错配修复蛋白MSH2调控跨损伤DNA合成与疾病发生研究

项目名称： 错配修复蛋白MSH2调控跨损伤DNA合成与疾病发生研究

项目编号： No.31471331

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： 郭彩霞

作者单位： 中国科学院北京基因组研究所

项目金额： 85万元

中文摘要： 跨损伤DNA合成（TLS）能利用特异的低保真度DNA 聚合酶在损伤DNA加合物对侧复制DNA，避免细胞产生DNA双链断裂甚至死亡。已知聚合酶Polη能正确复制紫外辐射产生的CPD加合物，缺失Polη使细胞的紫外突变率和皮肤癌发生率显著上升。然而由于TLS聚合酶在复制未损伤模板时的低保真性，体内TLS过程受到严格调控。我们最近研究意外发现错配修复关键分子MSH2能调控UV辐射诱发的PCNA单泛素化和TLS聚合酶招募。在本项目中，我们将应用多种分子和细胞生物学技术、结合临床样本，深入研究MSH2调控紫外辐射后PCNA单泛素化以及Polη功能的机制，探讨MSH2突变导致的Polη功能异常与疾病发生相关性。结果将有助于阐明基因组变异发生机制、明确多种DNA损伤应答通路之间的相互作用，对于深入理解癌症发生和进行肿瘤防治提供重要的理论基础。

中文关键词： 基因组稳定性；DNA损伤修复；DNA聚合酶；紫外辐射

英文摘要： Translesion DNA synthesis (TLS) can limit the production of DNA double-strand breaks and cell death by utilizing specialized DNA polymerases which have low fidelity to insert and/or extend nucleotides across lesions in genome. A best example is that Polη can bypass UV-induced CPD lesions correctly and efficiently, whose deficiency leads to a high mutation rate and skin tumors. Given their low fidelity when copy undamaged templates in vitro, it is believed that in vivo TLS process is strictly regulated. Recently, we found in surprise that MSH2, an important mismatch repair protein, can regulate PCNA monoubiquitination and TLS polymerase recruitment after UV irradiation. We will combine multiple cellular, biochemical & molecular techniques to explore the regulation mechanism of MSH2 on PCNA monoubiquitination and Polη function after UV irradiation in detail. We will also clarify whether Polη dysfunction caused by MSH2 mutations is related to the skin tumor development in some colon cancer patients. We believe these results will not only provide clues to the underlying mechanisms about genome variations, but also help us clarify the interplay among multiple pathways in DNA damage response, which will be important for understanding carcinogenesis and finding strategies to reduce its risk.

英文关键词： genome stability;DNA damage repair;DNA polymerase;UV irradiation