科凯恩综合征是一种罕见的高致死性“早衰症”，其发病机理是“转录偶联核苷酸剪切修复”（TC-NER）起始阶段中两个关键基因csb或csa突变异常，造成胞内DNA损伤无法修复导致细胞加速衰老死亡。CSB蛋白在TC-NER中如何协调被DNA损伤阻滞的RNA聚合酶II（Pol II）和下游修复蛋白的相互作用是当前的研究热点。而CSB另一重要功能“染色质重塑”，其分子机理还亟待深入研究，并且CSB染色质重塑与科凯恩综合征如何关联仍不清楚。申请人在前期大量TC-NER相关工作的基础上，拟结合结构生物学、生物化学、细胞生物学等手段系统研究CSB在染色质重塑方面的分子机制，包括N端自抑制的结构基础，CSB与核小体相互作用的分子表征等。在创造性构建“Pol II-核小体-CSB”体外转录系统的基础上，深入研究“转录偶联的染色质重塑”的分子机制，以期探索CSB染色质重塑与科凯恩综合征之间的病理学关系。

Cockayne syndrome is a rare and fatal "premature-aging disease". The main cause of this disease is that some mutations of csb or csa gene lead to failure of DNA repair to accelerate aging and death of cells at the initial stage of “transcription-coupled nucleotide excision repair” (TC-NER). Hence, the current study of CSB mainly focuses on how CSB coordinates the RNA polymerase II (Pol II) blocked by DNA damage and the downstream proteins in TC-NER pathway. Another important function of CSB is “chromatin remodeling”. However, its precise molecular mechanism is still largely unknown, which needs to be analyzed systemically. Especially, the correlation between CSB chromatin remodeling and Cockayne syndrome remains ambiguous. Based on our previous study and preliminary data about TC-NER, a research program that combines approaches of structural, biochemical, cellular biology will be assembled to solve these basic problems about chromatin remodeling by CSB, including N-terminal auto-inhibition, the representations by interacting with nucleosome, etc. Based on the creative construction of “Pol II-nucleosome-CSB” transcription system in vitro, the molecular mechanism of “transcription-coupled chromatin remodeling” will be studied in order to explore the relationship between the function of CSB chromatin remodeling and Cockayne syndrome.