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Exon junction complex shapes the m(6)A epitranscriptome

N6-methyladenosine (m(6)A), the most abundant modification of mRNA, is essential for normal development and dysregulation promotes cancer. m(6)A is highly enriched in the 3’ untranslated region (UTR) of a large subset of mRNAs to influence mRNA stability and/or translation. However, the mechanism re...

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Detalles Bibliográficos
Autores principales: Yang, Xin, Triboulet, Robinson, Liu, Qi, Sendinc, Erdem, Gregory, Richard I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9780246/
https://www.ncbi.nlm.nih.gov/pubmed/36550132
http://dx.doi.org/10.1038/s41467-022-35643-1
Descripción
Sumario:N6-methyladenosine (m(6)A), the most abundant modification of mRNA, is essential for normal development and dysregulation promotes cancer. m(6)A is highly enriched in the 3’ untranslated region (UTR) of a large subset of mRNAs to influence mRNA stability and/or translation. However, the mechanism responsible for the observed m(6)A distribution remains enigmatic. Here we find the exon junction complex shapes the m(6)A landscape by blocking METTL3-mediated m(6)A modification close to exon junctions within coding sequence (CDS). Depletion of EIF4A3, a core component of the EJC, causes increased METTL3 binding and m(6)A modification of short internal exons, and sites close to exon-exon junctions within mRNA. Reporter gene experiments further support the role of splicing and EIF4A3 deposition in controlling m(6)A modification via the local steric blockade of METTL3. Our results explain how characteristic patterns of m(6)A mRNA modification are established and uncover a role of the EJC in shaping the m(6)A epitranscriptome.