Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation

Nat Cell Biol. 2018 Mar;20(3):285-295. doi: 10.1038/s41556-018-0045-z. Epub 2018 Feb 23.

Abstract

N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic messenger RNAs (mRNAs) and is interpreted by its readers, such as YTH domain-containing proteins, to regulate mRNA fate. Here, we report the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1/2/3) as a distinct family of m6A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m6A)C sequence. In contrast to the mRNA-decay-promoting function of YTH domain-containing family protein 2, IGF2BPs promote the stability and storage of their target mRNAs (for example, MYC) in an m6A-dependent manner under normal and stress conditions and therefore affect gene expression output. Moreover, the K homology domains of IGF2BPs are required for their recognition of m6A and are critical for their oncogenic functions. Thus, our work reveals a different facet of the m6A-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as m6A readers in post-transcriptional gene regulation and cancer biology.

Publication types

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

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / genetics
  • Adenosine / metabolism
  • Binding Sites
  • Cell Movement
  • Cell Proliferation
  • Consensus Sequence
  • Female
  • Fetal Blood / cytology
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • HeLa Cells
  • Hematopoietic Stem Cells / enzymology
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Neoplasm Invasiveness
  • Protein Binding
  • Protein Biosynthesis
  • RNA Processing, Post-Transcriptional*
  • RNA Stability*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Uterine Cervical Neoplasms / enzymology
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / pathology

Substances

  • IGF2BP1 protein, human
  • IGF2BP2 protein, human
  • IGF2BP3 protein, human
  • RNA, Messenger
  • RNA-Binding Proteins
  • N-methyladenosine
  • Adenosine