DNA损伤修复因子CSB介导lncRNA-ZFAS1调控DNA损伤修复应答的作用机制研究

DNA损伤修复因子CSB的突变可引起儿童罕见神经系统疾病科凯恩氏综合症，发病机制不明确成为制约临床治疗手段开发的瓶颈。申请人前期研究成果表明CSB蛋白可作为转录因子调控神经发育相关基因的表达，从而保护性干预DNA损伤修复和神经元再生，但这一过程的具体机制和潜在靶标还不清楚。预实验结果观察到基因组非编码区域的表达在DNA损伤修复过程中的动态变化规律，其中被主动激活的lncRNA-ZFAS1与CSB的表达高度相关，这预示lncRNA-ZFAS1可能是调控DNA损伤修复与科凯恩氏综合症进程的关键因子。在此研究基础上，本项目拟深入探讨：① CSB蛋白调控靶标lncRNA-ZFAS1的分子机制。② 靶标lncRNA-ZFAS1参与DNA损伤修复应答的功能效应和作用机制。本研究将为丰富对长非编码RNA的生物学功能认知提供新思路，同时为长非编码RNA作为神经系统疾病干预靶点提供理论基础。

Mutations of the DNA damage repair factor CSB can cause children’s rare neurological disease Cockayne syndrome. The unclear pathogenesis has become a bottleneck restricting the development of clinical treatment. Our previous studies have proved that CSB protein acts as a transcription factor to regulate the expression of genes related to neural development, so as to protect from DNA damage and promote neural regeneration. However, the specific mechanism and potential target of this process are largely unknown. The results of pioneer experiments have illustrated the dynamic expression of non-coding regions of genome during the DNA repair process, among which lncRNA-ZFAS1 is actively induced and highly correlated with the expression of CSB, which indicates that lncRNA-ZFAS1 could be a key factor in regulating DNA repair process and the progression of Cockayne syndrome. In order to evaluate the underlying molecular mechanism, the applicant proposed the following key questions: 1. What is the specific mechanism by which CSB protein activates lncRNA-ZFAS1? 2. How does lncRNA-ZFAS1 activation participate in DNA damage response? This study will for the first time help clarifying the molecular mechanism of CSB protein regulating DNA damage repair process via mediating expression of lncRNA-ZFAS1, expanding the understand of the biological functions of long non-coding RNAs, and providing a theoretical basis for long non-coding RNA as an intervention target for central nerve system diseases.