CST复合物在维持端粒稳定性中的结构与功能研究

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 telomere binding proteins. Telomerase and telomere binding proteins play important roles in maintaining the completeness of genome and the stability of chromosomes, and are key factors in carcinogenesis and aging. Telomerase and telomere binding proteins have become one of the fast growing forefronts in biological science. Telomerase and telomere binding 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 CST complex which locates at single-strand DNA (ssNDA) region of telomere and participates in protecting and regulating telomere. We will focus on the structural basis of CST complex assembly, and the molecular mechanism of telomeric ssDNA recognition and association by CST complex. In addition, we will also study the relationship between CST complex and other telomere related proteins such as telomerase complex and DNA polymerase a – primase complex. The proposed study will provide a solid foundation for our understanding of telomerase and telomere binding proteins in maintaining chromosomal and genomic homeostasis.

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ssDNA结合蛋白CST复合物为研究对象，综合运用多种技术手段，在分子水平上探索CST复合物正确组装的结构基础，CST复合物识别与结合端粒ssDNA的分子机制，以及CST复合物与端粒酶复合物、DNA聚合酶a–引物酶复合物等其他端粒相关蛋白复合物之间的关系。研究成果可以为我们更好的理解端粒酶和端粒结合蛋白维持染色体和基因组动态平衡中的作用奠定重要的基础。

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。紧紧围绕项目计划书预定目标，综合运用多种技术手段，我们对CST等重要的端粒相关蛋白质复合物开展了系统性的研究，取得了多项突破性的研究成果，上述研究成果为相关疾病发病机理的探索及新型药物的研发等奠定了良好的理论基础。本项目执行过程中，多名人员参与了相关课题的研究工作，目前已有3名博士研究生顺利毕业。