Translational regulation of gene expression during oxidative stress conditions

我们的研究工作旨在了解真核细胞的反应，以酵母酿酒酵母作为模式生物氧化应激。所有需氧生物体在正常需氧代谢过程中或暴露于产生自由基的化合物后暴露于活性氧（ROS）。ROS可以对细胞造成广泛的损伤，并且据说当细胞存活机制无法科普ROS或由它们引起的损伤时，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，它也是生物技术，酿造和烘焙等行业特别关注的问题。这意味着理解氧化应激的原因和分子反应具有广泛的根本重要性。该项目的具体重点是翻译在调节基因表达中的作用，以响应和适应氧化应激条件。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，确定和表征调控机制，控制蛋白质生产过程中的压力条件下，将有利于工业研究人员，有兴趣在最大限度地提高蛋白质生产的生物系统的生物技术和生物制药applications.Although选定的基因的转录调控已被广泛研究，有越来越多的赞赏，选择的mRNA翻译也受到严格的监管。翻译起始是这种选择的关键步骤，这一过程的失调与许多疾病有关。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在潜在的易错条件下的持续基因表达，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应激。虽然氧化应激对蛋白质合成有广泛的抑制作用，但特定mRNA的翻译诱导对于适应它至关重要。本项目将使用尖端技术来研究氧化应激如何调节翻译，重点是确定和表征氧化应激耐受所需的mRNA特异性调节的例子。使用酵母模型，我们有初步的证据支持进化保守的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在氧化应激过程中的作用，这一点很重要，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.