Highlights

• More than 170 RNA modifications in various RNA types have been well-established, contributing to diverse biological functions.
• This study introduces several groundbreaking findings: (i) Identification of imG-14 as the predominant modification at the 37th position in tRNA^Phe of taxol-resistant strains, a departure from OHyW in wild-type strains. (ii) Chronic exposure of A2780 cancer cells to taxol induces drug resistance, suppresses TYW2 expression, and disrupts the OHyW biosynthetic pathway, increasing imG-14. (iii) Silencing TYW2 is a causative factor in cellular resistance to taxol-induced cytotoxicity, shedding new light on taxol resistance mechanisms.
• This study marks the first examination of the association between tRNA modifications and taxol resistance, utilizing tRNA profiling through LC-MS, potentially uncovering novel insights into cancer cell susceptibility to drug therapy akin to microRNA (miRNA) effects.

Summary

TYW2 enzyme downregulation increases the 4-demethylwyosine modification in tRNA, promoting cancer survival and resistance to taxol therapy. This finding introduces a novel mechanism for taxol resistance that can be addressed by reducing imG-14 deposition. More than 170 identified RNA modifications across various RNA types play pivotal roles in biological regulation.

In taxol-resistant strains, the predominant modification at the 37th position in tRNA^Phe is imG-14. While reprogramming of tRNA modifications has been associated with chemotherapy resistance, the underlying mechanism remains unclear.

Suppression of TYW2 expression in taxol-resistant strains leads to elevated imG-14 levels and cellular resistance to taxol-induced cytotoxicity. TYW2 has been identified in breast cancer and castration-resistant prostate cancer, where tRNA modifications serve as protective mechanisms against stress-induced cleavages. tRNA-derived fragments (tRFs), such as tRF^Phe, may influence cancer cell susceptibility to drug therapy.

This study delves into the connection between tRNA modifications and taxol resistance, employing multiple LC-MS approaches to explore dynamic changes in tRNA modifications in taxol-resistant cancer cells. Notably, the 37th position of tRNA^Phe exhibits chemical diversity across different species, contributing to the stability of tRNA structure and codon-anticodon interactions.

The research involves three taxol-resistant strains and aligns with the potential implications of previous work, suggesting that tRNA modifications may play a role in drug resistance. Reprogramming tRNA modifications could offer a strategy to overcome drug resistance in cancer therapy, as noted by Pan, emphasizing the need for further studies to comprehend the relationship between frameshift and taxol resistance.

Y. Pan, T.-M. Yan, J.-R. Wang, and Z.-H. Jiang, “The nature of the modification at position 37 of tRNA^Phe correlates with acquired taxol resistance,” Nucleic Acids Research, vol. 49, no. 1, pp. 38–52, Jan. 2021, doi: .