N6-Methyladenosine (m6A) is the predominant internal RNA modification in eukaryotic messenger RNAs (mRNAs) and plays a crucial role in mRNA stability. Here, using human cells, we reveal that m6A sites in the coding sequence (CDS) trigger CDS-m6A decay (CMD), a pathway that is distinct from previously reported m6A-dependent degradation mechanisms. Importantly, CDS m6A sites act considerably faster and more efficiently than those in the 3' untranslated region, which to date have been considered the main effectors. Mechanistically, CMD depends on translation, whereby m6A deposition in the CDS triggers ribosome pausing and transcript destabilization. The subsequent decay involves the translocation of the CMD target transcripts to processing bodies (P-bodies) and recruitment of the m6A reader protein YT521-B homology domain family protein 2 (YTHDF2). Our findings highlight CMD as a previously unknown pathway, which is particularly important for controlling the expression of developmental regulators and retrogenes.
- MeSH
- 3' Untranslated Regions MeSH
- Adenosine * analogs & derivatives metabolism genetics MeSH
- HEK293 Cells MeSH
- HeLa Cells MeSH
- Humans MeSH
- RNA, Messenger * genetics metabolism MeSH
- Open Reading Frames * MeSH
- RNA-Binding Proteins * genetics metabolism MeSH
- Protein Biosynthesis * MeSH
- Ribosomes metabolism genetics MeSH
- RNA Stability * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
N6-methyladenosine (m6A) is an abundant mRNA modification affecting mRNA stability and protein expression. It is a highly dynamic process, and its outcomes during postnatal heart development are poorly understood. Here we studied m6A machinery in the left ventricular (LV) myocardium of Fisher344 male and female rats (postnatal days one to ninety; P1-P90) using Western Blot. A downward pattern of target protein levels (demethylases FTO and ALKBH5, methyltransferase METTL3, reader YTHDF2) was revealed in male and female rat LVs during postnatal development. On P1, the FTO protein level was significantly higher in male LVs compared to females.
