Genetic requirements for executing SUMO stress signals and achieving stress tolerance

执行 SUMO 应激信号和实现应激耐受性的遗传要求

基本信息

批准号：
10514836
负责人：
Oliver none Kerscher
金额：
$ 43.64万
依托单位：
COLLEGE OF WILLIAM AND MARY
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：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10514836
关键词：
Abnormal Cell Acute Address Affect Alleles Binding Proteins Biological Biological Assay Biological Sciences Biology Biomedical Research Cancerous Cell Nucleus Cell physiology Cells Cellular Stress Cellular Stress Response Communicable Diseases Cytoplasm Cytoskeletal Proteins Cytoskeleton Development Developmental Process Disease Elements Environment Enzymes Eukaryotic Cell Excision Fostering Functional disorder Genes Genetic Genetic Transcription Goals Half-Life Health Human Individual Kluyveromyces Knowledge Link Malignant Neoplasms Mammalian Cell Mediating Medical Mentors Methods Mitochondria Mitochondrial Inheritance Modeling Modification Mutation Nerve Degeneration Normal Cell Organelles Organism Oxidants Oxides Pathway interactions Peptide Hydrolases Phenotype Pigments Play Process Proteins Publishing Radiation Reagent Reporter Research Resistance Ribosomes Role Saccharomyces cerevisiae Signal Transduction Sorting - Cell Movement Stress Students Sumoylation Pathway Temperature Testing Therapeutic Intervention Tissues Training Translations Ubiquitin Ubiquitination Variant Vesicle Work Yeasts biological adaptation to stress cancer cell career cell injury clinically relevant enzyme pathway experience fitness genetic approach genetic variant genotoxicity improved innovation interest man mutant novel pathogen pathogenic fungus prevent programs protein complex protein function proteotoxicity response stress tolerance stressor targeted treatment tissue culture transcriptional reprogramming ubiquitin ligase ubiquitin-protein ligase undergraduate student

项目摘要

Project Summary/Abstract: Temperature, radiation, oxidizing reagents, as well as shear and osmotic stress are environmental, extrinsic stressors that cause tissue and cellular damage. There is good evidence that organisms as diverse as yeast and humans utilize SUMO modification as part of their cellular stress response. SUMO is a small proteinaceous modifier that can be covalently linked to specific target proteins, affecting their activity, localization, interactions, and half-life. This project focuses on the SUMO Stress Response (SSR), the rapid increase of protein sumoylation after cells experience acute proteotoxic stress. The SSR is believed to play a cyto- protective role for normal cells, but it may also enhances the robustness of cancerous cells and some eukaryotic pathogens. Stress-induced sumoylation has profound effects on transcriptional reprogramming and protein complex integrity in the nucleus. However, there is little or no knowledge how the SSR affects cytoplasmic processes including cytoskeletal rearrangements, mitochondrial inheritance, vesicle sorting, and translation. Here we use the genetically tractable yeast Sacharomyces cerevisiae to address our hypothesis that cross-talk between protein sumoylation and ubiquitination in the cytoplasm plays a central role in cytoprotective effects initiated by dynamic stress-induced sumoylation. The specific aims of this project are 1) to use cell biological and genetic approaches, and an innovative yeast SUMO Stress Reporter strain, to dissect the choreography of the SSR. Specifically, to investigate evidence of stress-induced cooperativity of the SUMO E3 ligase Siz1 and the NEDD4/Rsp5 E3 ubiquitin ligase in the cytoplasm that may exert stress-induced control over cytoskeleton organization, mitochondrial inheritance, vesicle sorting, and translation. 2) To analyze a group of potential cytoplasmic SSR effector proteins we identified and to examine the functional consequences of genetic defects that result in their dysfunction. 3) To use innovative methods to identify variant SUMO pathway components that promote stress tolerance with the goal to ultimately test clinically-relevant alleles of SUMO pathway genes that may affect stress tolerance and the likelihood of cancer development. Our project is well-aligned with AREA program goals and will expose undergraduate students to meritorious research that is biomedically relevant.

项目摘要/摘要：温度，辐射，氧化试剂以及剪切和渗透应激为环境，外在应激源会导致组织和细胞损伤。有好有机体像酵母和人类一样多样化的有机体利用相扑修改为它们的细胞应力反应。 Sumo是一种小型蛋白质修饰符，可以共价与特定靶蛋白有关，影响其活性，定位，相互作用和半衰期。该项目的重点是相扑应力反应（SSR），蛋白质的快速增加细胞后的Sumoylation经历急性蛋白质毒性应激。据信SSR播放一个cyto- 正常细胞的保护作用，但也可能增强癌细胞的鲁棒性和一些真核病原体。压力诱导的sumoylation对转录具有深远的影响核中的重编程和蛋白质复杂完整性。但是，几乎没有或没有知道SSR如何影响包括细胞骨架重排的细胞质过程，线粒体遗传，囊泡排序和翻译。在这里，我们使用遗传处理酿酒酵母的酵母sacharomyces旨在解决我们的假设，即蛋白质之间的串扰细胞质中的Sumoylation和泛素化在细胞保护作用中起着核心作用由动态应力诱导的sumoylation引发。该项目的具体目的是1）细胞生物学和遗传方法，以及创新的酵母相扑应力报告菌株，解剖SSR的编排。具体而言，要研究压力引起的证据 Sumo E3连接酶SIZ1和NEDD4/RSP5 E3泛素连接酶的合作关系细胞质可能施加应力诱导的对细胞骨架组织的控制，线粒体继承，囊泡排序和翻译。 2）分析一组潜在的细胞质SSR 效应子蛋白我们确定并检查遗传缺陷的功能后果这会导致它们的功能障碍。 3）使用创新方法来识别变体Sumo途径以目标最终测试临床相关的目标的组成部分 Sumo途径基因的等位基因可能影响胁迫耐受性和癌症的可能性发展。我们的项目与区域计划的目标相结合，并将公开本科生从生物医学相关的有色化研究。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protein Modification Employing Non-Canonical Amino Acids to Prepare SUMOylation Detecting Bioconjugates.

DOI：
10.3390/pharmaceutics14122826
发表时间：
2022-12-16
期刊：
Pharmaceutics
影响因子：
5.4
作者：
Williard AC;Switzer HJ;Howard CA;Yin R;Russell BL;Sanyal R;Yu S;Myers TM;Flood BM;Kerscher O;Young DD
通讯作者：
Young DD

Chemical Genetics Screen of EVP4593 Sensitivity in Budding Yeast Identifies Effects on Mitochondrial Structure and Function.

DOI：
10.17912/micropub.biology.000806
发表时间：
2023
期刊：
microPublication biology
影响因子：
0
作者：
Hiestand, Lexie;Shen, Stella;Sloan, Willough;Nasiri, Hamid;Lashley, Dana;Kerscher, Oliver
通讯作者：
Kerscher, Oliver