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METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation
Open accessAbstract
SUMMARY 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/overexpressed in cancers and associates with poor patient survival. METTL1 depletion causes decreased abundance of m7G-modified tRNAs, 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, associates with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation via a remodeling of the mRNA ‘translatome’ to increase expression of growth-promoting proteins and represents a promising anti-cancer target.
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Cited by
McGaha, D. A., Collins, A., Ajisafe, L. O., Perdigao, C. C., Bondrowski, J. L., Fetsch, K., & Dunkle, J. A. (2025) · RNA · doi:10.1261/rna.080068.124
Metadata
- Authors
- Orellana, E. A., Liu, Q., Yankova, E., Pirouz, M., De Braekeleer, E., Zhang, W., Lim, J., Aspris, D., Sendinc, E., Garyfallos, D. A., Gu, M., Ali, R., Gutierrez, A., Mikutis, S., Bernardes, G. J. L., Fischer, E. S., Bradley, A., Vassiliou, G. S., Slack, F. J., Tzelepis, K., & Gregory, R. I.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 81
- Issue
- 16
- Pages
- 3323-3338.e14
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W3189444738
- Cited by
- 348
- References
- 8
- FWCI
- 15.83
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Orellana, E. A., Liu, Q., Yankova, E., Pirouz, M., De Braekeleer, E., Zhang, W., Lim, J., Aspris, D., Sendinc, E., Garyfallos, D. A., Gu, M., Ali, R., Gutierrez, A., Mikutis, S., Bernardes, G. J. L., Fischer, E. S., Bradley, A., Vassiliou, G. S., Slack, F. J., . . . Gregory, R. I. (2021). METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation. Molecular Cell. https://doi.org/10.1016/j.molcel.2021.06.031
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