Regulation and Functions of 3'UTRs in Cellular Stress

摘要 环境变化和暴露于毒素会导致不同种类的细胞应激，如氧化 应激、热休克、冷休克、低氧、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、神经疾病、 糖尿病和各种形式的癌症。转录和转录水平上的一系列应激反应机制 转录后水平帮助细胞在压力下生存并在恢复过程中恢复动态平衡 压力。我们最近发现，砷应激(AS)，一种常用的应激模型，会引起全球范围的缩短 在真核生物中广泛存在的一种转录后机制--3‘端非编码区通过交替的多聚腺苷作用被激活。 我们的长期目标是了解细胞内3‘非编码区调控的机制和后果 压力。在这项建议中，我们计划1)阐明AS中3‘UTR缩短背后的机制(S)，2) 研究AS诱导的3‘非编码区缩短对mRNA代谢的影响，以及3)分析应激- 在不同的细胞环境和不同的应激源下诱导3‘非编码区的变化。这个项目的结果将是 阐明一种新的适应性应激反应机制，有助于理解人类的病因 与细胞应激相关的疾病。

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.