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

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