DNA双链断裂修复通路与癌症发生及治疗密切相关，其缺陷引起的基因组不稳定性增加及体细胞突变是癌症发生的重要原因之一。解析DNA双链断裂修复过程的核心步骤及挖掘该过程的关键调控因子是理解癌症发生机制的重要途径。AMP依赖的蛋白激酶AMPKα是细胞能量状态的感受器及代谢途径的核心调节因子，但其在DNA损伤应答中的作用还少有报道。应用激光微辐射技术在核内定点诱发DNA双链断裂后，我们发现蛋白AMPKα（AMPKα1和AMPKα2亚基）被快速招募至断裂位点，且招募过程受多聚ADP-核糖化修饰（PAR）调控。AMPKα敲低导致X线造成的DNA损伤持续存在，表明其导致细胞修复速率下降。由此，本项目将重点研究AMPKα在双链断裂修复中的作用，鉴定其下游蛋白，解析其发挥功能的分子机制，进而以卵巢癌为模型探讨该功能的病理意义。研究结果将为DNA损伤修复机制提供新内容并为卵巢癌的治疗提供新思路。

DNA double-strand breaks repair pathways in mammalian cells are closely related to the occurrence and treatment of cancer. The increased genomic instability and somatic cell mutations caused by DNA double-strand break defect is one of the important causes of cancer. It is essential to dissect the key steps and screen novel regulators of DNA double-strand breaks repair process in understanding the mechanisms of cancer development. AMP-dependent protein kinase AMPKα is the sensor of cellular energy state and core regulator of metabolic pathways, but its involvment in DNA damage response has rarely been reported. Using laser micro-irradiation technique, we induced DNA double-strand breaks in specific regions of nucleus, and subsequently observed rapid recruitment of AMPKα (including AMPKα1 and AMPKα2) to damage sites. Inhibitor treatment assays revealed the recruitment was regulated by poly-ADP-ribosylation (PAR) modification. Moreover, AMPKα knockdown leaded to the persistence of DNA damage marker γH2AX in X-Ray treated cells, which indicated the decreased repair efficiency due to AMPKα deficiency. Based on the above results, in this project, we will focus on the function of AMPKα in double-strand breaks repair, identify its downstream target, elaborate the molecular mechanisms of its function and then explore the pathological significance of this function in ovarian cancer. This project will complement mechanisms of DNA double-strand breaks repair and provide new ideas for understanding the treatment of ovarian cancer.