Protein synthesis is a fundamental and essential process in all three domains of life. In the past decades, advances in biochemistry, biophysics, and structural biology have improved our knowledge on the molecular mechanisms of aminoacyl-tRNA (aa-tRNA) synthesis, translational quality control, peptide elongation, and ribosomal decoding. However, we are still at a very early stage of understanding how protein synthesis is regulated in living cells and how translational regulation affects the fitness of different organisms. Protein mistranslation (an increased level of translational errors) has been shown to cause growth defects in bacteria, mitochondrial dysfunction in yeast, and neurodegeneration in mammals. It is therefore commonly accepted that mistranslation is harmful to cells and needs to be avoided. Surprisingly, we and others have shown that mistranslation is increased during oxidative stress and viral infection, leading to a recent proposal that mistranslation may play adaptive roles under certain stress conditions. Experimental evidence to support this model is currently limited, and little is known about these adaptive mechanisms at the molecular level. The objective here is to define how bacteria respond to mistranslation. Specifically, we will (a) determine the mechanism by which mistranslation adapts E. coli to peroxide stress; (b) determine the impact of mistranslation on protein aggregation in E. coli; and (c) define the role of mistranslation caused by oxidative stres in E. coli. Such work will reveal previously unknown adaptive mechanisms by which bacteria survive severe stresses, and improve the knowledge of a new class of translational regulation that enhances phenotypic diversity and fitness through fine-tuning fidelity of protein synthesis.
Protein synthesis is a major pathway targeted by antibiotics. The rise of multi-drug resistant bacteria and a shortage of new antibiotics demand further understanding of the translational machinery to improve current treatment and develop the next generation of antibiotics. Our proposed work will reveal how bacteria take advantage of mistranslation for adaptation to severe stresses in order to survive host defense, therefore will provide a basis to facilitate future development of novel antimicrobial therapies.
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