenograft tumor mice model, we plan to study the sensitivity of the cancer cells bearing different BRCA1 mutations to PARP inhibitor, and to decipher the molecular mechanism of PARP inhibitor in breast cancer chemotherapy. This work will provide the specific targets for the treatment of BRCA1-deficient breast cancer, as well as the scientific basis for designing new PARP inhibitors.