Cap-specific terminal N 6-methylation of RNA by an RNA polymerase II-associated methyltransferase

Science. 2019 Jan 11;363(6423):eaav0080. doi: 10.1126/science.aav0080. Epub 2018 Nov 22.

Abstract

N 6-methyladenosine (m6A), a major modification of messenger RNAs (mRNAs), plays critical roles in RNA metabolism and function. In addition to the internal m6A, N 6, 2'-O-dimethyladenosine (m6Am) is present at the transcription start nucleotide of capped mRNAs in vertebrates. However, its biogenesis and functional role remain elusive. Using a reverse genetics approach, we identified PCIF1, a factor that interacts with the serine-5-phosphorylated carboxyl-terminal domain of RNA polymerase II, as a cap-specific adenosine methyltransferase (CAPAM) responsible for N 6-methylation of m6Am. The crystal structure of CAPAM in complex with substrates revealed the molecular basis of cap-specific m6A formation. A transcriptome-wide analysis revealed that N 6-methylation of m6Am promotes the translation of capped mRNAs. Thus, a cap-specific m6A writer promotes translation of mRNAs starting from m6Am.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Mass Spectrometry
  • Methylation
  • Methyltransferases / chemistry*
  • Nuclear Proteins / chemistry*
  • Protein Biosynthesis
  • Protein Domains
  • RNA Caps / chemistry*
  • RNA Polymerase II / chemistry*
  • Transcription Initiation Site

Substances

  • Adaptor Proteins, Signal Transducing
  • Nuclear Proteins
  • PCIF1 protein, human
  • RNA Caps
  • Methyltransferases
  • RNA Polymerase II