DNA双链断裂在所有DNA损伤中最为严重，这种损伤可被两条独立的通路——同源重组（HR）以及非同源末端连接（NHEJ）修复，而这种损伤的发生与修复的平衡与肿瘤发生、维持以及治疗关系紧密。肝癌恶性程度高，预后较差，是导致癌症相关死亡的第二大肿瘤。但是由于缺少合适的小鼠研究工具，在肝癌发生发展过程中，HR和NHEJ的效率及精确性的变化以及相应调控机制尚未被深入研究。申请人计划利用本课题组可用于体内检测HR和NHEJ的报告小鼠模型，结合化合物诱导小鼠肝癌发生的方法，研究肝癌发生过程中HR和NHEJ效率及精确性的变化。基于该现象的研究，申请人计划与临床合作获得大量的肝癌和癌旁标本，并结合TCGA数据库中相关数据，阐述肝癌发生过程中以及发生后HR和NHEJ的变化的调控机制。基于机制研究，申请人将探索是否可通过提高DNA修复能力预防肝癌，以及通过靶向HR和NHEJ治疗肝癌，为临床应用奠定理论基础。

DNA double strand breaks (DSBs) are the most detrimental type of DNA damage. Two repair pathways, homologous recombination (HR) and nonhomologous end joining (NHEJ), are responsible for fixing the broken ends. If DSBs are not repaired or improperly repaired, they may lead to tumorigenesis. Ironically, previous research has also indicated that tumor cells can take advantage of DNA DSB repair machineries to overcome replication stresses, making these pathways good targets for cancer therapy. However, most of research on tumorigenesis associated DNA DSB repair, and developing therapeutic methods by targeting DNA DSB repair, was performed using in vitro cultured cells. Whether DNA DSB repair changes during tumorigenesis in vivo has not been assessed due to a lack of an appropriate tool. Liver cancer is one of the deadliest cancers among all types of tumors and it is listed as the second leading cause of cancer mortality in the world. The methods of inducing hepatocellular carcinoma (HCC), the major type of liver cancer, in mice have been well established, rendering it an ideal model for studying the change of physiological parameters during tumorigenesis in vivo. Here using our newly developed knock-in mouse models for in vivo analysis of HR and NHEJ efficiency and fidelity we propose to accomplish the following goals: aim 1. to optimize the conditions for analyzing the efficiency of both pathways and NHEJ fidelity in mouse livers using our reporter mice; aim 2. to analyze the change of DSB repair efficiency and fidelity during HCC tumorigenesis; aim 3. to elucidate the regulatory mechanisms of tumorigenesis associated change of DSB repair using mouse models, clinical samples and data mining methods; aim 4. to study whether it is possible to prevent liver tumorigenesis by promoting DNA DSB repair efficiency and stabilizing genomes; aim 5. to study whether it is possible to treat HCC by targeting two DNA DSB repair pathways with small molecules.