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Choosing the right exit: How functional plasticity of the nuclear pore drives selective and efficient mRNA export

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Abstract The nuclear pore complex (NPC) serves as a central gate for mRNAs to transit from the nucleus to the cytoplasm. The ability for mRNAs to get exported is linked to various upstream nuclear processes including co‐transcriptional RNP assembly and processing, and only export competent mRNPs are thought to get access to the NPC. While the nuclear pore is generally viewed as a monolithic structure that serves as a mediator of transport driven by transport receptors, more recent evidence suggests that the NPC might be more heterogenous than previously believed, both in its composition or in the selective treatment of cargo that seek access to the pore, providing functional plasticity to mRNA export. In this review, we consider the interconnected processes of nuclear mRNA metabolism that contribute and mediate export competence. Furthermore, we examine different aspects of NPC heterogeneity, including the role of the nuclear basket and its associated complexes in regulating selective and/or efficient binding to and transport through the pore. This article is categorized under: RNA Export and Localization > Nuclear Export/Import RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications
Stages of the mRNP maturation, quality control and export pathway. Nascent mRNAs are capped and assembled with THO and TREX components that serve as adaptors for mRNA export receptors. Transcripts are generally spliced co‐transcriptionally and associate with the exon junction complex (EJC), serine rich proteins (SR) as well as various RNA‐binding proteins (RBPs), which enhance export kinetics by recruiting additional export receptors. Cleaved and polyadenylated transcripts associate with nuclear polyA‐binding proteins and are released from the transcription sites. Export competent mRNPs can either associate with a pore through direct interactions between export receptors and the NPC, or TREX‐2 mediated interactions between transcripts, the nuclear baskets and export receptors. It is assumed that cooperative interactions between the pore, the basket and RBPs ensure that only correctly processed transcripts have access to and translocate through the pore. Defects in capping, abortive transcription as well as inefficient splicing and/or polyadenylation can trigger mRNA degradation by the nuclear surveillance machineries, and several mRNP processing defects provide entry sites for 3′–5′ exosome decay (indicated by red dots). THO/TREX, TREX‐2, export receptor and basket deficiencies do not affect transcripts or their export in the same manner, with pronounced transcription/export defects observed for specific subsets of transcripts
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Nuclear pore heterogeneity. (a) In the yeast Saccharomyces cerevisiae, basket‐containing pores occupy the nucleoplasmic periphery, while nuclear pores along the nuclear membrane adjacent to the nucleolus lack a basket structure; in particular, the basket core components Mlp1 and Mlp2. (b) Upon heat‐shock of yeast cells, Mlp1 detaches from nuclear pores and assembles into nucleoplasmic granules. These granules also contain the bulk of sequestered mRNAs as well as TREX components and polyA‐binding proteins such as Nab2. While export receptors dissociate from bulk mRNPs upon heat shock, they facilitate the export of heat‐shock transcripts in a basket‐independent manner. (c) Potential models for NPC heterogeneity have been proposed in higher eukaryotes, which could be required to establish nuclear sub‐domains with specific chromatin organization, regulate the transport of specific cargos in a topological dependent manner or, similar to yeast, occupy specific regions along the nuclear periphery (adapted from D'Angelo et al., 2012)
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The nuclear basket may participate in different steps of selective mRNP export. (a) In metazoans, the basket has been linked to the formation of chromatin exclusion zones believed to be used as channels by mRNPs to access the nuclear pore. (b) mRNPs scan the nuclear periphery prior to export, and in yeast, this scanning behavior has been linked to the presence of the basket core component Mlp1 and its interaction with polyA‐binding proteins, which are suggested to increase residence time of mRNPs at the periphery and to facilitate binding/docking to the pore (c). The nuclear basket is believed to act as gatekeeper for aberrant mRNAs. However, at this point it is unclear whether the basket interacts with RBPs to recognize mature and export competent mRNPs or if aberrant transcripts are retained at the basket either to be matured or targeted for exosome‐mediated decay. (d) The basket proteins Mlp1 and TPR were shown to be important for gene gating, or tethering, of actively transcribed genes at the nuclear periphery; in this model, transcription at the periphery is suggested to provide and advantage for mRNA export that may be based on selectivity and/or efficiency. Tethering genes at the NPC was shown to involve TREX2/SAGA and/or export receptors associating with nascent transcripts
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Chromatin re‐organization and NPC‐tethering in human colon cancer cells enhances MYC mRNA export rates. Reduction of the MYC‐OSE distance correlates with a localization of MYC loci at nuclear pores. OSE‐mediated gene gating favors nucleocytoplasmic transport of MYC mRNA over nuclear decay and results in increased levels of cytoplasmic MYC mRNAs
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Export and Localization > Nuclear Export/Import

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