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Control of mammalian gene expression by selective mRNA export

Key Points

  • Nuclear export of mRNAs to the cytoplasm has been thought of as a 'one size fits all' default pathway.

  • Two conserved complexes have key roles in the nuclear export of mRNA: transcription-export complexes TREX and TREX-2.

  • Several recent examples indicate that specific biological pathways can be regulated by selective mRNA export, giving priority to some sets of mRNA over others.

  • Nuclear export of functionally related sets of transcripts may be regulated by specific mRNA-binding export factors that recognize specific sequence elements among the mRNAs.

  • mRNA export is a potentially important node in regulation of mammalian gene expression pathways.

  • There is accumulating evidence that dysregulation of mRNA export may contribute to the development of human disease.

  • Future research will provide key insights into how selective mRNA export pathways are regulated and how they are altered in disease.

Abstract

Nuclear export of mRNAs is a crucial step in the regulation of gene expression, linking transcription in the nucleus to translation in the cytoplasm. Although important components of the mRNA export machinery are well characterized, such as transcription-export complexes TREX and TREX-2, recent work has shown that, in some instances, mammalian mRNA export can be selective and can regulate crucial biological processes such as DNA repair, gene expression, maintenance of pluripotency, haematopoiesis, proliferation and cell survival. Such findings show that mRNA export is an unexpected, yet potentially important, mechanism for the control of gene expression and of the mammalian transcriptome.

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Figure 1: Steps of mRNA export from nuclear transcription to the cytoplasm.
Figure 2: Interactions between nuclear pore complex components and mRNA export complexes.
Figure 3: Examples of biological pathways that are regulated by selective mRNA export.

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Acknowledgements

The authors would like to thank Ed Hurt for critical reading of the manuscript. V.O.W. acknowledges the support of Ashok Venkitaraman and the UK Medical Research Council (MRC). This work was also supported by Cancer Research UK.

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Correspondence to Vihandha O. Wickramasinghe or Ronald A. Laskey.

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Glossary

Messenger ribonucleoprotein particles

(mRNPs). Complexes that are formed by coating of cellular mRNAs with RNA-binding proteins, ensuring correct packaging of mRNA for nuclear export.

Inositol polyphosphate multikinase

(IPMK). A kinase that is implicated in the synthesis of both inositol phosphates (inositol-1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4), InsP5 and InsP6) and phosphatidylinositol-3,4,5- trisphosphate.

Pluripotency

The potential ability of a cell to differentiate into any cell type of the three germ layers.

Spliceosomes

Large ribonucleoprotein complexes that catalyse the removal of intronic sequences from nuclear pre-mRNA. A spliceosome consists of five small nuclear ribonucleoproteins (snRNPs) and non-snRNP proteins, and it is remodelled extensively during its assembly and activation.

Exon–junction complex

(EJC). A multi-protein complex that is deposited onto newly synthesized and spliced mRNA 24 nt upstream of exon–exon junctions.

SR splicing factors

A family of RNA-binding splicing initiators that contain a domain rich in consecutive repeats of serine–arginine residues.

Homologous recombination

An error-free mechanism for repairing DNA double-strand breaks through DNA strand exchange. It is dependent on the recombinase DNA repair protein RAD51 homologue 1 and the tumour suppressor breast cancer susceptibility protein 2 (BRCA2).

Non-homologous end joining

(NHEJ). An error-prone mechanism for repairing DNA double-strand breaks through re-ligation of the broken ends without the need for a homologous template. It is dependent on the KU70–KU80 and XRCC4–XLF–DNA ligase IV complexes.

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Wickramasinghe, V., Laskey, R. Control of mammalian gene expression by selective mRNA export. Nat Rev Mol Cell Biol 16, 431–442 (2015). https://doi.org/10.1038/nrm4010

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