STRIPAK复合物调控DNA损伤修复及肠癌化疗耐药的功能与机制研究

结直肠癌是世界范围内高发恶性肿瘤，耐药是其临床治疗中面临的重大挑战。DNA损伤修复异常激活是驱动肿瘤耐药的重要机制。STRIPAK是一类进化保守的包含多个蛋白的超大复合物，与肿瘤等疾病密切相关。申请人专注于DNA损伤修复与肿瘤发生机理研究，发现了一系列重要的调控因子及其分子机制(J Exp Med 2020; PNAS 2018; PNAS 2017)。申请人所在团队近期报道了STRIPAK的整体组装结构，申请人进一步发现STRIPAK响应DNA损伤刺激而动态组装，促进DNA双链断裂损伤修复，影响肠癌细胞放化疗敏感性，并在耐药型病人组织中表达升高(未发表)。据此，本项目拟深入阐释该复合物调控DNA损伤修复的分子信号通路和机制，进而揭示其在肠癌化疗耐药过程中的异常变化与病理作用，探索耐药肿瘤再致敏的新途径。综上，本项目将在创新DNA损伤应答理论的同时，为克服肠癌耐药提供新的策略和靶标。

Colorectal Cancer (CRC) is one of the most prevalent malignant tumors worldwide. Though chemotherapy is widely used for treatment of CRC patients in clinic, drug resistance is one major challenge faced for its wide application. Aberrant activation of the DNA repair machinery acts as one key mechanism for acquired drug resistant in tumors. The striatin-interacting phosphatases and kinases (STRIPAK) complex was identified as a conserved supramolecular complex, and has been involved in multiple human diseases including cancer. The applicant has been focusing on characterization the molecular mechanisms during tumorigenesis, and has identified several key modulators, as well as elucidated their underlined molecular mechanisms, during tumor initiation and tumorigenesis processes (J Exp Med 2020; PNAS 2018; PNAS 2017). Recently, the applicant’s lab solved the core substructures of STRIPAK complex and revealed its dynamic assembly in response to stress conditions. Here the applicant found that DNA damage signals efficiently induce the assembly of STRIPAK complex, which reversely promotes the DNA double strand break (DSB) repair and confers the sensitivity of CRC cells to chemotherapy or radiotherapy. Interestingly, expression of several components in the complex were upregulated in drug resistant CRC patient samples (unpublished data). Based on these observations, the applicant will strive to decipher the signal transduction pathways and molecular mechanism (s) of how STRIPAK complex regulates DNA damage repair, and to reveal the abnormal changes and pathological association with CRC drug resistance, and at last to explore novel strategies to re-sensitize the drug resistant tumors to chemotherapy. Collectively, this study will not only shed lights on the identification of new regulatory network in DNA damage responses, but provide novel scientific evidences and potential targets to overcome the CRC drug-resistant issue in clinic.