Intron or no intron: a matter for nuclear pore complexes

Bonnet, Amandine; Palancade, Benoı̂t

doi:10.1080/19491034.2015.1116660

Cited by 16 publications

(18 citation statements)

References 49 publications

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“…This slight difference, as demonstrated in this work, is sufficient for Tpr to distinguish and retain aberrant mRNAs. It was previously suggested that formation of aberrant mRNAs might be signalled via a yet-to-be-identified intron-bound protein to retain the mRNA46. However, our results suggest that mRNA QC is achieved by cooperation of regulated stochastic interactions between the involved proteins rather than deterministic switch-like properties.…”

Section: Discussioncontrasting

confidence: 53%

“…While several different proteins are identified to be involved in retention of aberrant mRNAs, no detailed explanation for how aberrant mRNAs are distinguished is presented so far. It is not even clear whether normal mRNAs are selected to be exported (selection model), aberrant mRNAs are retained inside the nucleus (retention model), or a combination of both strategies is employed in eukaryotic cells46.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of RNA-binding proteins affinity to export receptors enables the nuclear basket proteins to distinguish and retain aberrant mRNAs

Soheilypour

Mofrad

2016

Sci Rep

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Export of messenger ribonucleic acids (mRNAs) into the cytoplasm is a fundamental step in gene regulation processes, which is meticulously quality controlled by highly efficient mechanisms in eukaryotic cells. Yet, it remains unclear how the aberrant mRNAs are recognized and retained inside the nucleus. Using a new modelling approach for complex systems, namely the agent-based modelling (ABM) approach, we develop a minimal model of the mRNA quality control (QC) mechanism. Our results demonstrate that regulation of the affinity of RNA-binding proteins (RBPs) to export receptors along with the weak interaction between the nuclear basket protein (Mlp1 or Tpr) and RBPs are the minimum requirements to distinguish and retain aberrant mRNAs. Our results show that the affinity between Tpr and RBPs is optimized to maximize the retention of aberrant mRNAs. In addition, we demonstrate how the length of mRNA affects the QC process. Since longer mRNAs spend more time in the nuclear basket to form a compact conformation and initiate their export, nuclear basket proteins could more easily capture and retain them inside the nucleus.

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Section: Discussioncontrasting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Regulation of RNA-binding proteins affinity to export receptors enables the nuclear basket proteins to distinguish and retain aberrant mRNAs

Soheilypour

Mofrad

2016

Sci Rep

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“…In particular, we observed that many of the downregulated genes were intronless, whereas all upregulated genes had introns. Whereas it is known that intron-containing genes are surveyed by quality control mechanisms to ensure that unspliced mRNAs are not exported (17), the export mechanisms of intronless genes have not been investigated in great detail. TREX has been suggested to be involved in export of intronless mRNAs in HeLa cells (33), NXF1/TAP pathway in exporting intronless histone H2A mRNA (34) and nuclear pore basket protein TPR in export of intronless transcripts (35).…”

Section: Discussionmentioning

confidence: 99%

“…The export of mRNAs is tightly coupled to their transcription and processing, with strict quality control preventing the export of misprocessed messengers, in particular pre-mRNAs with unspliced introns (17). Thus, a defect in a particular step from transcription, mRNA maturation and termination to export, is likely to have direct consequences on both upstream and downstream steps.…”

Section: Introductionmentioning

confidence: 99%

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

Woldegebriel

Kvist

Andersson

et al. 2020

Human Molecular Genetics

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Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.

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“…Eukaryotic cells have also evolved quality control mechanisms ensuring that only properly processed mRNAs reach the cytoplasm and are decoded by the translational machinery. These mechanisms include the EJC-dependent degradation of transcripts containing premature stop codons through nonsense-mediated decay (NMD) or the NXF1-dependent nuclear retention of unspliced transcripts mediated by the nucleoporin Tpr (21- 25). Consistent with these cellular quality control mechanisms, it has been widely reported that viral intron-containing transcripts including the 4-kb and the 9-kb mRNA produced during HIV-1 replication are retained and degraded in the host cell nucleus unless the viral protein Rev is present (26-30).…”

Section: Introductionmentioning

confidence: 99%

A Rev-CBP80-eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA

Toro-Ascuy

Rojas-Araya

García-de-Gracia

et al. 2018

Preprint

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33Gag synthesis from the full-length unspliced mRNA is critical for the production of the 34 viral progeny during human immunodeficiency virus type-1 (HIV-1) replication. While 35 most spliced mRNAs follow the canonical gene expression pathway in which the 36 recruitment of the nuclear cap-binding complex (CBC) and the exon junction complex 37 (EJC) largely stimulates the rates of nuclear export and translation, the unspliced mRNA 38 relies on the viral protein Rev to reach the cytoplasm and recruit the host translational 39 machinery. Here, we confirm that Rev ensures high levels of Gag synthesis by driving 40 nuclear export and translation of the unspliced mRNA. These functions of Rev are 41 supported by the CBC subunit CBP80, which binds Rev and the unspliced mRNA in the 42 nucleus and the cytoplasm. We also demonstrate that Rev interacts with the DEAD-box 43 RNA helicase eIF4AI, which translocates to the nucleus and cooperates with Rev to 44 promote Gag synthesis. Interestingly, molecular docking analyses revealed the assembly of 45 a Rev-CBP80-eIF4AI complex that is organized around the Rev response element (RRE). 46 Together, our results provide further evidence towards the understanding of the molecular 47 mechanisms by which Rev drives Gag synthesis from the unspliced mRNA during HIV-1 48 replication. 49 50 51 52 53 54 55 56 57 58 59 60 61 62Human Immunodeficiency Virus type-1 (HIV-1) gene expression is a complex process that 64 leads to the synthesis of fifteen proteins from one single primary transcript (1,2). Once the 65 proviral DNA has been integrated into the host cell genome, the RNA polymerase II drives 66 the synthesis of a 9-kb, capped and polyadenylated pre-mRNA that undergoes alternative 67 splicing generating more than 100 different transcripts classified into three main 68 populations (3,4). The so-called 2-kb multiply spliced transcripts code for the key 69 regulatory proteins Tat and Rev and the accessory protein Nef and are the dominant viral 70 mRNA species at early stages of viral gene expression (1,2,5). Unlike cellular mRNAs or 71 the 2-kb transcripts, which are spliced to completion before they exit the nucleus, HIV-1 72 and other complex retroviruses produce an important fraction of viral transcripts that 73 remain incompletely spliced (2,6). These 4-kb transcripts are expressed during the 74 intermediate phase of gene expression and are used for the synthesis of the envelope 75 glycoprotein (Env) and the accessory proteins Vif, Vpr and Vpu (2,6). Finally, the full-76 length 9-kb pre-mRNA in its unspliced form also reaches the cytoplasm to be used as an 77 mRNA template during the late stages of viral gene expression for the synthesis of the 78 major structural proteins Gag and Gag-Pol (1,2,6). 79Gene expression in eukaryotic cells occurs through the intricate connection of different 80 processes including transcription, splicing, nuclear export, translation and mRNA decay 81 and is regulated by the specific recruitment of nuclear proteins that together form the 82 messenger ribonuc...

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Intron or no intron: a matter for nuclear pore complexes

Cited by 16 publications

References 49 publications

Regulation of RNA-binding proteins affinity to export receptors enables the nuclear basket proteins to distinguish and retain aberrant mRNAs

Regulation of RNA-binding proteins affinity to export receptors enables the nuclear basket proteins to distinguish and retain aberrant mRNAs

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

A Rev-CBP80-eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA

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