RNMT is recruited to RNA by interaction with RNA G-quadraplexes

The 7-methylguanosine (m7G) cap protects RNA pol II transcripts from exonucleases and allows interaction with cap binding proteins which direct processing and translation. During m7G cap formation in mammals, nascent transcripts receive a guanosine cap which is methylated by RNA guanine-7 methyltransferase (RNMT). Unlike other capping enzymes which interact directly with RNA pol II, RNMT is recruited to the guanosine cap by interactions with RNA and the cap itself. RNMT is regulated during cell differentiation with significant impact on which RNAs are expressed and translated. The gene-specificity of RNMT was unexplained since RNMT in complex with activating subunit, RAM, binds to RNA without sequence preference. Through the development of improved RNA-protein detection, CLIP-ART, we report that RNMT interacts directly with RNA G4 quadraplexes (rG4). RNMT predominantly interacts with rG4s in the 5' UTR (untranslated regions) of mRNAs, indicating a mechanism for anchoring RNMT adjacent to the guanosine cap substrate. RNMT interacts with rG4s in transcripts which encode proteins involved in growth and proliferation. The RNMT-rG4 interaction is specific to the RNMT monomer, rather than RNMT-RAM, indicating a mechanism by which differential regulation of RNMT and RAM, can lead to cap methylation of specific RNAs involved in growth control.