ADAT2/3 complex-deposited tRNA inosines drives oncogenic transformation

Transfer RNAs (tRNAs) are subject to numerous posttranscriptional modifications that influence their maturation, stability, and function. Adenosine to Inosine (A-to-I) editingin thetRNA anticodon stem loop is an important modification that influences anticodon-codon recognition.However,the implications of tRNA editing in cancer and its potential for diagnostic and therapeutic applicationsare not yet well understood.We showed that the ADAT2/3 enzyme complex, responsible for this modification in humans, is amplified and overexpressed in several tumor types,with a higher amplification rate in sarcoma tumors, particularly liposarcomas. We determine that the ADAT complex works as an oncogene in these tumors and that its inhibition reduces tumor growth, offering a new approach to cancer treatment. In addition, we provided insight into the mechanisms of cancer development and progression, demonstrating that tRNA editing is required for higher mRNA translation of oncogenic proteins enriched with specific ADAT-sensitive codons. Thus, ADAT-mediated tRNA modification drives oncogenic transformation by remodeling the set of mRNAs being actively translated to increase expression of proteins that promote proliferation. Our results explain how cancer cells benefit from increased tRNA A-to-I editing and propose ADATs as potential therapeutic targets for the treatment of cancer. Overall design: To understand the role of A-to-I editing in tRNA in tumor development, we carried out small RNA-seq in ADAT2 knock-down cells. We identify the editing events deposited by ADAT2 enzyme and monitor their molecular functions on translation as well as physiological roles during tumor growth.