BARD1识别损伤的染色质并启动同源重组修复的机制研究

DNA复制对于遗传信息的稳定传递和生命繁衍至关重要，细胞DNA复制期产生的DNA双链断裂（DNA double-strand breaks，DSBs）是基因组稳定性的重大威胁。细胞通过同源重组——一种无错的修复途径——对复制期的DSB进行修复，确保遗传信息的准确稳定传递。前人研究表明，肿瘤抑制蛋白BRCA1与BARD1组成的异源二聚体在DSB修复上发挥重要作用。其中，BARD1蛋白通过识别染色质上特异的组蛋白修饰将BRCA1定位到DSB位点，在同源重组途径的选择过程中发挥决定性作用，但其分子机制并不清楚。申请人将测定BARD1与带有特定组蛋白修饰的核小体的复合物结构，在此基础上，通过生物化学、生物物理学以及细胞生物学等方法研究BRCA1-BARD1复合物识别损伤位点并促进同源重组修复的分子机制。该研究对于阐明DSB修复通路的调控机制以及其与癌症的关系具有重要的意义。

DNA replication is central to the stable transfer of genetic information and our life. DNA double-strand breaks (DSBs) generated during DNA replication are deleterious to genome integrity. Cells employ homologous recombination (HR)— an error-free repair pathway— to restore genetic information during S phage, thereby ensuring genome stability. Previous results showed that tumor suppressors BRCA1 and BARD1 constitute a heterodimer that plays a critical role in dictating the HR pathway. In response to DSB, BARD1 recognizes chromatin bearing specifically modified histones to direct localization of the BRCA1 at damaged sites and finally support homologous recombination, but the underlying mechanism remains unclear. Here, we propose to determine the structure of BARD1 in a complex with a modified nucleosome. Further, we aim to study the molecular mechanism by which BRCA1-BARD1 recognizes damaged chromatin and directs homologous recombination by integrating biochemical, biophysical, and cellular approaches. The knowledge we gain in this study is critical to understanding the regulation of the DSB repair pathway and will shed light on its relation to tumorigenesis.