Molecular mechanisms of intersecting human telomeric functions

人类端粒功能相交的分子机制 项目摘要/摘要 端粒在人类细胞中具有三种基本功能。首先，端粒保护染色体不受 灾难性的端到端融合，通过保护它们免受DNA损伤传感路径的影响。六人组 一种名为Shelterin的蛋白质复合体专门与端粒DNA结合，提供末端保护。第二，端粒 促进末端复制，允许干细胞/祖细胞和癌细胞等增殖细胞补充 染色体结束。一种名为端粒酶的复杂核糖核蛋白酶有助于解决末端复制问题。 端粒酶通过使用其RNA模板将端粒DNA添加到染色体末端来促进末端复制。 虽然体细胞中的端粒酶激活是癌症的标志，但干细胞中的端粒酶功能障碍 会导致一种称为端粒病的疾病。保护素必须保护染色体末端不受非法DNA融合的影响 但允许端粒酶达到相同的目的。一种名为TPP1的避难所蛋白在招聘过程中起着重要作用 端粒酶对端粒的作用，允许掩蔽素促进末端保护和末端复制，但分子 TP1在S期如何从末端保护模式切换到末端复制模式的机制尚不清楚 为人所知。第三，端粒帮助同源染色体进行配对和减数分裂交叉，以便于 配子制作。为了执行这一功能，端粒在核膜的帮助下附着在核膜上 减数分裂特异蛋白复合体TERB1-TERB2-Majin，与细胞骨架力量- 发电机械。这允许染色体移动，使同源染色体配对并 进行减数分裂交换。配对的减数分裂染色体必须防止端粒重组 核膜，但这是如何发生的，在分子水平上尚不清楚。照亮分子 三种端粒功能之间的相互作用将丰富我们对基因组完整性如何维护的理解 并为癌症、端粒病和不孕不育等疾病提出了新的治疗途径。这项建议 旨在应用端粒、端粒酶和减数分裂组装的知识，以及生物化学方面的专业知识， 结晶学和细胞生物学，以了解人类端粒如何执行其三个关键功能， 特别是在这些相互冲突的背景下。它还旨在发现新的责任因素 以支持这些功能并揭示其潜在的生化活动。最后，这项提议旨在 剖析这些功能中断导致疾病的分子机制，并测试新的 治疗发展的策略。提出了一种剖析黄褐斑的分子机制的方法 相交的端粒过程将增强我们对端粒如何使基因组完整性和 提出治疗机会，以解决疾病中的端粒功能障碍。

Molecular mechanisms of intersecting human telomeric functions Project Summary/Abstract Telomeres perform three essential functions in human cells. First, telomeres protect chromosomes against catastrophic end-to-end fusions by shielding them from the DNA damage sensing pathways. A six-membered protein complex called shelterin binds specifically to telomeric DNA to afford end protection. Second, telomeres facilitate end replication, allowing proliferating cells like stem/progenitor cells and cancer cells to replenish chromosome ends. A complex ribonucleoprotein enzyme called telomerase helps solve end replication. Telomerase facilitates end replication by adding telomeric DNA to chromosome ends using its RNA template. While telomerase activation in somatic cells is a hallmark of cancer, telomerase dysfunction in stem cells results in diseases called telomeropathies. Shelterin must protect chromosome ends from illicit DNA fusions but allow telomerase to access the same ends. A shelterin protein called TPP1 is instrumental in recruiting telomerase to telomeres, allowing shelterin to facilitate end protection and end replication, but the molecular mechanism of how TPP1 switches from end-protection mode to end-replication mode during S-phase is not known. Third, telomeres help homologous chromosomes undergo pairing and meiotic crossover to facilitate gamete production. To perform this function, telomeres attach to the nuclear envelope with the help of a meiosis-specific protein complex called TERB1-TERB2-MAJIN and connect with the cytoskeletal force- generating machinery. This allows chromosomes to move, enabling homologous chromosomes to pair up and undergo meiotic crossover. Paired meiotic chromosomes must be protected from telomeric recombination at the nuclear envelope, but how this occurs is not known at the molecular level. Illuminating the molecular interplay between the three telomeric functions will enrich our understanding of how genome integrity is upheld and suggest novel therapeutic avenues for diseases like cancers, telomeropathies, and infertility. This proposal aims to apply the knowledge of telomeres, telomerase, and meiotic assemblies, and expertise in biochemistry, crystallography, and cell biology to understand how human telomeres perform their three critical functions, especially in the contexts where these clash with one another. It also aims to discover new factors responsible for upholding these functions and reveal their underlying biochemical activities. Finally, this proposal aims to dissect the molecular mechanism of disease caused by the disruption of these functions and test new strategies for therapeutic development. The proposed approach to dissect the molecular mechanisms of intersecting telomeric processes will enhance our knowledge of how telomeres enable genome integrity and suggest therapeutic opportunities to tackle telomere dysfunction in disease.