Ali Raja H, Orellana Esteban A, Lee Su Hyun, Chae Yun-Cheol, Chen Yantao, Clauwaert Jim, Kennedy Alyssa L, Gutierrez Ashley E, Papke David J, Valenzuela Mateo, Silverman Brianna, Falzetta Amanda, Ficarro Scott B, Marto Jarrod A, Fletcher Christopher D M, Perez-Atayde Antonio, Alcindor Thierry, Shimamura Akiko, Prensner John R, Gregory Richard I, Gutierrez Alejandro
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Stem Cell Program, Boston Children's Hospital, Boston, MA, USA; Department of Molecular and Systems Biology, The Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Mol Cell. 2025 Mar 6;85(5):948-961.e11. doi: 10.1016/j.molcel.2025.01.003. Epub 2025 Jan 31.
Amplification of chromosomal material derived from 12q13-15 is common in human cancer and believed to result in overexpression of multiple collaborating oncogenes. To define the oncogenes involved, we overexpressed genes recurrently amplified in human liposarcoma using a zebrafish model of the disease. We found several genes whose overexpression collaborated with AKT in sarcomagenesis, including the tRNA methyltransferase METTL1. This was surprising, because AKT phosphorylates METTL1 to inactivate its enzymatic activity. Indeed, phosphomimetic S27D or catalytically dead alleles phenocopied the oncogenic activity of wild-type METTL1. We found that METTL1 binds the multi-tRNA synthetase complex, which contains many of the cellular aminoacyl-tRNA synthetases and promotes tRNA aminoacylation, polysome formation, and protein synthesis independent of its methyltransferase activity. METTL1-amplified liposarcomas were hypersensitive to actinomycin D, a clinical inhibitor of ribosome biogenesis. We propose that METTL1 overexpression promotes sarcomagenesis by stimulating tRNA aminoacylation, protein synthesis, and tumor cell growth independent of its methyltransferase activity.
源自12q13 - 15的染色体物质扩增在人类癌症中很常见，并且被认为会导致多个协同致癌基因的过表达。为了确定所涉及的致癌基因，我们使用该疾病的斑马鱼模型过表达了在人类脂肪肉瘤中反复扩增的基因。我们发现了几个基因，其过表达在肉瘤发生过程中与AKT协同作用，包括tRNA甲基转移酶METTL1。这很令人惊讶，因为AKT会磷酸化METTL1以使其酶活性失活。事实上，模拟磷酸化的S27D或催化失活的等位基因模拟了野生型METTL1的致癌活性。我们发现METTL1与多tRNA合成酶复合物结合，该复合物包含许多细胞氨酰 - tRNA合成酶，并促进tRNA氨基酰化、多核糖体形成和蛋白质合成，而与其甲基转移酶活性无关。METTL1扩增的脂肪肉瘤对放线菌素D高度敏感，放线菌素D是核糖体生物发生的临床抑制剂。我们提出，METTL1过表达通过刺激tRNA氨基酰化、蛋白质合成和肿瘤细胞生长来促进肉瘤发生，而与其甲基转移酶活性无关。
