Regulation of mRNA capping in the cell cycle

Abstract

The mRNA cap structure, which is added to nascent RNA pol II transcripts, recruits the protein complexes required for pre-mRNA transcript processing, mRNA export and translation initiation. The enzymes which catalyze mRNA cap synthesis are regulated by cellular signaling pathways which impact on their expression, localization and activity. Here we discuss the recent observation that the mRNA cap methyltransferase, RNMT, is phosphorylated on Thr-77 by CDK1-cyclin B1, which regulates its activity and the proteins with which it interacts. RNMT Thr-77 phosphorylation provides a burst of mRNA cap methyltransferase activity during early G1 phase at a time when transcription is reactivated following completion of the cell cycle. This co-ordination of transcription and mRNA capping makes an important contribution to gene expression in the cell; preventing RNMT Thr-77 phosphorylation inhibits cell proliferation. Here we discuss these findings and how mRNA cap synthesis may be regulated in other scenarios.

RNA guanine-7 methyltransferase catalyzes the methylation of cytoplasmically recapped RNAs

“…It was conceivable that RNMT might join the cytoplasmic capping complex by binding to the first SH3 domain or the SH2 domain of Nck1. However, RNMT lacks a proline-rich sequence necessary for SH3 domain binding, and while it does have a potential tyrosine phosphorylation site at Y10 ( 20 ), the sequence surrounding this tyrosine residue is incompatible with binding to the SH2 domain of Nck1 ( 27 ). Additionally, we saw no evidence for tyrosine phosphorylation by western blotting of immunoprecipitated cytoplasmic RNMT with anti-phosphotyrosine antibody.…”

“…The current study sought to identify the source of cytoplasmic cap methylation. Nuclear cap methylation is a regulated process ( 20 ) in which RNMT activity is stimulated by the binding of RNMT-activating miniprotein (RAM) to its C-terminal catalytic domain ( 21 ) and inhibited by loss of RAM ( 22 ). Regulation of RNMT and RAM by site-specific phosphorylation points to cap methylation as an evolving nexus of post-transcriptional control.…”

Interplay of mRNA capping and transcription machineries

“…The previous model of capping implies that capping plays a 'passive' role in regulating gene expression by preventing degradation of mRNAs [101]. Now it is clear that capping can be modulated to 'actively' regulate the fate of a bulk or a selected subset of mRNAs.…”

RNA-binding proteins and heat-shock protein 90 are constituents of the cytoplasmic capping enzyme interactome

“…Cells have a number of surveillance mechanisms for degrading uncapped or improperly capped mRNAs (30,31), and capping is required for RNA polymerase II transcription elongation and nuclear RNA export (32). Thus, if nuclear capping was diminished in geldanamycin-treated cells, the surviving cytoplasmic mRNAs should still be capped despite their lower levels.…”