DNA同源重组修复缺陷与乳腺癌发生显著相关，但已知的易感基因突变不能完全解释其肿瘤发生及靶向药物耐药机理，提示有重要分子和调控机制待发掘。我们基于自身前期研究（Nature Comms, 2016; Cell Reports, 2015），鉴定了同源重组修复关键因子BRCA2的新调控蛋白RINT1，初步研究表明其参与DNA损伤应答和同源重组修复。结合乳腺癌病例中生殖系突变报道，本研究拟：1.在细胞水平确证RINT1在DNA损伤应答中的功能定位及调控机制；2.鉴定RINT1/BRCA2互作区段，构建乳腺癌致瘤性RINT1突变的稳定细胞株，通过突变-遗传回补分析解析在细胞水平该复合物调控同源重组修复的分子机制；3.建立基于病理性突变的荷瘤裸鼠模型，评估荷瘤对PARP inhibitor药物的响应，确证乳腺癌病理性RINT1突变与同源重组修复之间功能联系, 完善乳腺癌发生机理为其诊疗提供理论参考

Defective DNA homologous combination repair (HR) predisposed to the breast cancer. However, neither the breast cancer tumorigenesis nor the drug resistance of the PARP inhibitor therapy could be comprehensively accounted for the HR deficiency dysregulated by the germline and acquired mutations within discovered susceptible genes. It indicates that some unknown factor and involved mechanism function as regulator imposing on HR signaling pathway. Based on our previous published studies（Nature Comms, 2016; Cell Reports, 2015） we have identified a novel BRCA2 regulator, RINT1. Our preliminary data suggest that RINT1 is involved in DNA damage response and is important for the proper progression of HR signaling pathway. Thus, concerning the published germline mutations of the RINT1, we propose the further study as below to dissect the functional role of RINT1 in DNA damage response, HR signaling regulation and breast cancer tumorigenesis..1. Study the role of RINT1 in response to DNA damage. .2. Study the regulation of BRCA2 by RINT1 and the subsequent outcome in HR repair signaling. .3. Through cellular and xenograft assay, study the function of the RINT1 germline mutation in the DNA homologous repair signaling and its role in the drug response with PARP inhibitor chemotherapy which targeting the defective HR pathway. .Our research would expand our knowledge of the role of RINT1 in DNA damage response, HR signaling and breast cancer tumorigenesis which will contribute to the resolution of the drug resistance of PARP inhibitor chemotherapy as well.