Regulation and Functions of 3'UTRs in Cellular Stress

总结 环境变化和暴露于毒素导致不同种类的细胞应激，例如氧化应激， 应激、热休克、冷休克、缺氧、营养应激、内质网应激等。 与许多人类疾病有关，如心血管疾病，神经系统疾病， 糖尿病和各种癌症。在转录和转录水平上， 转录后水平帮助细胞在压力下生存，并在从压力恢复期间恢复稳态。 应力我们最近发现，砷胁迫（AS），一种常用的应力模型，eliminate全球缩短 3'UTR通过选择性多聚腺苷酸化，一种在真核生物中广泛存在的转录后机制。 我们的长期目标是了解细胞中3'UTR调控的机制和后果， 应力在这项提案中，我们计划1）阐明AS中3'UTR缩短背后的机制，2） 检查AS诱导的3'UTR缩短对mRNA代谢的影响，以及3）分析应激- 在不同的细胞环境中和通过不同的应激物诱导3'UTR改变。该项目的成果将 阐明了一种新的适应性应激反应机制，并有助于了解人类 与细胞压力有关的疾病。

SUMMARY Environmental changes and exposure to toxins lead to cellular stress of different kinds, such as oxidative stress, heat shock, cold shock, hypoxia, nutritional stress, endoplasmic reticulum stress, etc. Cellular stress has been implicated in many human diseases, such as cardiovascular diseases, neurological disorders, diabetes, and various forms of cancer. A number of stress response mechanisms at both transcriptional and post-transcriptional levels help cells survive under stress and restore homeostasis during recovery from stress. We recently found that arsenic stress (AS), a commonly used stress model, elicits global shortening of 3’UTR through alternative polyadenylation, a widespread post-transcriptional mechanism in eukaryotes. Our long-term goal is to understand the mechanisms and consequences of 3’UTR regulation in cellular stress. In this proposal, we plan to 1) elucidate the mechanism(s) behind 3’UTR shortening in AS, 2) examine the consequences of AS-induced 3’UTR shortening for mRNA metabolism, and 3) analyze stress- induced 3’UTR changes in different cell contexts and by different stressors. The result of this project will elucidate a novel adaptive stress response mechanism, and help understand the etiology of human ailments associated with cellular stress.