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How cells get the message: dynamic assembly and function of mRNA–protein complexes

Key Points

  • Global approaches are defining the full complement of proteins with RNA-binding capacity in living cells.

  • RNA packaging by proteins begins during transcription and determines the fate of the RNA.

  • RNA-binding proteins (RBPs) can act as 'molecular rulers', sorting RNAs according to their length.

  • RBPs can link sequential and non-sequential processing steps.

  • A future challenge is to define the composition of individual mRNPs at different stages of remodelling.

Abstract

mRNA is packaged into ribonucleoprotein particles called mRNPs. A multitude of RNA-binding proteins as well as a host of associated proteins participate in the fate of mRNA from transcription and processing in the nucleus to translation and decay in the cytoplasm. Methodological innovations in cell biology and genome-wide high-throughput approaches have revealed an unexpected diversity of mRNA-associated proteins and unforeseen interconnections between mRNA-processing steps. Recent insights into mRNP formation in vivo have also highlighted the importance of mRNP packaging, which can sort RNAs on the basis of their length and determine mRNA fate through alternative mRNP assembly, processing and export pathways.

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Figure 1: mRNPs: co-transcriptional assembly and remodelling from transcription to translation and degradation.
Figure 2: Importance of co-transcriptional mRNA packaging during RNA-processing steps from transcription to export.
Figure 3: Coupling of sequential and non-sequential steps in RNA metabolism by RBPs.
Figure 4: Export of mRNPs.

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Acknowledgements

We thank members of our laboratory, T. Pederson and F. McNicoll for helpful discussions and comments on the manuscript. Work in our laboratory on mRNPs is supported by funding from the Max Planck Society and the German Research Foundation (NE-909/3-1 to K.M.N.), and long-term postdoctoral fellowships from the European Molecular Biology Organization (EMBO) and Fonds de recherche en santé du Québec (FRSQ; to M.M.-M.).

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Glossary

Messenger ribonucleoprotein particles

(mRNPs). Complexes composed of mature mRNAs bound by various RNA-binding proteins and associated proteins recruited via protein–protein interactions. The formation of mRNPs allows proper packaging of the mRNA, which is essential for efficient nuclear export.

5′ end capping

As soon as a nascent transcript emerges from RNA polymerase II during transcription, it is capped at its 5′ end. This 7-methylguanosine cap (m7G cap) protects the mRNA from degradation and is essential for its translation.

Peptidyl-prolyl-isomerases

(PPIs). A group of metabolic enzymes that catalyse the cistrans isomerization of peptide bonds in polypeptide chains. PPIs have important roles in the folding of newly synthesized proteins but were recently shown also to bind mRNAs.

RNA recognition motif

(RRM). One of the most abundant RNA-binding domains in eukaryotes.

Spliceosome

A ribonucleoprotein complex that is responsible for splicing nuclear precursor mRNA (pre-mRNA). It is composed of five small nuclear ribonucleoproteins (snRNPs) and more than 50 non-snRNP proteins, which recognize and assemble on exon–intron boundaries to catalyse intron removal from the precursor mRNA (pre-mRNA).

Dicer

An RNase III family endonuclease that processes double-stranded RNA and precursor microRNAs into small interfering RNAs and microRNAs, respectively.

Heterogeneous nuclear ribonucleoprotein particles

(hnRNPs). Complexes of newly synthesized precursor mRNA (pre-mRNA) and RNA-binding proteins, known as heterogeneous ribonucleoproteins, which form during transcription in the cell nucleus. The abundant hnRNP proteins regulate splicing and mark the RNA as immature. After splicing has occurred, the hnRNP proteins mainly remain bound to spliced introns.

Premature cleavage and polyadenylation

(PCA). Misprocessing of precursor mRNAs (pre-mRNA) by the cleavage and polyadenylation machinery. Truncated transcripts arise through the use of cryptic or inappropriate polyadenylation signals present at the 5′ end or within introns of the pre-mRNA.

R loops

Hybrid structures consisting of RNA and DNA in which RNA displaces a DNA strand to hybridize to its complementary DNA sequence.

Exon junction complex

(EJC). A protein complex that is deposited ~24 nucleotides upstream of the exon–exon junctions of newly synthesized, spliced mRNAs. The EJC contains four core proteins — eukaryotic initiation factor 4AIII (EIF4AIII), Y14, mago nashi homologue (MAGOH) and Barentsz (BTZ) — and several loosely associated proteins.

SR proteins

Evolutionarily conserved RNA-binding proteins with essential functions in precursor mRNA (pre-mRNA) splicing in metazoans. Individual SR proteins have distinct RNA-binding capacities and are important regulators of alternative splicing, while some also function in post-splicing steps of gene expression.

Balbiani ring

Chromosome puffs or large diffused uncoiled regions, which are the sites of RNA transcription, in the giant polytene chromosomes of Chironomus tentans salivary gland cells.

Exosome

A protein complex that has 3′ to 5′ exonuclease activity (although an endonuclease activity has also been described). Two forms of the exosome have been characterized that differ in their associated cofactors and cellular localization (one is nuclear and one is cytoplasmic).

Promoter upstream non-coding transcripts

(PROMPTs). A recently discovered class of human RNAs. PROMPTs are produced upstream of promoters of active protein-coding genes. They are mainly nuclear and have poly(A) tails and 5′ cap structures.

Nonsense-mediated mRNA decay

(NMD). The process by which mRNAs containing premature termination codons are destroyed to preclude the production of truncated and potentially deleterious protein products. It is also used in combination with specific alternative splicing events to control the levels of some proteins.

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Müller-McNicoll, M., Neugebauer, K. How cells get the message: dynamic assembly and function of mRNA–protein complexes. Nat Rev Genet 14, 275–287 (2013). https://doi.org/10.1038/nrg3434

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