Grant: Project Grant

In all life forms, information is stored as DNA, transcribed into mRNA, and then translated into protein. Recent medical progress, such as mRNA vaccines for COVID-19, has been facilitated by a thorough understanding of this process. The first step of protein synthesis is the physical linkage of an RNA adapter, tRNA, to the building blocks of proteins, amino acids. These molecules are then used to assemble proteins. The correct assignment of an amino acid to a tRNA is catalyzed by aminoacyl-tRNA synthetase. This is the moment in which the genetic code is interpreted by the assignment of a nucleic acid codon to an amino acid. In humans and mice, 8 of these aminoacyl-tRNA synthetases are clustered together to form a large protein complex, called the multisynthetase complex. Despite its discovery over 45 years ago, it is still not clear what the function of this complex is and this is partially due to our lack of detailed understanding on how the proteins in it are connected to each other. We have promising preliminary data to build on to finally understand what the complex looks like. In Aim 1, we will gain insights into its detailed structure. In Aim 2, we will use gene editing to construct model cell lines to mimic disease-causing defects found in human patients that suffer from brain development issues. In Aim 3, we will explore tissue-specific differences in MSC composition using a mouse model that we previously developed. This will enable us to understand how the formation of this large complex can influence how our aminoacyl-tRNA synthetases fine-tune their decisions on how to interpret the genetic code.