Tryptophanyl-tRNA synthetase-1 (WARS1) depletion and high tryptophan concentration lead to genomic instability in Caenorhabditis elegans

Abstract

Abstract The fidelity of translation is ensured by a family of proteins named aminoacyl-tRNA synthetases, making them crucial for development and survival. More recently, mutations in the tryptophanyl-tRNA synthetase (WARS1) have been linked to various human diseases, from intellectual disability to various types of cancer. To understand the function of WARS1, we investigated the effect of WARS-1 depletion during the mitotic and meiotic cell cycle in the developing germline of C. elegans and demonstrated the role of WARS-1 in genome integrity. wars-1 knockdown results in cell cycle arrest of the mitotically active germ cells. Such mitotic arrest is also associated with canonical DNA damage-induced checkpoint signaling in mitotic and meiotic germ cells. Significantly, such DNA checkpoint activation is associated with the morphological anomalies in chromatin structures that are the hallmarks of genome instability, such as the formation of chromatin bridges, micronuclei, and chromatin buds. We believe that WARS-1 depletion increases the intracellular concentration of tryptophan and an elevated level of its catabolites, leading to genomic instability. Our result demonstrates that exposing C. elegans to a high tryptophan dosage leads to DNA damage checkpoint activation. All in all, we have strong evidence that knocking down wars-1 results in defects in genomic integrity.