. 2025 Mar 6;85(5):948-961.e11.

doi: 10.1016/j.molcel.2025.01.003. Epub 2025 Jan 31.

A methyltransferase-independent role for METTL1 in tRNA aminoacylation and oncogenic transformation

Raja H Ali¹, Esteban A Orellana², Su Hyun Lee³, Yun-Cheol Chae³, Yantao Chen³, Jim Clauwaert⁴, Alyssa L Kennedy⁵, Ashley E Gutierrez¹, David J Papke⁶, Mateo Valenzuela¹, Brianna Silverman¹, Amanda Falzetta⁴, Scott B Ficarro⁷, Jarrod A Marto⁷, Christopher D M Fletcher⁶, Antonio Perez-Atayde⁸, Thierry Alcindor⁹, Akiko Shimamura¹⁰, John R Prensner⁴, Richard I Gregory¹¹, Alejandro Gutierrez¹²

Affiliations

¹ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
² 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.
³ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
⁴ Department of Pediatrics, Division of Pediatric Hematology/Oncology and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.
⁶ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Linde Program in Cancer Chemical Biology, Center for Emerging Drug Targets and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁰ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹¹ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Stem Cell Program, Boston Children's Hospital, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Harvard Initiative for RNA Medicine, Boston, MA, USA; Department of Molecular, Cell & Cancer Biology, UMass Chan Medical School, Worcester, MA, USA.
¹² Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: alejandro.gutierrez@stjude.org.

PMID: 39892392
PMCID: PMC11925124 (available on 2026-03-06)
DOI: 10.1016/j.molcel.2025.01.003

A methyltransferase-independent role for METTL1 in tRNA aminoacylation and oncogenic transformation

Raja H Ali et al. Mol Cell. 2025.

. 2025 Mar 6;85(5):948-961.e11.

doi: 10.1016/j.molcel.2025.01.003. Epub 2025 Jan 31.

Authors

Affiliations

¹ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
² 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.
³ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
⁴ Department of Pediatrics, Division of Pediatric Hematology/Oncology and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.
⁶ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Linde Program in Cancer Chemical Biology, Center for Emerging Drug Targets and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁰ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹¹ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Stem Cell Program, Boston Children's Hospital, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Harvard Initiative for RNA Medicine, Boston, MA, USA; Department of Molecular, Cell & Cancer Biology, UMass Chan Medical School, Worcester, MA, USA.
¹² Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: alejandro.gutierrez@stjude.org.

PMID: 39892392
PMCID: PMC11925124 (available on 2026-03-06)
DOI: 10.1016/j.molcel.2025.01.003

Abstract

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.

Keywords: AKT; METTL1; aminoacylation; sarcoma; tRNA; translation.

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Conflict of interest statement

Declaration of interests T.A. is a consultant for Bayer, AstraZeneca, and Astellas Pharma and receives research funding from Epizyme, EMD Serono, Karyopharm Therapeutics, SpringWorks Therapeutics, Astellas Pharma, Deciphera, and Pharma Mar. J.A.M. is a founder, equity holder, and advisor to Entact Bio, serves on the scientific advisory board (SAB) of 908 Devices, and receives or has received sponsored research funding from Vertex, AstraZeneca, Taiho, Springworks, TUO Therapeutics, and Takeda. J.R.P. is a consultant for ProFound Therapeutics. R.I.G. is a co-founder and advisory board member of Redona Therapeutics, and scientific advisor to Alida Biosciences. A.G. is an advisory board member of Attivare Therapeutics.

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A methyltransferase-independent role for METTL1 in tRNA aminoacylation and oncogenic transformation

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A methyltransferase-independent role for METTL1 in tRNA aminoacylation and oncogenic transformation

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