A Unified Model for the Function of YTHDF Proteins in Regulating m 6 A-Modified mRNA

Cell. 2020 Jun 25;181(7):1582-1595.e18. doi: 10.1016/j.cell.2020.05.012. Epub 2020 Jun 2.

Abstract

N6-methyladenosine (m6A) is the most abundant mRNA nucleotide modification and regulates critical aspects of cellular physiology and differentiation. m6A is thought to mediate its effects through a complex network of interactions between different m6A sites and three functionally distinct cytoplasmic YTHDF m6A-binding proteins (DF1, DF2, and DF3). In contrast to the prevailing model, we show that DF proteins bind the same m6A-modified mRNAs rather than different mRNAs. Furthermore, we find that DF proteins do not induce translation in HeLa cells. Instead, the DF paralogs act redundantly to mediate mRNA degradation and cellular differentiation. The ability of DF proteins to regulate stability and differentiation becomes evident only when all three DF paralogs are depleted simultaneously. Our study reveals a unified model of m6A function in which all m6A-modified mRNAs are subjected to the combined action of YTHDF proteins in proportion to the number of m6A sites.

Keywords: translation, mRNA stability, m(6)A, METTL3, YTHDF1, YTHDF2, YTHDF3, CLIP, RNA-binding.

Publication types

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

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / genetics
  • Adenosine / metabolism
  • Cell Differentiation
  • HeLa Cells
  • Humans
  • Methylation
  • Methyltransferases / metabolism
  • Protein Biosynthesis
  • RNA Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*

Substances

  • RNA, Messenger
  • RNA-Binding Proteins
  • YTHDF1 protein, human
  • YTHDF2 protein, human
  • YTHDF3 protein, human
  • N6-methyladenosine (m6A)
  • Methyltransferases
  • Adenosine