表观遗传调控是维持基因组稳定性的基础，在DNA损伤修复方面起重要作用，DNA损伤修复的失败是肿瘤发生发展的常见原因。我们前期发现染色质重塑蛋白LSH具有抵抗顺铂的杀伤作用，亦可抑制铁死亡，同时发现LSH与PARP1、γ-H2AX、FAM175a等DNA损伤修复相关蛋白存在相互作用，这些均提示LSH参与DNA损伤修复，然而其机制尚不清楚。本项目拟以肺癌为研究对象，探讨LSH在PARP1依赖性DNA损伤修复中的关键作用。一方面研究LSH有可能通过与FAM175a的相互作用参与DSBs损伤修复（NHEJ和HRR途径）；另一方面研究LSH可与TET2相互作用使ROS相关基因去甲基化从而影响ROS水平，同时可能促进细胞内BER途径的活化提高细胞损伤修复能力，从而抵抗铁死亡。本项目将解析LSH在肿瘤发生发展中的新机制，多角度揭示LSH调控DNA损伤修复模式的新机理。

Epigenetic regulation is the basis of the maintenance of genome stability and plays a critical role in the process of DNA damage repair. Failures of the DNA damage repair are a common cause of cancers progression. We previously demonstrate that chromatin remodeling protein LSH can resist cell death and ferroptosis that is induced by cisplatin. LSH also interacts with DNA damage repair related proteins including PARP1, γ-H2AX and FAM175a. These findings indicate that LSH is involved in DNA damage repair. However, the mechanism for this is yet unclear. The project will use lung cancer as model to explore the key role of LSH in DNA damage repair as a dependent manner of PARP1. On the one hand, LSH could participate in DSBs damage repair (NHEJ and HRR pathway) by interacting with FAM175a. On the other hand, LSH might interact with TET2 and affect ROS level through demethylation of ROS-related genes, and LSH may promote the activation of intracellular BER pathway to improve damage repair ability, thereby resisting Ferroptosis. This project will confirm the critical role of LSH in carcinogenesis and reveal the new mechanism of LSH in regulating DNA damage repair from multiple viewpoints.