AI Article Synopsis
- Chemical modifications of RNAs play a crucial role in gene regulation, particularly through m^6A methylation mediated by the METTL3-METTL14 complex.
- Mutations in METTL14, common in cancer, lead to altered m^6A modification patterns, promoting malignant cell growth without increasing overall m^6A levels in mRNAs.
- The study proposes a structural model explaining how the METTL3-METTL14 complex selectively modifies specific RNA sequences, emphasizing the significance of noncanonical methylation in altering gene expression and contributing to cancer development.
Article Abstract
Chemical modification of RNAs is important for post-transcriptional gene regulation. The METTL3-METTL14 complex generates most -methyladenosine (m A) modifications in mRNAs, and dysregulated methyltransferase expression has been linked to numerous cancers. Here we show that changes in m A modification location can impact oncogenesis. A gain-of-function missense mutation found in cancer patients, METTL14 , 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 m A 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 m A 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055151 | PMC |
| http://dx.doi.org/10.1101/2023.03.16.532618 | DOI Listing |
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