METTL1-mediated m 7 G 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.

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