Translational regulation of gene expression during oxidative stress conditions

我们的研究工作旨在了解真核细胞对氧化应激的反应，以酵母酿酒酵母为模式生物。所有需氧生物在正常有氧代谢过程中或暴露于自由基生成化合物后都会暴露于活性氧（ROS）。活性氧可以对细胞造成广泛的损伤，当细胞生存机制无法应对活性氧或其造成的损伤时，就会发生氧化应激。氧化损伤与各种疾病过程有关，包括癌症、衰老和神经退行性疾病，也是生物技术、酿造和烘焙等行业特别关注的问题。这意味着了解氧化应激的原因和分子反应具有广泛的基础重要性。这个项目的具体重点是翻译在调节基因表达响应和适应氧化应激条件中的作用。酿酒酵母具有广泛的工业应用，其中许多应用受到其在应激条件下合成蛋白质的能力的影响。因此，识别和描述在应激条件下控制蛋白质生产的调节机制将有利于工业研究人员，他们对最大化生物技术和生物制药应用中生物系统的蛋白质生产感兴趣。虽然选择基因的转录调控已经被广泛研究，但越来越多的人认识到要翻译的mRNA的选择也受到严格调控。翻译起始是这一选择的关键步骤，这一过程的错误调控与过多的疾病有关。细胞通常通过抑制翻译起始来响应氧化应激。这种蛋白质合成的减少阻止了基因在潜在易出错条件下的持续表达，并允许现有mrna和蛋白质的周转，同时基因表达被重新编程以应对压力。尽管氧化应激对蛋白质合成具有广泛的抑制作用，但特异性mrna的翻译诱导对于适应氧化应激至关重要。该项目将使用尖端技术来研究氧化应激如何调节翻译，重点是识别和表征氧化应激耐受性所需的mrna特异性调节的例子。利用酵母模型，我们有初步证据支持进化上保守的eIF4G翻译起始因子在调节氧化应激的翻译反应中的调节作用。该项目旨在了解eIF4G在氧化应激中的作用，这是很重要的，因为它的失调与许多疾病过程和衰老有关。

Our research efforts are aimed at understanding the responses of eukaryotic cells to oxidative stress using the yeast Saccharomyces cerevisiae as a model organism. All aerobic organisms are exposed to reactive oxygen species (ROS) during the course of normal aerobic metabolism or following exposure to radical-generating compounds. ROS can cause wide-ranging damage to cells and an oxidative stress is said to occur when the cellular survival mechanisms are unable to cope with the ROS or the damage caused by them. Oxidative damage is associated with various disease processes including cancer, ageing and neurodegenerative disorders and it is also of particular concern to industry including biotech, brewing and baking. This means that understanding the causes and the molecular responses to oxidative stress is of broad fundamental importance. This specific focus of this project is the role of translation in regulating gene expression in response and adaptation to oxidative stress conditions. The yeast Saccharomyces cerevisiae has a wide variety of industrial applications many of which are impacted upon by its capacity to synthesis proteins under conditions of stress. Thus identifying and characterizing regulatory mechanisms that control protein production during stress conditions will benefit industrial researchers, interested in maximising protein production from biological systems for biotechnological and biopharmaceutical applications.Although the regulation of the transcription of selected genes has been extensively studied, there is growing appreciation that the selection of the mRNA to be translated is also tightly regulated. Translation initiation is a crucial step for this selection and misregulation of this process has been linked with a plethora of diseases. Cells typically respond to an oxidative stress by inhibiting translation initiation. This reduction in protein synthesis prevents continued gene expression during potentially error-prone conditions as well as allowing for the turnover of existing mRNAs and proteins whilst gene expression is reprogrammed to deal with the stress. Although oxidative stress is widely inhibitory to protein synthesis, translational induction of specific mRNAs is critically important for adaptation to it. This project will use cutting edge technology to examine how oxidative stress regulates translation focussing on identifying and characterizing examples of mRNA-specific regulation which are required for oxidative stress tolerance. Using the yeast model, we have preliminary evidence supporting a regulatory role for the evolutionarily conserved eIF4G translation initiation factor in regulating the translational response to oxidative stress. This project aims to understand the role of eIF4G during oxidative stress which is important since its dysregulation has been implicated in many disease processes and ageing.