METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation

Esteban A Orellana; Qi Liu; Eliza Yankova; Mehdi Pirouz; Etienne De Braekeleer; Wencai Zhang; Jihoon Lim; Demetrios Aspris; Erdem Sendinc; Dimitrios A Garyfallos; Muxin Gu; Raja Ali; Alejandro Gutierrez; Sigitas Mikutis; Gonçalo J L Bernardes; Eric S Fischer; Allan Bradley; George S Vassiliou; Frank J Slack; Konstantinos Tzelepis; Richard I Gregory

doi:10.1016/j.molcel.2021.06.031

METTL1-mediated m⁷G modification of Arg-TCT tRNA drives oncogenic transformation

Mol Cell. 2021 Aug 19;81(16):3323-3338.e14. doi: 10.1016/j.molcel.2021.06.031. Epub 2021 Aug 4.

Authors

Esteban A Orellana¹, Qi Liu¹, Eliza Yankova², Mehdi Pirouz¹, Etienne De Braekeleer³, Wencai Zhang⁴, Jihoon Lim⁴, Demetrios Aspris⁵, Erdem Sendinc⁶, Dimitrios A Garyfallos⁷, Muxin Gu³, Raja Ali⁸, Alejandro Gutierrez⁹, Sigitas Mikutis¹⁰, Gonçalo J L Bernardes¹⁰, Eric S Fischer¹¹, Allan Bradley¹², George S Vassiliou¹³, Frank J Slack¹⁴, Konstantinos Tzelepis¹⁵, Richard I Gregory¹⁶

Affiliations

¹ 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.
² 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.
³ Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
⁴ Department of Pathology, Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
⁵ Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Karaiskakio Foundation, Nicandrou Papamina Avenue, 2032 Nicosia, Cyprus.
⁶ Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
⁷ 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.
⁸ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.
⁹ 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.
¹⁰ Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
¹¹ 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.
¹² Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK.
¹³ 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.
¹⁴ 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.
¹⁵ 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. Electronic address: kt404@cam.ac.uk.
¹⁶ 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; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Harvard Initiative for RNA Medicine, Boston, MA 02115, USA. Electronic address: rgregory@enders.tch.harvard.edu.

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.

Keywords: Arg-TCT; METTL1; N(7)-methylguanosine; cancer; m(7)G; oncogene; tRNA; translation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Carcinogenesis / genetics*
Guanosine / analogs & derivatives
Guanosine / genetics
Humans
Methylation
Methyltransferases / genetics*
Neoplasms / genetics*
Neoplasms / pathology
Oncogenes / genetics
RNA Processing, Post-Transcriptional / genetics
RNA, Messenger / genetics
RNA, Transfer / genetics
tRNA Methyltransferases / genetics*

Substances

8-methylguanosine
RNA, Messenger
Guanosine
RNA, Transfer
METTL1 protein, human
Methyltransferases
tRNA Methyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding