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Molecular Mechanisms of Telomere Length Homeostasis

端粒长度稳态的分子机制

基本信息

批准号：
9752642
负责人：
Feng Qiao
金额：
$ 39.4万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752642
关键词：
Architecture Biochemical Biological Models Biophysics Cell Cycle Cell Proliferation Cells Chromosomes Communication Complex Coupled DNA DNA Damage DNA Repair Degenerative Disorder Development Disease Elongation by Telomerase Ensure Event Fission Yeast Foundations Functional disorder Funding Genetic Goals Heart Hereditary Melanoma Holoenzymes Homeostasis Human Individual Length Link Malignant Neoplasms Molecular Mutation Pathway interactions Play Premature aging syndrome Process Proteins Recruitment Activity Regulation Research Resolution Role S Phase SS DNA BP Seminal Signal Pathway Site Structure Structure-Activity Relationship Syndrome Telomerase Telomerase RNA Component Therapeutic Ubiquitin Ubiquitination Yeast Model System anti aging cancer cell design genome integrity in vivo insight multicatalytic endopeptidase complex novel therapeutic intervention novel therapeutics recruit response spatiotemporal stem cell differentiation telomere tool tumorigenesis

项目摘要

Project Summary The long-term goal of this proposal is to understand, in detail, the molecular mechanisms of telomere length homeostasis through comprehensive biochemical, structural and functional characterizations of the telomeric shelterin complex and its interaction with telomerase. Telomeres ensure genome integrity by facilitating chromosome end replication through telomerase and protect the chromosome ends from DNA repair and degradation activities. Mutations in telomerase subunits or shelterin components have been linked to premature aging and cancer. 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. We will exploit the genetically amendable fission yeast model system and employ a combination of biochemical, high-resolution structural and genetic tools to achieve the following specific aims: 1. Elucidate the biochemical and structural basis of shelterin assembly and its role in telomere length control; 2. Determine the mechanistic basis for telomere switching from the telomerase non-extendible to extendible state; 3. Determine how the activation of non-extendible telomeric state is coupled to telomerase recruitment. Accomplishment of the proposed aims will provide new and significant mechanistic insights into the structure-function relationship and the dynamics of the shelterin complex, and set up the foundation for the development of new therapeutic approaches against diseases caused by telomere dysfunction, such as premature aging.

项目摘要这项提案的长期目标是详细了解端粒长度稳态通过全面的生化，结构和功能端粒shelterin复合物的表征及其与端粒酶的相互作用。端粒通过促进染色体末端复制来确保基因组的完整性，端粒酶和保护染色体末端的DNA修复和降解活动。端粒酶亚单位或shelterin成分的突变与过早衰老有关和癌症Shelterin复合物和shelterin-telomerase相互作用在肿瘤的发生发展中起重要作用。调节端粒DNA重复序列的合成并确定支持或抑制细胞增殖。我们将利用遗传学上可分离的裂变酵母模型系统并采用生物化学、高分辨率结构和遗传工具的组合，具体目标如下：1.阐明庇护的生物化学和结构基础组装及其在端粒长度控制中的作用; 2.确定以下方面的机械基础端粒从端粒酶不可延伸状态转变为可延伸状态; 3.确定如何不可延伸端粒状态的激活与端粒酶募集相关联。实现拟议的目标将提供新的和重要的机械见解，的结构-功能关系和动力学，并建立了基金会开发新的治疗方法，端粒功能障碍，如过早衰老。