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.

项目概要 端粒通过促进染色体末端复制来确保基因组完整性 端粒酶，其活性能够促进细胞增殖。不受控制的扩散可能 癌细胞中发生的端粒延长活性需要过度激活。反之，缺乏 端粒延长会导致退行性疾病或过早衰老。对端粒至关重要 结构和功能，保守的多功能庇护复合体与 端粒协调多种端粒活动。我们 NIGMS 的长期目标 MIRA 研究计划旨在以原子分辨率确定分子机制 通过全面的生化、结构和功能实现端粒长度稳态 端粒庇护蛋白复合物的表征、庇护蛋白-端粒酶相互作用，以及 端粒酶生物发生。端粒酶亚基或庇护蛋白成分的突变已被 与癌症和过早衰老的联系越来越紧密。庇护蛋白复合物和庇护蛋白端粒酶 相互作用在调节端粒 DNA 重复序列的合成和定义中起着重要作用 支持或限制细胞增殖的端粒长度。我们最近的努力取得了 庇护桥作用而非个人庇护所的概念进步 成分本身，在调节端粒长度和原子的里程碑确定 通过 X 射线晶体学观察庇护桥组装过程的视图。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。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 整个裂殖酵母庇护蛋白复合物组装的生化和结构基础以及 它在端粒长度控制中的作用； 2）确定掩体拆卸的机理依据； 3）通过Pof8确定端粒酶RNA折叠质控机制的结构基础 复杂的。拟议研究的完成将提供新的、重要的机制 深入了解染色体末端的维护，并为 开发针对端粒功能障碍引起的疾病的新治疗方法， 比如过早衰老。