Proteomics

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Cancer Mutations Rewire the RNA Methylation Specificity of METTL3-METTL14


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 m6A modification location, rather than the overall modification level, 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 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 detects RNA sequences. Together, our work highlights that m6A location is important for function and that noncanonical methylation sites may impact aberrant gene expression and oncogenesis.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Cell Culture

DISEASE(S): Liver Cancer

SUBMITTER: Yen-Yu Yang  

LAB HEAD: Yinsheng Wang

PROVIDER: PXD039447 | Pride | 2024-12-21

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
HepG2_BR1_1.raw Raw
HepG2_BR1_10.raw Raw
HepG2_BR1_11.raw Raw
HepG2_BR1_12.raw Raw
HepG2_BR1_13.raw Raw
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