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; 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.

与人端粒功能相交的分子机制 项目摘要/摘要 端粒在人类细胞中执行三个基本功能。首先，端粒保护染色体免受 灾难性的端到端融合通过将其免受DNA损伤感应途径的侵害。一个六人 称为庇护素的蛋白质复合物专门与端粒DNA结合，以提供最终保护。第二，端粒 促进最终复制，允许茎/祖细胞和癌细胞等增殖细胞补充 染色体结束。一种称为端粒酶的复杂核糖核蛋白酶有助于求解末端复制。 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最终复制。 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 导致疾病称为端粒病。庇护素必须保护染色体末端免受非法DNA融合 但是，允许端粒酶访问相同的末端。一种称为TPP1的庇护素蛋白有助于招募 端粒酶到端粒，使庇护所促进最终保护和最终复制，但分子 TPP1如何从终端保护模式转换为终端复制模式的机制不是 已知。第三，端粒可帮助同源染色体进行配对和减数分裂跨界 配子生产。为了执行此功能，端粒借助 减数分裂特异性蛋白质复合物称为Terb1-TERB2-Majin，并与细胞骨架力联系 生成机械。这使染色体可以移动，从而使同源染色体配对并 进行减数分裂跨界。必须保护成对的减数分裂染色体免受端粒重组的保护 核包膜，但在分子水平上不知道这种情况的发生。照亮分子 三个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 并提出了癌症，端粒病和不育症等疾病的新型治疗途径。这个建议 旨在应用端粒，端粒酶和减数分裂组合以及生物化学专业知识的知识， 晶体学和细胞生物学了解人类端粒如何执行三个关键功能， 尤其是在这些相互冲突的情况下。它还旨在发现负责的新因素 为了维护这些功能并揭示其潜在的生化活动。最后，该建议旨在 剖析因这些功能破坏引起的疾病的分子机制并测试新的 治疗发展的策略。提出的剖析方法的方法 相交的端粒过程将增强我们对端粒如何实现基因组完整性和 建议治疗机会解决疾病中端粒功能障碍的机会。