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Epitranscriptome & Cancer

Our most recent work has focused on elucidating the role of RNA methylation in gene expression control. We recently provided the very first functional evidence linking the epitranscriptome with cancer. In these pioneering studies we uncovered a role of the N6-methlyadenosine (m6A) methyltransferase METTL3 in promoting translation of certain oncogenes (including EGFR) to promote lung cancer cell growth, survival, invasion, and tumorigenesis in a mouse xenograft model. Mechanistically we found that METTL3 only promoted translation when bound to the 3’ UTR near a stop codon. Using biochemical approaches we found that METTL3 interacts with the eukaryotic translation initiation factor 3 subunit h (eIF3h) to promote translation of target mRNAs, suggesting an mRNA looping mechanism to facilitate ribosome recycling and translational control. Electron microscopy further supported this model, indicating that METTL3 bound to polyribosomes in close proximity to 5’ cap-binding proteins. METTL3 depletion reduced the translation efficiency of a large subset of mRNAs. We also uncovered the very first m6A epitranscriptomes of human tumor samples. This provides major insight into the molecular mechanisms and role of m6A in gene regulation and helped establish the epitranscriptome and cancer field.

  1. Lin, S., Choe, J., Du, P., Triboulet, R. and Gregory R. I. The m6A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell 2016, 62, 335-345. PMID: 27117702. PMC4860043.
  2. Choe J., Lin S., Zhang W., Liu Q., Wang L., Ramirez-Moya J., Du P., Kim W., Tang S., Sliz P., Santisteban P., George R. E., Richards W. G., Wong K. K., Locker N., Slack F. J., and Gregory R. I. mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature 2018, 561, 556-560. PMID: 30232453. PMC6234840.
  3. Li J., and Gregory R. I. Mining for METTL3 inhibitors to suppress cancer. Nat Struct Mol Biol 2021, 28 460-462. PMID: 34040230. PMC8197751.
  4. Orellana E. A., Liu, Q. D., Yankova E., Nelson M. D., De Braekeleer E., Zhang W., Kim J., Aspris D., Sendinc E., Garyfallos D., Gu M., Ali R., Gutierrez A., Mikutis S., Bernardes G., Fischer E., Bradley A., Vassiliou A., Slack F., Tzelepis K., and Gregory R. I. METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation. Mol Cell 2021, 81, 3323-3338. PMID: 34352207. PMC8380730.
  5. Ramírez-Moya J., Miliotis C., Baker A. R., Gregory R. I., Slack F. J., and Santisteban P. An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks. Mol Cancer 2021, 20, 115. PMID: 34496885. PMC8424981.