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

Abstract

N 6 -methyladenosine (m 6 A), a major modification of messenger RNAs (mRNAs), plays critical roles in RNA metabolism and function. In addition to the internal m 6 A, N 6 , 2′-O-dimethyladenosine (m 6 Am) 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 m 6 Am. The crystal structure of CAPAM in complex with substrates revealed the molecular basis of cap-specific m 6 A formation. A transcriptome-wide analysis revealed that N 6 -methylation of m 6 Am promotes the translation of capped mRNAs. Thus, a cap-specific m 6 A writer promotes translation of mRNAs starting from m 6 Am.