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METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation.
Orellana, Esteban A; Liu, Qi; Yankova, Eliza; Pirouz, Mehdi; De Braekeleer, Etienne; Zhang, Wencai; Lim, Jihoon; Aspris, Demetrios; Sendinc, Erdem; Garyfallos, Dimitrios A; Gu, Muxin; Ali, Raja; Gutierrez, Alejandro; Mikutis, Sigitas; Bernardes, Gonçalo J L; Fischer, Eric S; Bradley, Allan; Vassiliou, George S; Slack, Frank J; Tzelepis, Konstantinos; Gregory, Richard I.
Afiliación
  • Orellana EA; Stem Cell Program, 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.
  • Liu Q; Stem Cell Program, 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.
  • Yankova E; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Milner Therapeutics Institute, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK; Storm Therapeutics Ltd., Moneta Building (B280), Babraham Research Campus, Cambridge CB22 3AT, UK.
  • Pirouz M; Stem Cell Program, 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.
  • De Braekeleer E; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • Zhang W; Department of Pathology, Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
  • Lim J; Department of Pathology, Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
  • Aspris D; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Karaiskakio Foundation, Nicandrou Papamina Avenue, 2032 Nicosia, Cyprus.
  • Sendinc E; Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • Garyfallos DA; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK.
  • Gu M; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • Ali R; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.
  • Gutierrez A; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
  • Mikutis S; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
  • Bernardes GJL; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
  • Fischer ES; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • Bradley A; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK.
  • Vassiliou GS; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Karaiskakio Foundation, Nicandrou Papamina Avenue, 2032 Nicosia, Cyprus; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK.
  • Slack FJ; Department of Pathology, Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Harvard Initiative for RNA Medicine, Boston, MA 02115, USA.
  • Tzelepis K; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Milner Therapeutics Institute, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK.
  • Gregory RI; Stem Cell Program, 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; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Dep
Mol Cell ; 81(16): 3323-3338.e14, 2021 08 19.
Article en En | MEDLINE | ID: mdl-34352207
ABSTRACT
The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (m7G) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of m7G-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of m7G-modified tRNAs, in particular Arg-TCT-4-1, and increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, Arg-TCT expression is elevated in many tumor types and is associated with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation through a remodeling of the mRNA "translatome" to increase expression of growth-promoting proteins and represents a promising anti-cancer target.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: ARNt Metiltransferasas / Carcinogénesis / Metiltransferasas / Neoplasias Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: ARNt Metiltransferasas / Carcinogénesis / Metiltransferasas / Neoplasias Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos