类泛素化修饰Neddylation在DNA损伤应答中的调控作用及分子机制

项目名称： 类泛素化修饰Neddylation在DNA损伤应答中的调控作用及分子机制

项目编号： No.31470754

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 郑晓峰

作者单位： 北京大学

项目金额： 90万元

中文摘要： DNA损伤会造成基因组的不稳定，导致肿瘤等恶性疾病的发生。蛋白质翻译后修饰在DNA损伤应答调节中发挥重要作用，目前研究较多的是泛素化和SUMO化修饰，但有关类泛素化修饰Neddylation的报道非常少，在DNA损伤应答中已鉴定的Neddylation底物非常有限。我们的前期工作发现DNA损伤应答蛋白H2A和PCNA能够发生Neddylation。本课题将围绕Neddylation在DNA损伤应答中的调控作用及分子机制这个核心科学问题开展研究：鉴定DNA损伤应答中新的Neddylation底物蛋白，寻找并鉴定其E3连接酶，揭示其发生Neddylation的分子机制；研究Neddylation与泛素化修饰在DNA损伤应答中的相互作用关系；阐明Neddylation在DNA损伤应答中的调控作用。该研究将有助于深入理解肿瘤等疾病发生的分子机理，为寻找新的治疗靶点提供理论基础。

中文关键词： 类泛素化修饰；DNA损伤应答；分子机制；泛素化修饰；E3；连接酶

英文摘要： DNA damage induced by numerous environmental and internal hazards triggers genomic instability, and ultimately promotes tumorigenesis. To cope with these damages, cells have developed a DNA damage response （DDR）system to sense and repair DNA lesions. Various protein modifications play important roles during DNA damage response. Both Ubiquitin and members of the SUMO family have been widely studied and shown to participate in DNA damage response. However, the physiological functions of Neddylation in DNA damage remains unclear. The neddylation conjugation pathway has a pivotal role in regulation of numerous biological processes. But very limited Neddylation substrates in DNA damage response have been identified so far, and further investigations are necessary. Our previous work has found that H2A and PCNA that invovled in DNA damage response could be modified by NEDD8. In this study, we will carry out a series of experiments to investigate the regulatory functions of Neddylation in DNA damage response and elucidate the underlying mechanism. We will identify novel substrates that could be covalently conjugated by NEDD8 during DNA damage response; we will identify the E3 ligases of these NEDD8 sustrates, and elucidate the underlying molecular mechanism of Neddylation of these DDR proteins. We will further investigate the effect of Neddylation on the recruitment of DNA damage repair proteins and clarify the physiological roles of protein neddylation in DNA damage response. As ubiquitination plays important role in the DNA damage response process, the overall structure of NEDD8 is very similar to ubiquitin and these two types of modification occur on the same lysine residue in some proteins, we will also study the relationship between protein ubiquitination and neddylation, and assess the spatio-temporal variability of these two modifications during DNA damage response. These studies will help us to further understand the molecular mecahnisms of diseases such as tumorigenesis, and provide insight for drug design in the future.

英文关键词： Neddylation;DNA damage response;molecular mechanism;ubiquitination;E3 ligase