Cancer mutations rewire the RNA methylation specificity of METTL3-METTL14

Zhang, C.; Tunes, L.; Hsieh, M.-H.; Wang, P.; Kumar, A.; Khadgi, B. B.; Yang, Y.-Y.; Doxtader, K. A.; Herrell, E.; Koczy, O.; Setlem, R.; Zhang, X.; Evers, B. M.; Wang, Y.; Xing, C.; Zhu, H.; Nam, Y.

doi:10.1101/2023.03.16.532618

bioRxiv · 10.1101/2023.03.16.532618

Cancer mutations rewire the RNA methylation specificity of METTL3-METTL14

Zhang, C.·Tunes, L.·Hsieh, M.-H.·Wang, P.·Kumar, A.·Khadgi, B. B.·Yang, Y.-Y.·Doxtader, K. A.·Herrell, E.·Koczy, O.·Setlem, R.·Zhang, X.·Evers, B. M.·Wang, Y.·Xing, C.·Zhu, H.·Nam, Y.

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Abstract

Chemical modification of RNAs is important for post-transcriptional gene regulation. The METTL3-METTL14 complex generates most N6-methyladenosine (m6A) modifications in mRNAs, and dysregulated methyltransferase expression has been linked to numerous cancers. Here we show that changes in m6A modification location can impact oncogenesis. A gain-of-function missense mutation found in cancer patients, METTL14R298P, promotes malignant cell growth in culture and in transgenic mice. The mutant methyltransferase preferentially modifies noncanonical sites containing a GGAU motif and transforms gene expression without increasing global m6A levels in mRNAs. The altered substrate specificity is intrinsic to METTL3-METTL14, helping us to propose a structural model for how the METTL3-METTL14 complex selects the cognate RNA sequences for modification. Together, our work highlights that sequence-specific m6A deposition is important for proper function of the modification and that noncanonical methylation events can impact aberrant gene expression and oncogenesis.

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Zhang, C., Tunes, L., Hsieh, M.-H., Wang, P., Kumar, A., Khadgi, B. B., Yang, Y.-Y., Doxtader, K. A., Herrell, E., Koczy, O., Setlem, R., Zhang, X., Evers, B. M., Wang, Y., Xing, C., Zhu, H., Nam, Y.. 2023-03-16. Cancer mutations rewire the RNA methylation specificity of METTL3-METTL14. https://doi.org/10.1101/2023.03.16.532618

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