Role of translation elongation factor 1B (eEF1B) in regulating protein synthesis in response to oxidative stress in yeast

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All organisms must respond to changes in their external environment. With the availability of genome sequences much attention has focused on analyzing the changes in gene expression/transcription profiles during these adaptive responses. The translation of mRNA into protein is a fundamental component of the gene expression pathway. However, relatively little is known regarding the role of translational control mechanisms in the response to stress conditions, which is the focus of this proposed study. This application is based on our preliminary findings showing that oxidative stress causes a rapid inhibition of protein synthesis. Such a global inhibition of protein synthesis is widely recognised as a response of biological systems to stress conditions. Preventing protein synthesis during stress conditions may allow time for organisms to direct gene expression towards the production of new molecules required to protect against or detoxify the stress. Our data show that oxidative stress inhibits protein synthesis at multiple levels. The goal of this comprehensive research programme is to understand the molecular details of these regulatory mechanisms. This study will focus on oxidative stress which is a major problem for most biological systems. Reactive oxygen species and free radicals are produced as toxic by-products of normal metabolism and through exposure to environmental factors including sunlight. All organisms, including humans, contain effective antioxidants such as vitamins A and C and enzymes, such as catalase and superoxide dismutase, that can detoxify these harmful molecules. However, under extreme conditions reactive oxygen species can overwhelm the antioxidant defences resulting in a so-called 'oxidative stress'. It is important to understand how cells respond to an oxidative stress because it is implicated in many diseases including cancer, neurodegenerative and cardiovascular diseases. In addition, oxidative damage to cells and tissues can contribute to the decline in physiological function that occurs in ageing cells. This research will make use of the yeast Saccharomyces cerevisiae as a model organism. Yeast offers an ideal model system to study these types of processes since it is genetically tractable and has served as the organism of choice for most post-genomic studies. There is also a high degree of conservation between the stress-protective systems in yeast and human cells making it an ideal organism for this study.