Grant: Discovery Grants Program - Individual

An important step in the regulation of gene expression is at the level of protein synthesis. During protein synthesis, also known as translation, the genetic codes embedded in mRNA molecules are used to synthesize proteins, which are responsible for the majority of cellular functions. It is estimated that more than 80% of a prokaryotic cell's energy is spent on synthesizing proteins, highlighting the importance of this essential cellular process. Many medically important antibiotics also exert their activities by targeting translation. Abnormalities in translation have been linked to important human conditions such as cancer. Translation control is used to regulate the expression of a variety of mRNAs under different physiological conditions such as embryonic development and apoptosis. Protein synthesis and its control has been the subject of vigorous investigations over many decades and much has been learned. However, characterization of the genes and complex pathways that influence protein synthesis, as well as its cross communication with other cellular processes, requires more investigation. Here, we propose to study the novel influence of two proteins, Bsc5 and Mrh4, on the process of translation in the eukaryotic model organism yeast, Saccharomyces cerevisiae. Bsc5 protein appears to affect termination codon recognition. We previously observed that deletion of BSC5 gene increases the frequency of stop codon bypass (readthrough). Since BSC5 gene contains a premature stop codon, a possible mode of its regulation of gene expression is through the bypass of this premature stop codon where Bsc5 protein negatively self-regulates its own expression. Here, we propose to further confirm and investigate the influence of Bsc5 protein on the process of protein synthesis. Mrh4 protein is thought to be involved in remodeling of RNA molecules. Our previous data suggests that it may play a role in the translation of mRNAs that contain inhibitory secondary structures. Here, we propose to further validate this observation and to study the mechanism by which Mrh4 protein can affect protein synthesis. Using a loss-of-function array of yeast strains we also plan to study other genes that can influence the expression of mRNAs with inhibitory secondary structures. By studying the process of translation, we gain a better understanding of the unifying principles of protein synthesis in nature and derive novel strategies that could be used in medical applications, such as advancement of new and improved anti-microbial compounds.