| Literature DB >> 34352207 |
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.
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.Entities:
Keywords: Arg-TCT; METTL1; N(7)-methylguanosine; cancer; m(7)G; oncogene; tRNA; translation
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Year: 2021 PMID： 34352207 PMCID： PMC8380730 DOI： 10.1016/j.molcel.2021.06.031
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 19.328