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

• 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
• 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

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.

项目概要/摘要： 温度，辐射，氧化剂，以及剪切和渗透应力， 导致组织和细胞损伤的环境、外在应激因素。有好 有证据表明，酵母和人类等多种生物利用SUMO修饰作为 细胞应激反应SUMO是一种小的蛋白质修饰剂，可以共价结合 与特定的靶蛋白相关联，影响其活性、定位、相互作用和半衰期。 本项目主要研究SUMO应激反应（SSR），即蛋白质的快速增加， 细胞经历急性蛋白毒性应激后的类小泛素化。战略科学军团被认为是... 对正常细胞有保护作用，但它也可能增强癌细胞的鲁棒性， 一些真核生物病原体应激诱导的类小泛素化对转录水平有着深刻的影响， 重编程和蛋白质复合物的完整性。然而，很少或没有 了解SSR如何影响细胞质过程，包括细胞骨架重排， 线粒体遗传、囊泡分选和翻译。在这里，我们使用遗传上易于处理的 酵母酿酒酵母，以解决我们假设，蛋白质之间的串扰 细胞质中的SUMO化和泛素化在细胞保护作用中起核心作用 由动态应激诱导的类小泛素化引发。该项目的具体目标是：1）使用 细胞生物学和遗传学方法，以及创新的酵母SUMO压力报告菌株， 剖析战略科学军团的舞蹈编排具体来说，为了调查压力引起的 SUMO E3连接酶Siz 1和NEDD 4/Rsp 5 E3泛素连接酶在细胞中的协同性 细胞质，可能发挥压力诱导的控制细胞骨架组织，线粒体 遗传、囊泡分选和翻译。2)分析一组潜在的细胞质SSR标记 我们确定的效应蛋白，并检查遗传缺陷的功能后果， 导致他们功能障碍。3)使用创新方法鉴定变异SUMO通路 促进压力耐受性的成分，目的是最终测试临床相关的 SUMO途径基因的等位基因可能影响应激耐受性和癌症的可能性 发展我们的项目与区域计划目标保持一致，并将暴露 本科生值得研究，是生物医学相关的。

项目成果

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
• 作者: Hiestand, Lexie;Shen, Stella;Sloan, Willough;Nasiri, Hamid;Lashley, Dana;Kerscher, Oliver
• 通讯作者: Kerscher, Oliver