5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m 5 C reader

Cell Res. 2017 May;27(5):606-625. doi: 10.1038/cr.2017.55. Epub 2017 Apr 18.


5-methylcytosine (m5C) is a post-transcriptional RNA modification identified in both stable and highly abundant tRNAs and rRNAs, and in mRNAs. However, its regulatory role in mRNA metabolism is still largely unknown. Here, we reveal that m5C modification is enriched in CG-rich regions and in regions immediately downstream of translation initiation sites and has conserved, tissue-specific and dynamic features across mammalian transcriptomes. Moreover, m5C formation in mRNAs is mainly catalyzed by the RNA methyltransferase NSUN2, and m5C is specifically recognized by the mRNA export adaptor ALYREF as shown by in vitro and in vivo studies. NSUN2 modulates ALYREF's nuclear-cytoplasmic shuttling, RNA-binding affinity and associated mRNA export. Dysregulation of ALYREF-mediated mRNA export upon NSUN2 depletion could be restored by reconstitution of wild-type but not methyltransferase-defective NSUN2. Our study provides comprehensive m5C profiles of mammalian transcriptomes and suggests an essential role for m5C modification in mRNA export and post-transcriptional regulation.

MeSH terms

  • 5-Methylcytosine / metabolism*
  • Amino Acid Sequence
  • Base Sequence
  • HeLa Cells
  • Humans
  • Male
  • Methyltransferases / metabolism*
  • Models, Biological
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Organ Specificity / genetics
  • Protein Binding
  • RNA Transport / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism*
  • Testis / embryology
  • Testis / metabolism
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*


  • ALYREF protein, human
  • Nuclear Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Transcription Factors
  • 5-Methylcytosine
  • Methyltransferases
  • NSUN2 protein, human