Regulation of mRNA cap methylation

Abstract

The 7-methylguanosine cap added to the 5' end of mRNA is essential for efficient gene expression and cell viability. Methylation of the guanosine cap is necessary for the translation of most cellular mRNAs in all eukaryotic organisms in which it has been investigated. In some experimental systems, cap methylation has also been demonstrated to promote transcription, splicing, polyadenylation and nuclear export of mRNA. The present review discusses how the 7-methylguanosine cap is synthesized by cellular enzymes, the impact that the 7-methylguanosine cap has on biological processes, and how the mRNA cap methylation reaction is regulated.

Figure 1. Synthesis of the 7-methylguanosine cap

(a) The 7-methylguanosine cap. The methyl group of 7-methylguanosine is indicated in red. (b) Reactions that synthesize the 7-methylguanosine cap. The synthesis is described in detail in the text. Enzymes which catalyse reactions are indicated above the reactions, and the names of the enzymes from S. cerevisiae, S. pombe and Homo sapiens are indicated below the reactions.

Figure 2. RNMT functional domains

(a) The minimal domain required for cap methyltransferase activity is indicated (residues 120–476). The SAM-binding domain/motif I, VL(E/D)LGCGKG, is shown. Residues essential for cap methyltransferase activity and cell viability are indicated in red: residues found in the human mRNA cap methytransferase RNMT are indicated in normal type; and those found in the S. cerevisiae cap methyltransferase ABD1 are indicated in italics. (b) Nuclear localization signals are indicated in green. Importin α (Impα)- and RNA-binding sites are indicated in pink.

Figure 3. mRNA cap methylation occurs co-transcriptionally

RNA polymerase II is recruited to chromatin with the CTD hypophosphorylated. At the initiation of transcription, TFIIH phosphorylates CTD on Ser⁵. Enzymes which catalyse the formation of the 7-methylguanosine cap, RNGTT and RNMT, are recruited to the phosphorylated CTD, proximal to their substrate, the 5′ end of nascent RNA. An animation of this Figure is available at http://www.BiochemJ.org/bj/425/0295/bj4250295add.htm.

Figure 4. Up-regulation of mRNA cap methylation

(a) Myc binds to DNA proximal to transcription initation sites. Myc binds to TFIIH subunits, promotes TFIIH recruitment to chromatin and enhances CTD phosphorylation. Then RNGTT and RNMT bind to phosphorylated CTD and catalyse formation of the 7-methylguanosine cap. (b) SAM is the methyl donor for the cap methylation reaction catalysed by the mRNA cap methyltransferase RNMT. SAH is the byproduct of the reaction, which inhibits RNMT. SAHH hydrolyses SAH to adenosine and homocysteine, thus relieving repression of the RNMT.