Translating the four-letter code of RNA into the twenty-two-letter alphabet of proteins is a central feature of cellular life. Cells have evolved a number of so-called quality control strategies to ensure the accuracy of this process and to prevent accumulation of errors in cellular proteins. However, these mechanisms do not seem to operate the same way all the time. Rather, they appear to vary when cells experience environmental stress. The goal of this research is to understand this variation and its effect on cellular fitness. The results could reveal new insights on how this quality control pathway could be used as a key control point for manipulating microbial growth and development. The project will integrate laboratory research and training programs for students at graduate, undergraduate and high school levels, including members of historically underrepresented minorities. The project will also establish a program for mentoring and lab-shadowing for community college transfer students to promote their productive engagement in STEM research.
The accuracy of translating the genetic code determines how faithfully the information in a genome is transformed into proteins with correct amino acid sequences. Aminoacyl-tRNA synthetases play a key role in accurate translation by correctly pairing cognate tRNAs with their corresponding amino acids. Aminoacyl-tRNA synthetases select the correct tRNA with comparative ease due to the unique sequences and structures found in these small RNAs. By contrast, the simplicity of amino acid structures makes discrimination between them far more difficult, posing a potential threat to accurate translation of the genetic code and by extension, to healthy cell growth. To prevent the accumulation of errors during translation of the genetic code, many synthetases have several quality control mechanisms to limit the attachment of incorrect or near-cognate amino acids to tRNAs. These synthetase proofreading activities provide quality control checkpoints that help to prevent the formation of an aberrant proteome. Despite the intrinsic need for high accuracy during translation of the genetic code, the requirements for quality control vary depending on cellular physiology and changes in environmental growth conditions. While translation quality control by synthetases has not been shown to be essential in any organism, both its presence and absence can be critical for optimal growth and cellular fitness under various conditions in different organisms. This project will use state-of-the art quantitative and genetic approaches to investigate to what extent synthetase quality control can vary depending on environmental conditions and to determine whether such changes in accuracy are beneficial, detrimental or neutral to cellular fitness.
