WARS-1 DEPLETION DISTURBS TRYPTOPHAN METABOLISM AT THE LEVEL OF KYNURENINE, LEADING TO DNA DAMAGE INDUCED APOPTOSIS

Abstract

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. Many studies have reported AaRSs involvement in the physiological activities through non-canonical functions such as translation initiation, post-translational modification, and angiogenesis. 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. Previously, 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. Such an increase in apoptosis depends on CED-3/caspase and CEP-1/p53 activity. Here, we show that the genotoxicity caused by the wars-1 RNAi is linked to the cellular accumulation of Trp and its catabolites. While only a small fraction of Trp taken up by organisms is utilized for protein synthesis, the majority is catabolized into various biomolecules, such as serotonin and Kynurenine (Kyn), the latter being the primary product of Trp catabolism. We show that the cellular accumulation of Kyn, resulting from the knockdown of key enzymes in the Trp degradation pathway, significantly induces DNA damage-induced apoptosis mediated by CEP-1/p53. This finding underscores the complex interplay between Trp metabolism and DNA damage-induced apoptosis, offering a new insight into the regulation of amino acid metabolism and DNA damage-induced apoptotic cell death. Additionally, using RNA sequencing, we have shown that acute exposure to tryptophan induces differential gene expression in worms. The upregulated genes were enriched in gene ontology (GO) terms related to detoxification, while the downregulated genes were associated with locomotion and vulval cell fate.

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences