N6-methyladenosine-dependent regulation of messenger RNA stability

The mRNAs of higher eukaryotes are extensively modified internally with N6-methyladenosine, but the specific functional role of this modification has been unclear; here this modification on mRNA is shown to be recognized by several proteins, the modification and its recognition serve to regulate the RNA’s lifetime. The messenger RNAs of higher eukaryotes are extensively modified with N6-methyladenosine, but the functional role of this modification has been unclear. Chuan He and colleagues now show that in human cells, these modified bases are recognized by a family of proteins, YTHDF2, not only in mRNAs, but also in a variety of non-coding RNAs. Once bound, these proteins mediate degradation of the RNA by targeting it to cellular RNA decay sites. In this way, the modification serves as a regulator of the RNA's lifetime. N6-methyladenosine (m6A) is the most prevalent internal (non-cap) modification present in the messenger RNA of all higher eukaryotes1,2. Although essential to cell viability and development3,4,5, the exact role of m6A modification remains to be determined. The recent discovery of two m6A demethylases in mammalian cells highlighted the importance of m6A in basic biological functions and disease6,7,8. Here we show that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) ‘reader’ protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m6A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies9. The carboxy-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA, whereas the amino-terminal domain is responsible for the localization of the YTHDF2–mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m6A modification is recognized by selectively binding proteins to affect the translation status and lifetime of mRNA.