Cancer mutations rewire the RNA methylation specificity of METTL3-METTL14.

ABSTRACT: Chemical modification of RNAs is important for posttranscriptional gene regulation. The METTL3-METTL14 complex generates most N⁶-methyladenosine (m⁶A) modifications in messenger RNAs (mRNAs), and dysregulated methyltransferase expression has been linked to cancers. Here we show that a changed sequence context for m⁶A can promote oncogenesis. A gain-of-function missense mutation from patients with cancer, METTL14^R298P, increases malignant cell growth in culture and transgenic mice without increasing global m⁶A levels in mRNAs. The mutant methyltransferase preferentially modifies noncanonical sites containing a GGAU motif, in vitro and in vivo. The m⁶A in GGAU context is detected by the YTH family of readers similarly t

SUBMITTER: Zhang C 

PROVIDER: S-EPMC11661435 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature