N6-methyladenosine-dependent regulation of messenger RNA stability

N6 -methyladenosine (m6 A) is the most prevalent internal (non-cap) modification presentin themessenger RNA of all higher eukaryotes1,2. Although essential to cell viability and development3–5, the exact role ofm6 A modification remains to be determined. The recent discovery of two m6 A demethylasesinmammalian cells highlighted theimportance of m6 A in basic biological functions and disease6–8. Here we show that m6 A 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(m6 A)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 carboxyterminal domain of YTHDF2 selectively binds to m6 A-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 m6 A modification is recognized by selectively binding proteins to affect the translation status and lifetime of mRNA.