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 项目总结/摘要 端粒在人类细胞中执行三种基本功能。首先，端粒保护染色体免受 灾难性的端到端融合，通过屏蔽它们从DNA损伤传感途径。六元 一种叫做shelterin的蛋白质复合物特异性地与端粒DNA结合以提供末端保护。第二，端粒 促进末端复制，允许增殖细胞如干/祖细胞和癌细胞补充 染色体末端一种叫做端粒酶的复杂的核糖核蛋白酶帮助解决末端复制。 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 导致端粒病变庇护必须保护染色体末端免受非法DNA融合 但允许端粒酶到达相同的末端。一种名为TPP 1的庇护蛋白在招募中起作用 端粒酶的端粒，允许shelterin促进末端保护和末端复制，但分子 TPP 1在S阶段期间如何从端保护模式切换到端复制模式的机制不 知道的第三，端粒帮助同源染色体进行配对和减数分裂交换， 配子产生为了实现这一功能，端粒在一种蛋白质的帮助下附着在核膜上。 减数分裂特异性蛋白质复合物称为TERB 1-TERB 2-MAJIN，并与细胞骨架力连接- 发电机械这使得染色体可以移动，使同源染色体配对， 进行减数分裂交换。成对的减数分裂染色体必须在端粒重组时得到保护。 核被膜，但这是如何发生的是不知道在分子水平上。照亮了分子 这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持的理解 并为癌症、端粒疾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，以及生物化学的专业知识， 晶体学和细胞生物学来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情况下。它还旨在发现新的因素， 以维持这些功能并揭示其潜在的生化活性。最后，本建议旨在 剖析这些功能被破坏所导致的疾病的分子机制， 治疗发展战略。提出的方法来剖析分子机制， 交叉的端粒过程将增强我们对端粒如何使基因组完整性的认识， 提示了解决疾病中端粒功能障碍的治疗机会。