Understanding ER chaperone-mediated RNR regulation

了解 ER 伴侣介导的 RNR 调节

基本信息

批准号：
10046751
负责人：
Andrew William Truman
金额：
$ 44万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046751
关键词：
Binding Breast Cancer Cell Cell Death Cell Survival Cell model Cell physiology Cells Client Complex DNA Maintenance DNA biosynthesis Data Development Disease Elements Endoplasmic Reticulum Genome Homodimerization Human Human Pathology In Vitro Individual Location Malaria Malignant Neoplasms Mammalian Cell Mediating Mediator of activation protein Molecular Molecular Biology Molecular Chaperones Organism Oxidation-Reduction Phenotype Play Process Proliferating Protein Biosynthesis Proteins Regulation Replication-Associated Process Resistance Ribonucleotide Reductase Ribonucleotide Reductase Inhibitor Ribonucleotide Reductase Subunit Role Saccharomycetales Structure Techniques Testing Triapine Validation Virus Diseases Work Yeasts base cancer cell cancer therapy cancer type endoplasmic reticulum stress genome integrity hydroxyurea in vivo inhibitor/antagonist innovation insight misfolded protein novel novel therapeutics protein folding protein misfolding spatiotemporal

项目摘要

Project Summary BiP/Kar2 is a universally conserved molecular chaperone based in the endoplasmic reticulum that performs a variety of functions in the cell including protein folding of both newly synthesized and denatured protein “clients” and targeted degradation of terminally misfolded proteins. In yeast, Kar2 function is regulated by co-chaperones such as Sec63, Jem1 and Scj1. While Scj1 and Jem1 appear to have some redundant functions, previous studies have demonstrated phenotypic differences between cells lacking Scj1 or Jem1. The specific roles of Jem1 and Scj1 in activating Kar2 and their particular client portfolio remains undetermined. All organisms require correct and accurate replication of DNA to grow and proliferate. Misregulation of DNA replication can result in either cell death or cancer. Our recent studies have uncovered a role for Scj1 and Kar2 in regulating genome integrity. While ER chaperone function and genome integrity are fundamental cellular processes, no connection between them has previously been established. Our recent studies suggest that this ER chaperone-genome integrity connection may be conserved in mammalian cells as loss of ERdj1 (co-chaperone of mammalian Kar2, BiP) sensitizes cells to DNA replication inhibitors such as triapine and hydroxyurea. Any strategy that lowers the rate of DNA replication in cells may form the basis of novel anticancer therapies. In this proposal, we expect to gain further mechanistic insight into how ER chaperones and co- chaperones control DNA replication. We propose to use both molecular biology and state-of-the-art mass spectrometric techniques in and yeast and cancer cells to achieve the aims of the objectives in our proposal. The scope of this work has broad implications for a variety of diseases associated with DNA replication and ER molecular chaperone function, including many types of cancer, viral infection and malaria. !

项目概要 BiP/Kar2 是一种普遍保守的分子伴侣，在内质网中执行以下操作：细胞中的多种功能，包括新合成和变性蛋白质“客户”的蛋白质折叠在酵母中，Kar2 功能受到共伴侣的调节。例如 Sec63、Jem1 和 Scj1，而 Scj1 和 Jem1 似乎有一些冗余功能，以前的研究。已经证明缺乏 Scj1 或 Jem1 的细胞之间存在表型差异 Jem1 和 Jem1 的具体作用。 Scj1 激活 Kar2 及其特定客户组合的情况尚未确定。所有生物体都需要正确且准确的 DNA 复制才能生长和增殖。 DNA 复制可能导致细胞死亡或癌症。我们最近的研究发现了 Scj1 和 Scj1 的作用。 Kar2 调节基因组完整性，而 ER 伴侣功能和基因组完整性是细胞的基础。进程之间，之前尚未建立它们之间的连接。我们最近的研究表明，这种内质网伴侣-基因组完整性连接可能在哺乳动物细胞中 ERdj1（哺乳动物 Kar2 的共伴侣，BiP）的缺失会使细胞对 DNA 复制变得敏感任何降低细胞内 DNA 复制速率的抑制剂，如三硫平和羟基脲。形成新型抗癌疗法的基础。在这个提案中，我们期望获得关于 ER 伴侣和合作者如何进一步机制的见解。我们建议利用分子生物学和最先进的质量技术来控制 DNA 复制。酵母和癌细胞中的光谱技术，以实现我们提案中的目标。这项工作的范围对与 DNA 复制相关的多种疾病具有广泛的影响 ER分子伴侣功能，包括多种癌症、病毒感染和疟疾。！