Depletion of tryptophanyl-tRNA synthetase and tryptophan accumulation triggers p53-dependent apoptosis.

Aminoacyl tRNA synthetases (AaRSs) are enzymes that play a role in maintaining translational fidelity by ensuring the accurate loading of amino acids to their cognate tRNAs. Mutations in the AaRSs are linked to diverse human diseases, including neurological disorders and various types of cancer. Among AaRSs, mutations in wars-1, a tryptophanyl tRNA synthetase, have been associated with cancer. Despite the extensive knowledge of WARS-1, there is no comprehensive understanding of its contribution to pathogenesis. In our previous study, we discovered the impact of WARS-1 on genomic integrity. We showed that WARS-1 depletion leads to a significant accumulation of free tryptophan (Trp), resulting in pronounced genomic instability, including the formation of chromatin bridges and micronuclei, and cell cycle arrest. In this study, we demonstrate that wars-1 knockdown induces apoptosis in the germline of C. elegans.