m(6)A in mRNA coding regions promotes translation via the RNA helicase-containing YTHDC2

Dynamic mRNA modification in the form of N(6)-methyladenosine (m(6)A) adds considerable richness and sophistication to gene regulation. The m(6)A mark is asymmetrically distributed along mature mRNAs, with approximately 35% of m(6)A residues located within the coding region (CDS). It has been suggested that methylation in CDS slows down translation elongation. However, neither the decoding feature of endogenous mRNAs nor the physiological significance of CDS m(6)A has been clearly defined. Here, we found that CDS m(6)A leads to ribosome pausing in a codon-specific manner. Unexpectedly, removing CDS m(6)A from these transcripts results in a further decrease of translation. A systemic analysis of RNA structural datasets revealed that CDS m(6)A positively regulates translation by resolving mRNA secondary structures. We further demonstrate that the elongation-promoting effect of CDS methylation requires the RNA helicase-containing m(6)A reader YTHDC2. Our findings established the physiological significance of CDS methylation and uncovered non-overlapping function of m(6)A reader proteins.