Coupling mechanisms coordinating mRNA translation with stages of the mRNA lifecycle

Abstract

Gene expression involves a series of consequential processes, beginning with mRNA synthesis and culminating in translation. Traditionally studied as a linear sequence of events, recent findings challenge this perspective, revealing coupling mechanisms that coordinate key steps of gene expression, even when spatially and temporally distant. In this review, we focus on translation, the final stage of gene expression, and examine its coupling with key stages of mRNA metabolism: synthesis, processing, export, and decay. For each of these processes, we provide an overview of known instances of coupling with translation. Furthermore, we discuss the role of high-throughput technologies in uncovering these intricate interactions on a genome-wide scale. Finally, we highlight key challenges and propose future directions to advance our understanding of how coupling mechanisms orchestrate robust and adaptable gene expression programs.

Keywords: Translation; coupling; decay; export; processing; transcription.

Figure 1.

Scheme of the couplings mediated by the translation initiation factor eIF4E. Following mRNA transcription, eIF4E can interact with the capping enzyme RNMT to facilitate capping of mRNAs. Moreover, eIF4E can associate with the spliceosome in a cap-dependent manner and affect its composition, influencing specific splicing events for thousands of genes. Being able to associate with some components of the polyadenylation machinery, e.g. the enzyme CPFS3 which recognizes the polyadenylation sites, eIF4E also plays a role in the 3’ end processing. Furthermore, eIF4E mediates the export of 4ESE mRNAs, containing binding sites for LRPPRC that in turn can bind CRM1, a major export protein. Finally, eIF4E recruits mRNAs to the ribosome to its cap-binding activity and, being associated with the cap, inhibits the action of the decapping enzymes.

Figure 2.

Scheme of the coupling mechanisms: Ticker arrows represent natural couplings, depicted in black if they involve translation and in grey otherwise. Thinner arrows indicate translation-related long-range couplings. Each edge lists the factors mediating couplings in eukaryotes (green) and yeast (orange).