YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex

Nat Commun. 2016 Aug 25:7:12626. doi: 10.1038/ncomms12626.


Methylation at the N6 position of adenosine (m(6)A) is the most abundant RNA modification within protein-coding and long noncoding RNAs in eukaryotes and is a reversible process with important biological functions. YT521-B homology domain family (YTHDF) proteins are the readers of m(6)A, the binding of which results in the alteration of the translation efficiency and stability of m(6)A-containing RNAs. However, the mechanism by which YTHDF proteins cause the degradation of m(6)A-containing RNAs is poorly understood. Here we report that m(6)A-containing RNAs exhibit accelerated deadenylation that is mediated by the CCR4-NOT deadenylase complex. We further show that YTHDF2 recruits the CCR4-NOT complex through a direct interaction between the YTHDF2 N-terminal region and the SH domain of the CNOT1 subunit, and that this recruitment is essential for the deadenylation of m(6)A-containing RNAs by CAF1 and CCR4. Therefore, we have uncovered the mechanism of YTHDF2-mediated degradation of m(6)A-containing RNAs in mammalian cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / genetics
  • Adenosine / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Methylation
  • Polyadenylation
  • Protein Binding / genetics
  • Protein Domains / genetics
  • RNA Stability*
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / isolation & purification
  • RNA-Binding Proteins / metabolism*
  • Receptors, CCR4 / genetics
  • Receptors, CCR4 / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Ribonucleases / genetics
  • Ribonucleases / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • CCR4 protein, human
  • CNOT1 protein, human
  • CNOT8 protein, human
  • RNA, Messenger
  • RNA-Binding Proteins
  • Receptors, CCR4
  • Recombinant Proteins
  • Transcription Factors
  • YTHDF2 protein, human
  • Ribonucleases
  • mRNA deadenylase
  • Adenosine