The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements

Mukherjee, Devi; Gao, Min; O’Connor, J. P.; Raijmakers, Reinout; Pruijn, Ger J. M.; Lutz, Carol S.; Wilusz, Jeffrey

doi:10.1093/emboj/21.1.165

Cited by 348 publications

(321 citation statements)

References 67 publications

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“…In HeLa extracts, the addition of RNA containing an adenylate/uridylate-rich element (ARE) increased their 3 0 -5 0 exonucleolytic decay rate. The inactivation of EXOSC9 highly decreased the efficiency of the exonucleolytic decay, showing the central role of EXOSC9 in mRNA decay (Mukherjee et al, 2002). In human HEp-2 cells, it has been shown that the knockdown of EXOSC9 led to a twofold increase in b-globulin containing an ARE (van Dijk et al, 2007).…”

Section: Translation Initiationmentioning

confidence: 99%

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Dietrich

Neuenschwander

Bucher

et al. 2012

Animal

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The effects of mycotoxins in the production of animal feed were investigated using broiler chickens. For the feeding trial, naturally Fusarium mycotoxin-contaminated wheat was used, which mainly contained deoxynivalenol (DON). The main effects of DON are reduction of the feed intake and reduced weight gain of broilers. At the molecular level, DON binds to the 60 S ribosomal subunit and subsequently inhibits protein synthesis at the translational level. However, little is known about other effects of DON, for example, at the transcriptional level. Therefore, a microarray analysis was performed, which allows the investigation of thousands of transcripts in one experiment. In the experiment, 20 broilers were separated into four groups of five broilers each at day 1 after hatching. The diets consisted of a control diet and three diets with calculated, moderate concentrations of 1.0, 2.5 and 5.0 mg DON/kg feed, which was attained by exchanging uncontaminated wheat with naturally mycotoxin-contaminated wheat up to the intended DON concentration. The broilers were held at standard conditions for 23 days. Three microarrays were used per group to determine the significant alterations of the gene expression in the liver (P , 0.05), and qPCR was performed on the liver and the jejunum to verify the results. No significant difference in BW, feed intake or feed conversion rate was observed. The nutrient uptake into the hepatic and jejunal cells seemed to be influenced by genes: SLC2A5 (fc: 21.54, DON2.5), which facilitates glucose and fructose transport and SLC7A10 (fc: 11.49, DON5), a transporter of D-serine and other neutral amino acids. In the jejunum, the palmitate transport might be altered by SLC27A4 (fc: 21.87, DON5) and monocarboxylates uptake by SLC16A1 (fc: 21.47, DON5). The alterations of the SLC gene expression may explain the reduced weight gain of broilers chronically exposed to DON-contaminated wheat. The decreased expressions of EIF2AK3 (fc: 21.29, DON2.5/5) and DNAJC3 (fc: 21.44, DON2.5) seem to be related to the translation inhibition. The binding of DON to the 60 S ribosomal subunit and the subsequent translation inhibition might be counterbalanced by the downregulation of EIF2AK3 and DNAJC3. The genes PARP1, MPG, EME1, XPAC, RIF1 and CHAF1B are mainly related to single-strand DNA modifications and showed an increased expression in the group with 5 mg DON/kg feed. The results indicate that significantly altered gene expression was already occurring at 2.5 mg DON/kg feed.

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Section: Translation Initiationmentioning

confidence: 99%

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Dietrich

Neuenschwander

Bucher

et al. 2012

Animal

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“…In particular, adaptor proteins like RNA helicases or effector proteins such as ribonucleases might unfold and degrade the target respectively Wilson et al, 2001b;Mukherjee et al, 2002).…”

Section: Cis and Trans-acting Factor Interactionsmentioning

confidence: 99%

“…It has been shown in a cell-free RNA decay system that the exosome is required for rapid degradation of ARE-containing mRNAs Mukherjee et al, 2002). Two models have been proposed to explain how the exosome distinguishes an ARE-RNA substrate.…”

Section: Mechanisms Of Exosome Activationmentioning

confidence: 99%

“…Two models have been proposed to explain how the exosome distinguishes an ARE-RNA substrate. One model relies on the observation that the exosomal protein PM-Scl75 is an ARE-binding protein: this suggests a mechanism of direct loading of the exosome onto unstable AREcontaining mRNAs (Mukherjee et al, 2002). However, the homologue of E. coli RNAase PH, PM-Scl75, does not contain any known RNA-binding domain, so that its targeting to specific RNA substrates that contain AREs is more likely to be regulated by additional proteinprotein interactions.…”

Section: Mechanisms Of Exosome Activationmentioning

confidence: 99%

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Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

Bevilacqua

Ceriani

Capaccioli

et al. 2003

Journal Cellular Physiology

294

259

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Recent evidence suggests that gene expression may be regulated, at least in part, at post-transcriptional level by factors inducing the extremely rapid degradation of messenger RNAs. These factors include reactions between adenyl-uridyl-rich elements (AREs) of the relevant mRNA and either specific proteins that bind to these elements or exosomes. This review deals with examples of the proteins (AU-rich binding proteins, AUBPs) and exosomes, which have been shown to form complexes with AREs and bring about rapid degradation of the relevant mRNA, and with certain other factors, which protect the RNA from such degradation. The biochemical and physiological factors underlying the stability of messenger RNAs carrying the ARE motifs will be reviewed in the light of their emerging significance for cell physiology, human pathology, and molecular medicine. We also consider the possible application of the results of recent insights into the mechanisms to pharmacological interventions to prevent or cure disorders, especially developmental disorders, which the suppression of gene expression may bring about. Molecular targeting of specific steps in protein degradation by synthetic compounds has already been utilized for the development of pharmacological therapies.

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“…AREs are known to destabilize certain mRNAs, thereby affecting their expression levels. Although the exact mechanism of AREenhanced mRNA degradation is still unknown, it is thought to occur through the exosome pathway [63,64]. Antisense Alu elements harbor a Poly(T) which is complementary to the terminal A stretch, and it was estimated in this study that half of the longest AREs derived from antisense Alu elements [62].…”

Section: A-to-i Editing Of Embedded Alu Rnasmentioning

confidence: 99%

Useful ‘junk’: Alu RNAs in the human transcriptome

Häsler

Samuelsson

Strub

2007

Cell. Mol. Life Sci.

135

119

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Abstract. Alu elements are the most abundant repetitive elements in the human genome; they are amplified by retrotransposition to reach the present number of more than one million copies. Alu elements can be transcribed in two different ways, by two independent polymerases. Free Alu RNAs are transcribed by Pol III from their own promoter, while embedded Alu RNAs are transcribed by Pol II as part of protein-and non-protein-coding RNAs. Recent studies have demonstrated that both free and embedded Alu RNAs play a major role in posttranscriptional regulation of gene expression, for example by affecting protein translation, alternative splicing and mRNA stability. These discoveries illustrate how a part of the junk DNA content of the human genome has been recruited to important functions in regulation of gene expression.

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The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements

Cited by 348 publications

References 67 publications

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

Useful ‘junk’: Alu RNAs in the human transcriptome

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