Ramirez-Moya Julia, Antika Titi Rindi, Liu Qi, Xiong Xushen, Ali Raja, Gutierrez Alejandro, Gregory Richard I
Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Molecular, Cell, and Cancer Biology Department, UMass Chan Medical School, Worcester, MA 01605, USA.
J Mol Biol. 2025 Sep 2:169414. doi: 10.1016/j.jmb.2025.169414.
Transfer RNAs (tRNAs) are subject to various chemical modifications that influence their stability or function. Adenosine to Inosine (A-to-I) editing in the tRNA anticodon at position A34 is an important modification that expands anticodon-codon recognition at the wobble position and is required for normal mRNA translation. The relevance of tRNA editing in cancer remains unexplored. Here we show that the genes encoding the ADAT2/3 deaminase complex, responsible for A-to-I tRNA editing in humans, are commonly amplified and/or overexpressed in several tumor types including liposarcoma (LPS). We find that LPS cell growth and tumorigenicity is dependent on ADAT2/3 tRNA editing activity. Mechanistically, we find decreased tRNA editing upon ADAT2 depletion, defective translation of a subset of mRNAs, and altered protein homeostasis. Thus, ADAT2 promotes oncogenesis and the translation of growth promoting mRNAs that are enriched in NNC codons that lack cognate tRNAs and therefore depend on A-I tRNA editing for decoding and mRNA translation. Our results identify ADAT2/3 as a potential new cancer therapeutic target.
转运RNA（tRNA）会经历各种化学修饰，这些修饰会影响其稳定性或功能。tRNA反密码子第34位的腺苷到肌苷（A-to-I）编辑是一种重要的修饰，它扩展了摆动位置上反密码子与密码子的识别，是正常mRNA翻译所必需的。tRNA编辑在癌症中的相关性仍未得到探索。在这里，我们表明，在人类中负责A-to-I tRNA编辑的编码ADAT2/3脱氨酶复合物的基因，在包括脂肪肉瘤（LPS）在内的几种肿瘤类型中通常会扩增和/或过表达。我们发现LPS细胞生长和致瘤性依赖于ADAT2/3 tRNA编辑活性。从机制上讲，我们发现ADAT2缺失后tRNA编辑减少，一部分mRNA的翻译存在缺陷，并且蛋白质稳态发生改变。因此，ADAT2促进肿瘤发生以及富含NNC密码子的生长促进mRNA的翻译，这些密码子缺乏同源tRNA，因此依赖A-I tRNA编辑来进行解码和mRNA翻译。我们的结果确定ADAT2/3是一个潜在的新的癌症治疗靶点。
