Cancer mutations rewire the RNA methylation specificity of METTL3-METTL14
Chemical modification of RNAs is important for posttranscriptional gene regulation. The METTL3-METTL14 complex generates most <i>N</i><sup>6</sup>-methyladenosine (m<sup>6</sup>A) modifications in messenger RNAs (mRNAs), and dysregulated methyltransferase expression has been linked to cancers. Here we show that a changed sequence context for m<sup>6</sup>A can promote oncogenesis. A gain-of-function missense mutation from patients with cancer, METTL14<sup>R298P</sup>, increases malignant cell growth in culture and transgenic mice without increasing global m<sup>6</sup>A levels in mRNAs. The mutant methyltransferase preferentially modifies noncanonical sites containing a GGAU motif, in vitro and in vivo. The m<sup>6</sup>A in GGAU context is detected by the YTH family of readers similarly to the canonical sites but is demethylated less efficiently by an eraser, ALKBH5. Combining the biochemical and structural data, we provide a model for how the cognate RNA sequences are selected for methylation by METTL3-METTL14. Our work highlights that sequence-specific m<sup>6</sup>A deposition is important and that increased GGAU methylation can promote oncogenesis.
Authors
- Yunsun Nam (ORCID: https://orcid.org/0000-0002-7939-8626)
- Xunzhi Zhang (ORCID: https://orcid.org/0000-0002-3599-1751)
- Yinsheng Wang (ORCID: https://orcid.org/0000-0001-5565-283X)
- Luiza Guimarães Tunes (ORCID: https://orcid.org/0000-0002-7177-0059)
- Brijesh B. Khadgi (ORCID: https://orcid.org/0000-0002-6206-2552)
- Robyn Scott (ORCID: https://orcid.org/0000-0001-6450-4708)
- Hao Zhu (ORCID: https://orcid.org/0000-0002-8417-9698)
- Emily Herrell (ORCID: https://orcid.org/0000-0002-4620-1778)
- Bret M. Evers (ORCID: https://orcid.org/0000-0001-5686-0315)
- Yen‐Yu Yang
- Katelyn A. Doxtader Lacy
- Chi Zhang (ORCID: https://orcid.org/0000-0002-9209-4934)
- Ashwani Kumar (ORCID: https://orcid.org/0000-0002-8806-111X)
- Chao Xing (ORCID: https://orcid.org/0000-0002-1838-0502)
- Ping Wang (ORCID: https://orcid.org/0000-0002-5636-8280)
- Meng-Hsiung Hsieh (ORCID: https://orcid.org/0000-0001-9791-1318)
Institutions
- University of California, Riverside (US)
- Southwestern Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-12-20
- DOI
- https://doi.org/10.1126/sciadv.ads4750
- Citations
- 10
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- U.S. Department of Energy
- University of Texas Southwestern Medical Center