m ⁶A-dependent regulation of messenger RNA stability

Abstract

N ⁶ -methyladenosine (m ⁶A) is the most prevalent internal (non-cap) modification present in the messenger RNA (mRNA) of all higher eukaryotes ^{1, 2} . Although essential to cell viability and development ^{3– 5} , the exact role of m ⁶A modification remains to be determined. The recent discovery of two m ⁶A demethylases in mammalian cells highlighted the importance of m ⁶A in basic biological functions and disease ^{6– 8} . Here we show that m ⁶A is selectively recognized by the human YTH domain family 2 (YTHDF2) 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(m ⁶A)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 bodies ⁹ . The C-terminal domain of YTHDF2 selectively binds to m ⁶A-containing mRNA whereas the N-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m ⁶A modification is recognized by selective-binding proteins to affect the translation status and lifetime of mRNA.