N6-methyladenosine-dependent regulation of messenger RNA stability

Nature. 2014 Jan 2;505(7481):117-20. doi: 10.1038/nature12730. Epub 2013 Nov 27.


N(6)-methyladenosine (m(6)A) is the most prevalent internal (non-cap) modification present in the messenger RNA of all higher eukaryotes. Although essential to cell viability and development, the exact role of m(6)A modification remains to be determined. The recent discovery of two m(6)A demethylases in mammalian cells highlighted the importance of m(6)A in basic biological functions and disease. Here we show that m(6)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(m(6)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 bodies. The carboxy-terminal domain of YTHDF2 selectively binds to m(6)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 m(6)A modification is recognized by selectively binding proteins to affect the translation status and lifetime of mRNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Adenosine / pharmacology
  • Base Sequence
  • DNA-Binding Proteins / genetics
  • HeLa Cells
  • Humans
  • Minor Histocompatibility Antigens
  • Nucleotide Motifs
  • Organelles / genetics
  • Organelles / metabolism
  • Protein Binding
  • Protein Biosynthesis
  • RNA Stability* / drug effects
  • RNA Transport
  • RNA, Messenger / chemistry*
  • RNA, Messenger / metabolism*
  • RNA, Untranslated / chemistry
  • RNA, Untranslated / metabolism
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / classification
  • RNA-Binding Proteins / metabolism*
  • Substrate Specificity


  • DNA-Binding Proteins
  • Minor Histocompatibility Antigens
  • RNA, Messenger
  • RNA, Untranslated
  • RNA-Binding Proteins
  • SON protein, human
  • YTHDF2 protein, human
  • N-methyladenosine
  • Adenosine

Associated data

  • GEO/GSE46705
  • GEO/GSE49339