YTHDC1 mediates nuclear export of N 6-methyladenosine methylated mRNAs

Elife. 2017 Oct 6;6:e31311. doi: 10.7554/eLife.31311.

Abstract

N6-methyladenosine (m6A) is the most abundant internal modification of eukaryotic messenger RNA (mRNA) and plays critical roles in RNA biology. The function of this modification is mediated by m6A-selective 'reader' proteins of the YTH family, which incorporate m6A-modified mRNAs into pathways of RNA metabolism. Here, we show that the m6A-binding protein YTHDC1 mediates export of methylated mRNA from the nucleus to the cytoplasm in HeLa cells. Knockdown of YTHDC1 results in an extended residence time for nuclear m6A-containing mRNA, with an accumulation of transcripts in the nucleus and accompanying depletion within the cytoplasm. YTHDC1 interacts with the splicing factor and nuclear export adaptor protein SRSF3, and facilitates RNA binding to both SRSF3 and NXF1. This role for YTHDC1 expands the potential utility of chemical modification of mRNA, and supports an emerging paradigm of m6A as a distinct biochemical entity for selective processing and metabolism of mammalian mRNAs.

Keywords: RNA modification; RNA processing; biochemistry; cell biology; gene regulation; human; mRNA export.

MeSH terms

  • Active Transport, Cell Nucleus*
  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nucleocytoplasmic Transport Proteins / metabolism
  • Protein Binding
  • RNA Splicing Factors / genetics
  • RNA Splicing Factors / metabolism*
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / metabolism
  • Serine-Arginine Splicing Factors / metabolism

Substances

  • NXF1 protein, human
  • Nerve Tissue Proteins
  • Nucleocytoplasmic Transport Proteins
  • RNA Splicing Factors
  • RNA, Messenger
  • RNA-Binding Proteins
  • SRSF3 protein, human
  • YTHDC1 protein, human
  • Serine-Arginine Splicing Factors
  • N-methyladenosine
  • Adenosine