The asymmetric m 6A deposition suggests that regional methylation may have distinct functional consequences. For mature mRNAs, there is a strong enrichment of m 6A around the stop codon and 3′ UTR 13, 14. By affecting nearly all the aspects of mRNA metabolism, m 6A marks an ever growing list of cellular and physiological functions.ĭespite the tremendous progress in the functional characterization of m 6A modification, the regional effects of mRNA methylation remain obscure. A recent study reported that m 6A also repels certain RNA-binding proteins 12, forming an additional layer in controlling dynamic RNA–protein interaction. The biological effect of m 6A largely depends on m 6A reader proteins, such as YTH domain-containing proteins 11. The m 6A topology is achieved by two opposing enzyme systems: the methyltransferase complex comprising a core heterodimer of METT元–METTL14 (refs 7, 8), and m 6A demethylases FTO and ALKBH5 (refs 9, 10). The m 6A content varies substantially across various species, tissues, and cellular environments 6, suggesting an extensive regulation of methylation dynamics. N 6-methyladenosine (m 6A) is the most abundant internal base modification occurring on eukaryotic mRNAs. To date, more than 150 distinct modifications have been identified on RNA species 5. One such parallel code is the chemical modification of nucleotides within mRNAs 4. One fundamental question is how cells fine-tune the TE for individual transcripts by integrating parallel codes embedded within the nucleotide sequence. Besides the nucleotide sequence, the flexible nature of mRNA molecules implies that particular shape can also encode regulatory information guiding translational control 3. Factors contributing to ribosomal pausing are likely to be multifaceted. Frequent ribosomal pausing decreases the overall translation efficiency (TE) by reducing the elongation speed and limiting the amount of free ribosomes available for other protein synthesis. Recent findings from ribosome profiling studies show that the translation machinery proceeds not at a constant rate but rather in a stop-and-go traffic manner 1, 2. The importance of the coding region (CDS) is apparent because the elongation speed directly controls the translational output. Both the 5′ and 3′ untranslated regions (UTRs) bear many cis-acting elements that are intricately linked to the regulation of translation initiation. mRNAs carry the genetic information that is translated by ribosomes. Our findings established the physiological significance of CDS methylation and uncovered non-overlapping function of m 6A reader proteins.Ī grand challenge in the postgenomic era is to elucidate complex layers of regulatory elements beyond the nucleotide sequence. We further demonstrate that the elongation-promoting effect of CDS methylation requires the RNA helicase-containing m 6A reader YTHDC2. A systemic analysis of RNA structural datasets revealed that CDS m 6A positively regulates translation by resolving mRNA secondary structures. Unexpectedly, removing CDS m 6A from these transcripts results in a further decrease of translation. Here, we found that CDS m 6A leads to ribosome pausing in a codon-specific manner. However, neither the decoding feature of endogenous mRNAs nor the physiological significance of CDS m 6A has been clearly defined. It has been suggested that methylation in CDS slows down translation elongation. The m 6A mark is asymmetrically distributed along mature mRNAs, with approximately 35% of m 6A residues located within the coding region (CDS). Dynamic mRNA modification in the form of N 6-methyladenosine (m 6A) adds considerable richness and sophistication to gene regulation.
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