Molecular mechanisms of intersecting human telomeric functions

人类端粒功能交叉的分子机制

• 批准号: 10550394
• 负责人: Jayakrishnan Nandakumar
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-06 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10550394
• 关键词: Binding; Biochemical; Biochemistry; Biological; Cell Proliferation; Cells; Cellular biology; Chromosomes; Complex; Crystallography; Cytoskeleton; DNA; DNA Damage; Disease; Ensure; Enzymes; Functional disorder; Genetic Crossing Over; Genetic Recombination; Genome; Germ Cells; Human; Infertility; Knowledge; Malignant Neoplasms; Meiosis; Molecular; Nuclear Envelope; Pathway interactions; Process; Production; Proteins; RNA; Ribonucleoproteins; S phase; Somatic Cell; Structure; Telomerase; Testing; Therapeutic; cancer cell; genome integrity; human disease; novel therapeutic intervention; novel therapeutics; protein complex; recruit; stem cells; stem-like cell; telomere; therapeutic development

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.

人类端粒功能交叉的分子机制 项目概要/摘要 端粒在人体细胞中执行三个基本功能。首先，端粒可以保护染色体免受 通过保护它们免受 DNA 损伤传感途径的影响来实现灾难性的端到端融合。六人组成 称为庇护蛋白的蛋白质复合物与端粒 DNA 特异性结合以提供末端保护。二、端粒 促进末端复制，使干细胞/祖细胞和癌细胞等增殖细胞得以补充 染色体末端。一种称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 导致称为端粒病的疾病。 Shelterin 必须保护染色体末端免遭非法 DNA 融合 但允许端粒酶访问相同的末端。一种名为 TPP1 的庇护蛋白有助于招募 端粒酶连接到端粒，使庇护蛋白能够促进末端保护和末端复制，但分子 TPP1 在 S 阶段如何从末端保护模式切换到末端复制模式的机制尚不明确。 已知。第三，端粒帮助同源染色体进行配对和减数分裂交叉，以促进 配子的产生。为了执行此功能，端粒借助 减数分裂特异性蛋白复合物，称为 TERB1-TERB2-MAJIN，与细胞骨架力相连 发电机械。这使得染色体能够移动，使同源染色体能够配对并结合 进行减数分裂交叉。必须保护配对减数分裂染色体免于端粒重组 核膜，但在分子水平上尚不清楚这是如何发生的。照亮分子 三种端粒功能之间的相互作用将丰富我们对如何维护基因组完整性的理解 并提出了癌症、端粒病和不孕症等疾病的新治疗途径。这个提议 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， 晶体学和细胞生物学，以了解人类端粒如何发挥其三个关键功能， 尤其是在这些因素相互冲突的情况下。它还旨在发现新的影响因素 以维持这些功能并揭示其潜在的生化活性。最后，本提案旨在 剖析由这些功能破坏引起的疾病的分子机制并测试新的 治疗开发策略。所提出的剖析分子机制的方法 交叉端粒过程将增强我们对端粒如何实现基因组完整性和 提出解决疾病中端粒功能障碍的治疗机会。