AMPK参与DNA损伤修复的蛋白调控网络及其分子机制研究

Cancer is kind of diseases caused by multiple factors, featured as high heterogeneity from internal environment and high adaptability to external environment. Despites of differences in tumor types and individual microenvironments, it is believed that cancer share common molecular features such as metabolic stress, DNA damage stress, escape of immune supervision. This study focused on the role of AMPK, a core cellular energy sensor, in cancer development and therapy. Based on the information from systematic quantitative proteomics and bioinformatics analysis, we wanted to understand: 1) the molecular mechanism and biologic function of AMPK-mediated phosphorylation on its new substrate candidate, 53BP1 involved in DNA damage repair, as well as the possibility that enhanced anti-tumor effect achieved by AMPK inhibition in combination with DNA damage agents; 2) the molecular mechanism of AMPK’s function in perturbing cancer related sensitive signaling network and histone posttranslational modification, as well as the feasibility of combination cancer therapy with AMPK inhibition. The purpose of this study is to provide new clues for understanding AMPK’s role in the development of tumorigenesis and important theoretical basis for understanding whether AMPK could be a new target in cancer therapy.

肿瘤是一类多因素导致的复杂疾病，表现为肿瘤内部环境的高异质性和对外部环境的高适应性。尽管肿瘤存在种类差异和个体差异，但在代谢压力、DNA损伤修复异常、免疫逃逸等方面具有共同的分子特征。本项目拟以细胞能量代谢核心感受器AMPK为研究切入点，在前期获得的系统定量组学和生物信息学分析数据基础上，从发现AMPK新底物和新调控网络出发，深入探讨1）AMPK直接磷酸化DNA损伤修复核心蛋白53BP1的分子机制、参与DNA损伤修复生物学功能及其与DNA损伤药物联用的可行性；2）AMPK扰动肿瘤相关重要信号网络及组蛋白翻译后修饰的分子机制及与相关抗肿瘤药物联用的可行性。旨在为理解AMPK参与DNA损伤修复及肿瘤发生发展生物学功能提供新线索，为确证AMPK是否可成为肿瘤新靶点提供重要理论依据。

肿瘤是一类多因素导致的复杂疾病，表现为肿瘤内部环境的高异质性和对外部环境的高适应性。尽管肿瘤存在种类差异和个体差异，但在代谢压力、DNA损伤修复异常、免疫逃逸等方面具有共同的分子特征。本项目以细胞能量代谢核心感受器AMPK为研究切入点，在前期获得的系统定量组学和生物信息学分析数据基础上，从发现AMPK新底物和新调控网络出发，深入探讨了1）AMPK直接磷酸化DNA损伤修复核心蛋白53BP1的分子机制、参与DNA损伤修复生物学功能。具体来说我们发现AMPK通过促进53BP1的招募促进c-NHEJ，而维持基因组稳定性；AMPK直接磷酸化下游新底物53BP1-S1317位点调控DNA损伤修复；AMPK所介导的S1317位点的磷酸化促进c-NHEJ和基因组稳定性。2）AMPK扰动肿瘤相关重要信号网络及组蛋白翻译后修饰的分子机制及与相关抗肿瘤药物联用的可行性，利用组蛋白修饰组学揭示AMPK调控乙酰化修饰，并发现AMPK抑制剂和抗肿瘤药物JQ-1联用的治疗策略。旨在为理解AMPK参与DNA损伤修复及肿瘤发生发展生物学功能提供新线索，为确证AMPK是否可成为肿瘤新靶点提供重要理论依据。