雷特综合症致病蛋白MeCP2在DNA损伤修复中的功能及分子机制研究

雷特综合症（Rett syndrome，RTT）是一种严重影响儿童语言、精神和运动能力的神经遗传病，甲基化CpG结合蛋白2（methyl-CpG-binding protein 2, MeCP2）基因突变是导致RTT的主要原因，但RTT病理发生的分子机制尚未明确。以往研究主要聚焦在MeCP2的转录调控和染色质结构调节。然而，目前人们对MeCP2分子功能的了解还很不全面，尤其是其在不依赖转录调控的功能方面还不清楚。我们前期结果显示MeCP2突变的RTT模型小鼠大脑中存在明显的DNA修复延迟，提示MeCP2参与了DNA损伤后的修复过程。因此，本研究将利用RTT模型小鼠，在细胞及动物水平上解析MeCP2招募到DNA损伤位点的分子机理，阐明MeCP2在DNA损伤修复通路中的功能及分子机制，明确MeCP2突变导致的DNA修复障碍与RTT之间的内在联系，从而为该疾病治疗手段的研发提供新思路。

Rett syndrome (RTT) is a severe and progressive neurodevelopmental disorder characterized by the loss of spoken language and motor skills during early childhood. Mutations of the methyl-CpG binding protein 2 (MeCP2) gene are the most prevalent causes of classical RTT cases. However, the precise pathogenic mechanisms of RTT remain uncertain. Previous studies focus on the critical roles of MeCP2 in transcriptional regulation and modulating chromatin structure. However, our current knowledge about its molecular function is not comprehensive. Apart from the role of MeCP2 in transcriptional regulation, its other biological functions have not been fully explored. Recently, we found that the brains from RTT model mice manifest prolonged DNA damage response, indicating it functions in the DNA repair process after DNA damage. Therefore, in the present project, we will explore how MeCP2 is recruited to the sites of DNA damage. We will further investigate the detailed functions and molecular mechanisms of MeCP2 in DNA repair in cells as well as in RTT model mice. These findings will help us for a deeper understanding of the link of DNA repair and the molecular mechanism underlying RTT, and for offering new therapeutic targets for the disease cure.