Pol II 转录过程中检测到模板链上的DNA损伤引发TCR。CSB是TCR发生时最先被招募的蛋白因子。CSB功能异常导致科凯恩氏综合症，其临床表现为各种生长发育缺陷、光敏感、身体和智力发育障碍及未老先衰等症状。申请人在Pol II处理DNA损伤的结构基础及CSB相关的功能研究中积累了丰富经验，相关研究成果发表于Nature和PNAS。之前的研究阐明了CSB蛋白家族存在的N端自抑制的分子机制。本课题拟在前期工作的基础上，通过研究CSB或其同源蛋白（Rhp26等）及CSB/Rhp26与其相互作用因子（dsDNA，Pol II，核小体）形成的复合物结构和功能，阐明如下关键科学问题：CSB N端自抑制的结构基础；CSB如何调控Pol II相关的转录及TCR；CSB如何调控染色质重组；CSB氨基酸位点的突变与科凯恩氏综合症的关联性。期望为科凯恩氏综合症的诊治提供新的药物靶点和理论依据。

TCR（Transcription Coupled DNA Repair）is a DNA damage repair pathway that is initiated when transcribing Pol II detects the DNA damage on the DNA template. CSB is the first protein factor to be recruited when TCR occurs. It is a dsDNA-dependent ATPase and belongs to SWI2 / SNF2 protein family. CSB also functions as both a transcription factor and a chromatin remodeler. The dysfunction of CSB causes Cockayne syndrome, an autosomal recessive genetic disorder characterized by a variety of growth and developmental defects, photosensitivity, physical and mental retardation, premature aging and other clinical symptoms. The Applicant has accumulated extensive experience in the structural basis of Pol II processing different DNA damages and the functional studies of CSB, and the results have been published in Nature and PNAS accordingly. Our previous study has identified the mechanism of the conserved self-inhibition at the N-terminus of CSB family proteins. Based on the previous studies, this proposal is to study the structures and functions of CSB or its homologous protein (Rhp26, etc.) and CSB / Rhp26 complex with its interaction factors (such as dsDNA, Pol II, and nucleosome) to clarify the following key scientific questions: the structural basis of the self-inhibition at CSB N-terminus; how does CSB regulate Pol II-related transcription and TCR; how does CSB regulate chromatin remodeling; and What is the potential linkage between CSB site mutations and the Cockayne syndrome? This eventually provides new targets and theoretical basis for the diagnosis and treatment of Cockayne syndrome.