N6-methyladenosine (m6A) is installed onto mRNA at the consensus motif DRACH by m6A methyltransferases and is recognized by readers that mediate its downstream effects. Mysteriously, m6A exhibits biased distribution on mRNAs, showing enrichment at long internal exons and near stop codons, whereas the DRACH motifs have a relatively even distribution. Uzonyi et al. developed a simple m6A-deposition model to explain this phenomenon, revealing that m6A is installed onto the DRACH motif in a nonselective manner unless it is within a fixed distance (100 nt) of the splice junctions, a region known to be bound by the exon junction complex (EJC). Using a massively parallel reporter assay and published transcriptomic data, the authors found that the DRACH motif itself was sufficient for m6A installation. Distancing DRACH motifs from splice junctions recovered m6A levels, which gradually increased once the distance exceeded 100 nt and plateaued at approximately 200 nt. Degradation of a core component of the EJC led to the accumulation of m6A in areas near the splice junctions that are normally devoid of m6A, which suggests that the EJC might mediate the exclusion of m6A. The authors also propose that m6A conveys nuclear splicing information to the cytoplasm to dictate RNA decay. These findings offer a re-examination of the basis of transcriptome-wide m6A distribution and provide a mechanistic connection between splicing and RNA stability.
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