Mechanism and functions of DALRD3-dependent tRNA modification

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PROJECT SUMMARY Numerous genetic variants in tRNA modification enzymes have been linked to devastating neurodevelopmental and neurological disorders. However, the molecular mechanisms underpinning these pathologies are unknown. Why is it that perturbations to many different tRNA modification enzymes and thus, changes to the various chemical modifications they catalyze, seem to affect the brain more so than other organs? To resolve this question, our lab seeks to elucidate the molecular and cellular roles of tRNA modification enzymes in human health and disease. We have recently uncovered a novel tRNA synthetase-like mimic, DALRD3, that is required for a specific chemical modification in a subset of human tRNAs. Our preliminary results suggest that the DALRD3-dependent modification impacts tRNA conformational stability and function. Notably, we have also identified an autosomal-recessive variant in the DALRD3 gene that causes loss of function and the neurological disorder epileptic encephalopathy. Based upon these findings, we propose that DALRD3-mediated modification plays a critical role in the proper function of specific tRNAs important for protein synthesis during neurodevelopment. In our first Aim, we will define the requirements for tRNA recognition and modification dependent in DALRD3 and its cognate tRNA substrates. For our second Aim, we will measure the impact of DALRD3-dependent modification on tRNA structure and function. In our final Aim, we will determine the role of DALRD3-dependent tRNA modification on global protein translation in the brain through ribosome profiling. In total, the proposed research will have broad implications in understanding how tRNA modifications can impact proper neurodevelopment. Although DALRD3 was an unexpected player in tRNA modification, we now have a new target to explore potential therapeutics for individuals suffering from epileptic encephalopathies linked to tRNA biology.