POT1-TPP1保护端粒单链DNA的分子机制

项目名称： POT1-TPP1保护端粒单链DNA的分子机制

项目编号： No.31500625

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 武健

作者单位： 上海交通大学

项目金额： 20万元

中文摘要： 端粒是真核生物线性染色体末端的特殊结构，其DNA长度受端粒酶和端粒结合蛋白的严格调控。端粒酶和端粒结合蛋白对维持基因组完整性与染色体稳定性至关重要，并在癌症与衰老等过程中发挥重要作用。有关端粒酶和端粒结合蛋白的研究已成为生命科学前沿快速发展的热点领域，与之相关的生物学问题也已成为生命科学研究的主要任务，对这些问题的解答具有重要的生物学意义和潜在的应用价值。在本项目中，我们将以端粒结合蛋白Shleterin复合物核心组分POT1和TPP1为研究对象，综合运用多种技术手段，在分子水平上探索POT1-TPP1复合物的功能与结构基础、特异性识别与结合端粒ssDNA的分子机制、POT1-TPP1-ssDNA所形成的端粒DNA末端高级结构的分子基础，以及它们的结构变化导致的功能失调与重要疾病发生发之间的关系。研究成果可为相关的疾病机理探索及新型药物研发等奠定重要的基础。

中文关键词： 蛋白质；DNA；端粒；结构稳定性

英文摘要： Telomeres, the ends of linear eukaryotic chromosomes, are characterized by multiple protein complexes and tandem repeats of a short DNA sequence whose length is tightly regulated by telomerase and telomeric proteins. Telomerase and telomeric proteins play important roles in maintaining the completeness of genome and the stability of chromosomes, and are key factors in carsinogenesis and aging. Telomerase and telomeric proteins have become one of the fast growing forefronts in biological science. Telomerase and telomeric proteins related key scientific issues have also become the major research focus and the answers to these questions will have great impact on life science research with important application values. In this project, we will employ a combination of structural biology, molecular biology, biochemistry, and cell biology to study the structure and function of POT1 and TPP1, which are the core components of Shelterin complex and locate at single-strand DNA region of telomere. We will focus on the molecular mechanism of telomeric ssDNA recognition and association by POT1-TPP1, and the structural basis of specific structure formed by POT1-TPP1-ssDNA at the end of telomere. In addition, we will also study the relationship between dysfunctional telomeres and diseases. The proposed study will provide a solid foundation for our understanding of telomere and telomerase and open a new horizon on noval drug development.

英文关键词： Protein;DNA;Telomere;Structural stability