Exploring Players in DNA Damage Response and Genomic Instability

The fidelity of translation is ensured by a family of proteins named aminoacyl-tRNA synthetases (ARSs), making them crucial for development and survival. More recently, mutations in the tryptophanyl-tRNA synthetase 1 (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 Caenorhabditis elegans (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 demonstrated that knocking down wars-1 results in an elevation of the intracellular concentration of Tryptophan and its catabolites, a surprising finding emphasizing the impact of cellular amino acid availability and organismal/individual dietary uptake on genome integrity. Our result demonstrates that exposing C. elegans to a high tryptophan dosage leads to DNA damage checkpoint activation and a significant increase in the tryptophan metabolites. Targeting tryptophan catabolism, the least utilized amino acid in nature, can be important in developing new therapeutic approaches for cancer. Moreover, the proteomics analysis revealed significant disruptions in proteins associated with ribosomes, cellular structure, and developmental processes upon WARS-1 depletion, suggesting a broad impact on cellular protein dynamics and homeostasis. Proteomic changes upon WARS-1 depletion further confirmed the experimental data. All in all, we have strong evidence that knocking down wars-1 results in defects in genomic integrity.

The human genome is constantly exposed to factors that can cause DNA damage, making the DNA damage response (DDR) critical for maintaining genomic stability and preventing tumor cell characteristics like uncontrolled proliferation. Cisplatin, a key chemotherapy drug, has been instrumental in treating various cancers, but its resistance remains a major challenge. Our study investigated the DNA damage response (DDR) and chemoresistance mechanisms, focusing on the role of cisplatin in cancer therapy through a quantitative proteomics approach in C. elegans. We explored the complex effects of cisplatin as a genotoxic agent, revealing significant alterations in proteins and pathways in response to treatment, particularly emphasizing the role of glutathione S transferases (GSTs) in detoxification and chemoresistance.

This research highlighted the necessity for personalized cancer treatments to combat chemoresistance. By incorporating translocation analysis, we provided insights into protein dynamics crucial for understanding the DDR and developing strategies to overcome drug resistance in cancer therapy. Our comprehensive approach combined proteomics, functional enrichment, structural biology, and translocation analysis, advancing our knowledge of genomic stability maintenance and the interplay between cellular repair mechanisms and chemotherapeutic interventions. This study will contribute to developing targeted cancer therapies, emphasizing the potential of precision oncology in enhancing treatment outcomes for patients with drug resistance.