Molecular functions of the TRMT1 tRNA modification enzyme

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PROJECT SUMMARY Intellectual disability (ID) is a prevalent neurodevelopmental disorder affecting more than 1 in 100 individuals worldwide. Recent genetic studies have linked numerous cases of ID to variants in proteins that modify the chemical structure of RNA. However, the mechanisms by which tRNA modification enzymes influence brain development are enigmatic. Here, we focus on deciphering the biological role of tRNA methyltransferase 1 (TRMT1), a tRNA modification enzyme important for human neurodevelopment. Individuals with TRMT1 mutations exhibit cognitive deficits, growth delay and brain abnormalities early in age. We have discovered that TRMT1 modifies more than half of all tRNAs in mammalian cells and is required for the stability of certain tRNAs. Moreover, loss of TRMT1 in human cells causes proliferation defects and up-regulation of pathways involved in protein folding. To understand the function of TRMT1 in neurodevelopment, we have generated a novel TRMT1-deficient mouse strain which exhibits brain and developmental abnormalities. Based upon these findings, we propose that TRMT1-catalyzed modifications play a critical role in the biogenesis and function of tRNAs to ensure proper levels of protein synthesis during mammalian growth and development. In our first Aim, we will use new tRNA sequencing technologies to determine the role of TRMT1-catalyzed modifications in tRNA stability and function. In our second Aim, we will use ribosome profiling approaches to decipher the role of TRMT1-catalyzed tRNA modification in translation. For our final Aim, we will define the spatiotemporal requirement for TRMT1 in mouse brain development. Altogether, the proposed research will forge new connections between RNA modification, protein synthesis and neurodevelopment.