Control of mammalian gene expression by selective mRNA export

Wickramasinghe, Vihandha O.; Laskey, Ronald A.

doi:10.1038/nrm4010

Cited by 185 publications

(175 citation statements)

References 153 publications

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“…from plasmids). For example, mRNA produced in the nucleus is bound to multiple mRNA export binding proteins which can impact protein production [13]. In addition, mRNA produced ex vivo and optimized for therapeutic applications contains chemical modifications which may impact RNA thermodynamics and structure and subsequent protein translation [14].…”

Section: Discussionmentioning

confidence: 99%

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

et al. 2018

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ABSTRACTmRNA based therapies hold great promise for the treatment of genetic diseases. However, this therapeutic approach suffers from multiple challenges including the short half-life of exogenously administered mRNA and subsequent protein production. Modulation of untranslated regions (UTR) represents one approach to enhance both mRNA stability and translation efficiency. The current studies describe and validate screening methods using a diverse set of 5′UTR and 3′UTR combinations for improved expression of the Arginase 1 (ARG1) protein, a potential therapeutic mRNA target. Data revealed a number of critical aspects which need to be considered when developing a screening approach for engineering mRNA improvements. First, plasmid-based screening methods do not correlate with protein expression driven by exogenously expressed mRNA. Second, improved ARG1 protein production was driven by increased translation and not improved mRNA stability. Finally, the 5′ UTR appears to be the key driver in protein expression for exogenously delivered mRNA. From the testing of the combinatorial library, the 5′UTR for complement factor 3 (C3) and cytochrome p4502E1 (CYP2E1) showed the largest and most consistent increase in protein expression relative to a reference UTR. Collectively, these data provide important information for the development and optimization of therapeutic mRNAs.

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Section: Discussionmentioning

confidence: 99%

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

et al. 2018

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“…In order to be exported from the nucleus to the cytoplasm mRNA molecules must bind a transport receptor that interacts with NPC components to activate translocation through the pore (for reviews, see Natalizio and Wente, 2013;Björk and Wieslander, 2014;Wickramasinghe and Laskey, 2015;Elbarbary and Maquat, 2016). Most mRNAs use the export receptor NXF1 (nuclear export factor 1, also known as Tap in humans and Mex67p in yeast) and its cofactor NXT1 (also known as p15).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of the spliceosome subunit SF3b triggers exon junction complex-independent nonsense-mediated decay

Carvalho

Martins

Rino

et al. 2017

Journal of Cell Science

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Spliceostatin A, meayamycin, and pladienolide B are small molecules that target the SF3b subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP). These compounds are attracting much attention as tools to manipulate splicing and for use as potential anticancer drugs. We investigated the effects of these inhibitors on mRNA transport and stability in human cells. Upon splicing inhibition, unspliced pre-mRNAs accumulated in the nucleus, particularly within enlarged nuclear speckles. However, a small fraction of the premRNA molecules were exported to the cytoplasm. We identified the export adaptor ALYREF as being associated with intron-containing transcripts and show its requirement for the nucleo-cytoplasmic transport of unspliced pre-mRNA. In contrast, the exon junction complex (EJC) core protein eIF4AIII failed to form a stable complex with intron-containing transcripts. Despite the absence of EJC, unspliced transcripts in the cytoplasm were degraded by nonsensemediated decay (NMD), suggesting that unspliced transcripts are degraded by an EJC-independent NMD pathway. Collectively, our results indicate that although blocking the function of SF3b elicits a massive accumulation of unspliced pre-mRNAs in the nucleus, intron-containing transcripts can still bind the ALYREF export factor and be transported to the cytoplasm, where they trigger an alternative NMD pathway.

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“…This includes the critical steps of the 5' capping, splicing and 3' end-processing [1][2][3][4][5]. All of these processes are considered to be vital as well as strict quality control regulations that, eventually, aim to ensure the competency of the transcribed mRNA.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of mRNA Maturation by Compounds Which Have a Flavonoid Skeleton

Kurata¹,

Morimoto²,

Kawamura³

et al. 2017

BMB

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Post-transcriptional modifications of nascent mRNA include 5' capping, splicing and 3' end polyadenylation, resulting in the emergence of mature mRNA. Recent findings indicate that mRNA splicing inhibitors can be potential anti-cancer candidates. Soy-isoflavone fractions displayed an inhibitory effect of mRNA processing among a number of dietary components. Two major components of the isoflavone fraction, daidzin and genistin did not have an inhibitory activity against mRNA maturation. The aglycone form of them also failed to inhibit mRNA maturation. Instead, compounds with flavone skeleton inhibited the mRNA maturation in the nucleus. Considering that the structural difference between flavone and isoflavone compounds is that B-ring is attached either on the 2' or 3' position of C-ring, respectively, anti-mRNA maturation activity may require a defined structural basis. These data indicate that compounds with flavone skeleton specifically alter the mRNA processing step.

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Control of mammalian gene expression by selective mRNA export

Cited by 185 publications

References 153 publications

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

Pharmacological inhibition of the spliceosome subunit SF3b triggers exon junction complex-independent nonsense-mediated decay

Inhibition of mRNA Maturation by Compounds Which Have a Flavonoid Skeleton

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