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

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. [Display omitted] •METTL1-mediated tRNA modification drives oncogenic transformation•Changes in the tRNA pool remodel the mRNA “translatome” in a codon-biased manner•Arg-TCT-4-1 is a METTL1 substrate with oncogenic properties•METTL1 and Arg-TCT-4-1 upregulation increases expression of growth-promoting proteins Orellana et al. demonstrate that overexpression of the m7G RNA methyltransferase METTL1 induces oncogenic cell transformation and cancer. Moreover, the increased abundance of m7G-modified tRNAs, in particular Arg-TCT-4-1, leads to increased translation of mRNAs involved in cell growth that are enriched in the corresponding AGA codon.