miR-34a directly targets tRNAiMet precursors and affects cellular proliferation, cell cycle, and apoptosis

Abstract

It remains unknown whether microRNA (miRNA/miR) can target transfer RNA (tRNA) molecules. Here we provide evidence that miR-34a physically interacts with and functionally targets tRNA_i^Met precursors in both in vitro pulldown and Argonaute 2 (AGO2) cleavage assays. We find that miR-34a suppresses breast carcinogenesis, at least in part by lowering the levels of tRNA_i^Met through AGO2-mediated repression, consequently inhibiting the proliferation of breast cancer cells and inducing cell cycle arrest and apoptosis. Moreover, miR-34a expression is negatively correlated with tRNA_i^Met levels in cancer cell lines. Furthermore, we find that tRNA_i^Met knockdown also reduces cell proliferation while inducing cell cycle arrest and apoptosis. Conversely, ectopic expression of tRNA_i^Met promotes cell proliferation, inhibits apoptosis, and accelerates the S/G2 transition. Moreover, the enforced expression of modified tRNA_i^Met completely restores the phenotypic changes induced by miR-34a. Our results demonstrate that miR-34a directly targets tRNA_i^Met precursors via AGO2-mediated cleavage, and that tRNA_i^Met functions as an oncogene, potentially representing a target molecule for therapeutic intervention.

Keywords: apoptosis; cell cycle; miR-34a; proliferation; tRNAiMet.