Role of POT1 in telomere length regulation

POT1 在端粒长度调节中的作用

基本信息

批准号：
10618842
负责人：
Sandy S Chang
金额：
$ 33.5万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-09 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618842
关键词：
ATR checkpoint Address Adopted Aging Amino Acids Binding Binding Proteins Biochemical Biological Assay Bone Marrow Transplantation Bone marrow failure Cell Aging Cell Line Cell Maintenance Cell Proliferation Cells Chromosomal Rearrangement Chromosome abnormality Complex Cytoprotection DNA Binding DNA Damage DNA Double Strand Break DNA biosynthesis DNA replication fork Data Development Disease Dyskeratosis Congenita Excision Failure Functional disorder Future Generations Genes Genetic Genome Genome Stability Goals Hematopoietic stem cells Homeostasis Homologous Gene Human In Vitro Knockout Mice Length Malignant Neoplasms Mediating Metabolism Molecular Mus Mutate Mutation Nature Pathway interactions Phenotype Play Premature aging syndrome Property Proteins Public Health Regulation Repression Role SS DNA BP Single-Stranded DNA Structure TP53 gene Telomerase Telomere Length Maintenance Telomere Maintenance Telomere-Binding Proteins Testing Therapeutic Studies cancer initiation genetic approach in vivo loss of function mouse genome mouse model mutant novel premature prevent protein function recruit replication factor A replication stress response single molecule stem cell function stem cells telomere

ATR checkpoint Address Adopted Aging Amino Acids Binding Binding Proteins Biochemical Biological Assay Bone Marrow Transplantation Bone marrow failure Cell Aging Cell Line Cell Maintenance Cell Proliferation Cells Chromosomal Rearrangement Chromosome abnormality Complex Cytoprotection DNA Binding DNA Damage DNA Double Strand Break DNA biosynthesis DNA replication fork Data Development Disease Dyskeratosis Congenita Excision Failure Functional disorder Future Generations Genes Genetic Genome Genome Stability Goals Hematopoietic stem cells Homeostasis Homologous Gene Human In Vitro Knockout Mice Length Malignant Neoplasms Mediating Metabolism Molecular Mus Mutate Mutation Nature Pathway interactions Phenotype Play Premature aging syndrome Property Proteins Public Health Regulation Repression Role SS DNA BP Single-Stranded DNA Structure TP53 gene Telomerase Telomere Length Maintenance Telomere Maintenance Telomere-Binding Proteins Testing Therapeutic Studies cancer initiation genetic approach in vivo loss of function mouse genome mouse model mutant novel premature prevent protein function recruit replication factor A replication stress response single molecule stem cell function stem cells telomere

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项目摘要

Project Summary We will use state-of-the-art biochemical, cellular and genetic approaches to understand mechanistically how ssDNA binding proteins protect telomeres from activating a DNA damage response, regulate its length and replication. Using novel in vitro biochemical assays, we will examine whether the molecular distinctions between RPA and hPOT1 underlie their unique functions at telomeres. We will define the residues in hPOT1 that are required to repress telomere end protection and C-strand resection (Aim 1). We will determine mechanistically how POT1b promotes telomere length maintenance, and use hematopoietic stem cells conditionally depleted of endogenous POT1a/b to define the amino acid residues involved in telomere elongation necessary for the stem cell maintenance (Aim 2). We will explore how POT1a protects telomeres from replication stress. Finally, we used BioID to identify Claspin as a telomere interacting protein involved in DNA replication at telomeres devoid of POT1a (Aim 3). The proposed studies present a unique opportunity to address some of the most important questions in the telomere field.

项目摘要我们将使用最先进的生化，细胞和遗传方法来理解从机械上讲，ssDNA结合蛋白如何保护端粒免于激活DNA损伤响应，调节其长度和复制。使用新颖的体外生化测定法，我们将检查RPA和HPOT1之间的分子区别是否是其独特的基础端粒功能。我们将定义HPOT1中抑制端粒所需的残留物最终保护和C链切除（AIM 1）。我们将从机械上确定如何pot1b 促进端粒长度维持，并使用有条件耗尽的造血干细胞内源性pot1a/b的定义与端粒伸长有关的氨基酸残基干细胞维护所必需的（AIM 2）。我们将探索POT1A如何保护端粒来自复制应力。最后，我们使用生物治疗将链球蛋白识别为端粒相互作用蛋白参与没有pot1a的端粒中的DNA复制（AIM 3）。提出的研究一个独特的机会，可以解决端粒领域中一些最重要的问题。