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。不受控制的扩散可能 发生在癌细胞中需要端粒延伸活性的过度激活。相反，缺乏 端粒延长会导致退行性疾病或过早衰老。端粒的关键作用 结构和功能，保守的多功能避难所综合体与 端粒协调多个端粒活动。我们NIGMS的长期目标是 Mira的研究计划是在原子分辨率下确定分子机制 通过全面的生化、结构和功能实现端粒长度动态平衡 端粒掩蔽素复合体的特征、掩蔽素-端粒酶的相互作用 端粒酶的生物发生。端粒酶亚基或保护素成分的突变已经被 越来越多的人与癌症和过早衰老有关。保护素复合体与保护素-端粒酶 相互作用在调节端粒DNA重复序列的合成和确定 支持或限制细胞增殖的端粒长度。我们最近的努力已经达到了 避难所在桥梁中的作用，而不是单个避难所的概念进展 成分本身，在调节端粒长度和确定原子标志性方面 用x射线结晶学观察桥架组装过程中的遮蔽物。我们积累的 专业知识和之前的成功使我们有能力深化调查。在未来的五年里，我们 旨在解决该领域的以下三个基本问题：1)阐明 全裂解酵母避难所复合体组装的生化和结构基础 它在端粒长度控制中的作用：2)决定了掩体解体的机制基础； 3)用POF8确定端粒酶RNA折叠质量控制机制的结构基础 很复杂。拟议研究的完成将提供新的和重要的机制 对维持我们染色体末端的洞察，并为 开发治疗端粒功能障碍引起的疾病的新方法， 比如过早衰老。