Molecular Mechanisms of Telomere Length Homeostasis

端粒长度稳态的分子机制

• 批准号: 10624040
• 负责人: Feng Qiao
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-13 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624040
• 关键词: Address; Biochemical; Biogenesis; Cell Proliferation; Cells; Chromosomal Stability; Chromosomes; Complex; DNA; Degenerative Disorder; Development; Disease; Ensure; Fission Yeast; Foundations; Functional disorder; Homeostasis; Individual; Investigation; Length; Link; Maintenance; Malignant Neoplasms; Molecular; Mutation; National Institute of General Medical Sciences; Play; Positioning Attribute; Premature aging syndrome; Process; Proliferating; Quality Control; RNA Folding; Research; Resolution; Role; Structure; Telomerase; Telomerase RNA Component; Therapeutic; X-Ray Crystallography; cancer cell; design; genome integrity; insight; novel therapeutic intervention; programs; stem cell differentiation; success; telomere

Project Summary Telomeres ensure genome integrity by facilitating chromosome end replication through telomerase, the activity of which enables cellular proliferation. Uncontrolled proliferation as may occur in cancer cells requires hyper-activation of telomere-extension activity. Conversely, lack of telomere extension results in degenerative disorders or premature aging. Critical to telomere structure and function, the conserved multifunctional shelterin complex associates with telomeres to coordinate multiple telomere activities. The long-term objective of our NIGMS MIRA research program is to determine, at the atomic resolution, molecular mechanisms of telomere length homeostasis through comprehensive biochemical, structural, and functional characterizations of the telomeric shelterin complex, shelterin-telomerase interactions, and telomerase biogenesis. Mutations in telomerase subunits or shelterin components have been increasingly linked to cancer and premature aging. Shelterin complex and shelterin-telomerase interactions play essential roles in regulating synthesis of telomeric DNA repeats and defining telomere lengths that support or restrict cell proliferation. Our recent efforts have achieved the conceptual advancement on the role of shelterin bridge, rather than individual shelterin component per se, in regulating telomere length and the landmark determination of the atomic views of shelterin bridge assembly process by x-ray crystallography. Our accumulated expertise and prior success position us to deepen our investigations. In the next five years, we aim to address the following three fundamental questions in the field: 1) Elucidate the biochemical and structural basis of the assembly of whole fission yeast shelterin complex and its role in telomere length control; 2) Determine the mechanistic basis of shelterin disassembly; 3) Determine the structural basis of telomerase RNA folding quality control mechanism by Pof8 complex. Accomplishment of the proposed studies will provide new and significant mechanistic insights into the maintenance of our chromosome ends and set up the foundation for the development of new therapeutic approaches against diseases caused by telomere dysfunction, such as premature aging.

项目摘要 端粒通过促进染色体末端复制来确保基因组的完整性， 端粒酶，其活性使细胞增殖。不受控制的扩散， 发生在癌细胞中需要过度激活端粒延伸活性。相反，缺乏 端粒延长导致退行性疾病或过早衰老。对端粒至关重要 结构和功能，保守的多功能shelterin复合物与 端粒协调多种端粒活动。NIGMS的长期目标 MIRA研究计划是确定，在原子分辨率，分子机制， 端粒长度稳态通过全面的生化，结构和功能， 端粒shelterin复合物的表征，shelterin-telomerase相互作用，和 端粒酶生物合成端粒酶亚单位或shelterin组分的突变已经被证实是一种重要的基因突变。 与癌症和过早衰老的联系越来越紧密。shelterin复合物和shelterin-telomerase 相互作用在调节端粒DNA重复序列的合成和定义 支持或限制细胞增殖的端粒长度。我们最近的努力取得了 在概念上提出了桥梁掩蔽作用，而不是单个掩蔽作用 组分本身，在调节端粒长度和原子的标志性决定 通过x射线晶体学观察桥梁组装过程中的遮挡。我们积累的 专业知识和先前的成功使我们能够深化我们的调查。在未来五年，我们 旨在解决该领域的以下三个基本问题：1）阐明 完整裂殖酵母shelterin复合物组装的生物化学和结构基础， （2）确定了端粒解体的机制基础; 3)用Pof8确定端粒酶RNA折叠质量控制机制的结构基础 复杂.完成拟议的研究将提供新的和重要的机制， 深入了解我们的染色体末端的维护，并为我们的研究奠定了基础。 开发针对端粒功能障碍引起的疾病的新治疗方法， 例如过早衰老。