scholarly journals Insights into the assembly and architecture of a Staufen-mediated mRNA decay (SMD)-competent mRNP

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Manjeera Gowravaram ◽  
Juliane Schwarz ◽  
Sana K. Khilji ◽  
Henning Urlaub ◽  
Sutapa Chakrabarti
Keyword(s):  
Catalytic Activity ◽  
Cross Talk ◽  
Untranslated Region ◽  
Mrna Decay ◽  
Molecular Mechanisms ◽  
Rna Helicase ◽  
Secondary Structures ◽  
Nonsense Mediated Mrna Decay ◽  
In Cells

Abstract The mammalian Staufen proteins (Stau1 and Stau2) mediate degradation of mRNA containing complex secondary structures in their 3’-untranslated region (UTR) through a pathway known as Staufen-mediated mRNA decay (SMD). This pathway also involves the RNA helicase UPF1, which is best known for its role in the nonsense-mediated mRNA decay (NMD) pathway. Here we present a biochemical reconstitution of the recruitment and activation of UPF1 in context of the SMD pathway. We demonstrate the involvement of UPF2, a core NMD factor and a known activator of UPF1, in SMD. UPF2 acts as an adaptor between Stau1 and UPF1, stimulates the catalytic activity of UPF1 and plays a central role in the formation of an SMD-competent mRNP. Our study elucidates the molecular mechanisms of SMD and points towards extensive cross-talk between UPF1-mediated mRNA decay pathways in cells.

scholarly journals The 5′-untranslated region regulates ATF5 mRNA stability via nonsense-mediated mRNA decay in response to environmental stress

FEBS Journal ◽  
2013 ◽  
Vol 280 (18) ◽  
pp. 4693-4707 ◽  
Author(s):  
Masaya Hatano ◽  
Mariko Umemura ◽  
Natsumi Kimura ◽  
Takashi Yamazaki ◽  
Hitoshi Takeda ◽  
...  
Keyword(s):  
Environmental Stress ◽  
Mrna Stability ◽  
Untranslated Region ◽  
Mrna Decay ◽  
Nonsense Mediated Mrna Decay

Aberrant termination triggers nonsense-mediated mRNA decay

2006 ◽  
Vol 34 (1) ◽  
pp. 39-42 ◽  
Author(s):  
N. Amrani ◽  
S. Dong ◽  
F. He ◽  
R. Ganesan ◽  
S. Ghosh ◽  
...  
Keyword(s):  
Quality Control ◽  
Untranslated Region ◽  
Mrna Decay ◽  
Premature Termination ◽  
Control Mechanism ◽  
Premature Termination Codon ◽  
Release Factor ◽  
Mrna Decapping ◽  
Nonsense Mediated Mrna Decay ◽  
Quality Control Mechanism

NMD (nonsense-mediated mRNA decay) is a cellular quality-control mechanism in which an otherwise stable mRNA is destabilized by the presence of a premature termination codon. We have defined the set of endogenous NMD substrates, demonstrated that they are available for NMD at every round of translation, and showed that premature termination and normal termination are not equivalent biochemical events. Premature termination is aberrant, and its NMD-stimulating defects can be reversed by the presence of tethered poly(A)-binding protein (Pab1p) or tethered eRF3 (eukaryotic release factor 3) (Sup35p). Thus NMD appears to be triggered by a ribosome's failure to terminate adjacent to a properly configured 3′-UTR (untranslated region), an event that may promote binding of the UPF/NMD factors to stimulate mRNA decapping.

scholarly journals Regulation of H-ras Splice Variant Expression by Cross Talk between the p53 and Nonsense-Mediated mRNA Decay Pathways

2007 ◽  
Vol 27 (20) ◽  
pp. 7315-7333 ◽  
Author(s):  
Jérôme Barbier ◽  
Martin Dutertre ◽  
Danielle Bittencourt ◽  
Gabriel Sanchez ◽  
Lise Gratadou ◽  
...  
Keyword(s):  
Cross Talk ◽  
Splice Variant ◽  
Mrna Decay ◽  
Splice Variants ◽  
Genotoxic Stress ◽  
Term Treatment ◽  
Short Term Treatment ◽  
P53 Overexpression ◽  
Long Term Treatment ◽  
Nonsense Mediated Mrna Decay

ABSTRACT When cells are exposed to a genotoxic stress, a DNA surveillance pathway that involves p53 is activated, allowing DNA repair. Eukaryotic cells have also evolved a mechanism called mRNA surveillance that controls the quality of mRNAs. Indeed, mutant mRNAs carrying premature translation termination codons (PTCs) are selectively degraded by the nonsense-mediated mRNA decay (NMD) pathway. However, in the case of particular genes, such as proto-oncogenes, mutations that do not create PTCs and therefore that do not induce mRNA degradation, can be harmful to cells. In this study, we showed that the H-ras gene in the absence of mutations produces an NMD-target splice variant that is degraded in the cytosol. We observed that a treatment with the genotoxic stress inducer camptothecin for 6 h favored the production of the H-ras NMD-target transcript degraded in the cytosol by the NMD process. Our data indicated that the NMD process allowed the elimination of transcripts produced in response to a short-term treatment with camptothecin from the major proto-oncogene H-ras, independently of PTCs induced by mutations. The camptothecin effects on H-ras gene expression were p53 dependent and involved in part modulation of the SC35 splicing factor. Interestingly, a long-term treatment with camptothecin as well as p53 overexpression for 24 h resulted in the accumulation of the H-ras NMD target in the cytosol, although the NMD process was not completely inhibited as other NMD targets are not stabilized. Finally, Upf1, a major NMD effector, was necessary for optimal p53 activation by camptothecin, which is consistent with recent data showing that NMD effectors are required for genome stability. In conclusion, we identified cross talk between the p53 and NMD pathways that regulates the expression levels of H-ras splice variants.

scholarly journals Upf1/Upf2 Regulation of 3′ Untranslated Region Splice Variants of AUF1 Links Nonsense-Mediated and A+U-Rich Element-Mediated mRNA Decay

2006 ◽  
Vol 26 (23) ◽  
pp. 8743-8754 ◽  
Author(s):  
Lili Banihashemi ◽  
Gerald M. Wilson ◽  
Neha Das ◽  
Gary Brewer
Keyword(s):  
Mammalian Cells ◽  
Mrna Decay ◽  
Rna Binding ◽  
Splice Variants ◽  
Dominant Negative ◽  
Enhanced Expression ◽  
Nonsense Mediated Mrna Decay ◽  
Translational Termination ◽  
Development Proceeds ◽  
In Cells

ABSTRACT AUF1 is an RNA-binding protein that targets mRNAs containing A+U-rich elements (AREs) for rapid cytoplasmic turnover. Alternative pre-mRNA splicing produces five variants of AUF1 mRNA that differ in the composition of their 3′-untranslated regions (3′-UTRs). Previous work suggested that this heterogeneity in 3′-UTR sequence could regulate AUF1 expression by two potential mechanisms. First, AUF1 may regulate its own expression by binding to AREs in 3′-UTR splice variants that retain intron 9. The second potential mechanism, and the focus of this report, is regulation of a subset of 3′-UTR splice variants by the nonsense-mediated mRNA decay (NMD) pathway. Two of the five AUF1 mRNA 3′-UTR variants position the translational termination codon more than 50 nucleotides upstream of an exon-exon junction, creating a potential triggering signal for NMD in mammalian cells. Disruption of cellular NMD pathways by RNA interference-mediated knockdown of Upf1/Rent1 or Upf2/Rent2 or transfection of a dominant-negative Upf1 mutant specifically enhanced expression of these two candidate NMD substrate mRNAs in cells, involving stabilization of each transcript. Ribonucleoprotein immunoprecipitation experiments revealed that both Upf1 and Upf2 can associate with an NMD-sensitive AUF1 mRNA 3′-UTR variant in cells. Finally, quantitation of AUF1 mRNA 3′-UTR splice variants during murine embryonic development showed that the expression of NMD-sensitive AUF1 mRNAs is specifically enhanced as development proceeds, contributing to dynamic changes in AUF1 3′-UTR structures during embryogenesis. Together, these studies provide the first evidence of linkage between the nonsense- and ARE-mediated mRNA decay pathways, which may constitute a new mechanism regulating the expression of ARE-containing mRNAs.

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