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Yi Jin, Fang Zhang, Zhenfa Ma, Zhuqing Ren
BACKGROUND: Nonsense-mediated mRNA decay (NMD) is a RNA quality surveillance system for eukaryotes. It prevents cells from generating deleterious truncated proteins by degrading abnormal mRNAs that harbor premature termination codon (PTC). However, little is known about the molecular regulation mechanism underlying the inhibition of NMD by microRNAs. RESULTS: The present study demonstrated that miR-433 was involved in NMD pathway via negatively regulating SMG5. We provided evidence that (1) overexpression of miR-433 significantly suppressed the expression of SMG5 (P < 0...
2016: BMC Molecular Biology
Christoph Schweingruber, Paolo Soffientini, Marc-David Ruepp, Angela Bachi, Oliver Mühlemann
Proximity-dependent trans-biotinylation by the Escherichia coli biotin ligase BirA mutant R118G (BirA*) allows stringent streptavidin affinity purification of proximal proteins. This so-called BioID method provides an alternative to the widely used co-immunoprecipitation (co-IP) to identify protein-protein interactions. Here, we used BioID, on its own and combined with co-IP, to identify proteins involved in nonsense-mediated mRNA decay (NMD), a post-transcriptional mRNA turnover pathway that targets mRNAs that fail to terminate translation properly...
2016: PloS One
Giuseppe Balistreri, Peter Horvath, Christoph Schweingruber, David Zünd, Gerald McInerney, Andres Merits, Oliver Mühlemann, Claus Azzalin, Ari Helenius
In addition to classically defined immune mechanisms, cell-intrinsic processes can restrict virus infection and have shaped virus evolution. The details of this virus-host interaction are still emerging. Following a genome-wide siRNA screen for host factors affecting replication of Semliki Forest virus (SFV), a positive-strand RNA (+RNA) virus, we found that depletion of nonsense-mediated mRNA decay (NMD) pathway components Upf1, Smg5, and Smg7 led to increased levels of viral proteins and RNA and higher titers of released virus...
September 10, 2014: Cell Host & Microbe
Tatsuaki Kurosaki, Wencheng Li, Mainul Hoque, Maximilian W-L Popp, Dmitri N Ermolenko, Bin Tian, Lynne E Maquat
Nonsense-mediated mRNA decay (NMD) controls the quality of eukaryotic gene expression and also degrades physiologic mRNAs. How NMD targets are identified is incompletely understood. A central NMD factor is the ATP-dependent RNA helicase upframeshift 1 (UPF1). Neither the distance in space between the termination codon and the poly(A) tail nor the binding of steady-state, largely hypophosphorylated UPF1 is a discriminating marker of cellular NMD targets, unlike for premature termination codon (PTC)-containing reporter mRNAs when compared with their PTC-free counterparts...
September 1, 2014: Genes & Development
Junho Choe, Sang Ho Ahn, Yoon Ki Kim
Histone biogenesis is tightly controlled at multiple steps to maintain the balance between the amounts of DNA and histone protein during the cell cycle. In particular, translation and degradation of replication-dependent histone mRNAs are coordinately regulated. However, the underlying molecular mechanisms remain elusive. Here, we investigate remodeling of stem-loop binding protein (SLBP)-containing histone mRNPs occurring during the switch from the actively translating mode to the degradation mode. The interaction between a CBP80/20-dependent translation initiation factor (CTIF) and SLBP, which is important for efficient histone mRNA translation, is disrupted upon the inhibition of DNA replication or at the end of S phase...
August 2014: Nucleic Acids Research
Sutapa Chakrabarti, Fabien Bonneau, Steffen Schüssler, Elfriede Eppinger, Elena Conti
Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that recognizes mRNAs with premature stop codons and targets them for rapid degradation. Evidence from previous studies has converged on UPF1 as the central NMD factor. In human cells, the SMG1 kinase phosphorylates UPF1 at the N-terminal and C-terminal tails, in turn allowing the recruitment of the NMD factors SMG5, SMG6 and SMG7. To understand the molecular mechanisms, we recapitulated these steps of NMD in vitro using purified components...
August 2014: Nucleic Acids Research
Hana Cho, Sisu Han, Ok Hyun Park, Yoon Ki Kim
Suppressor of morphogenesis in genitalia 1 (SMG1), a member of the phosphatidylinositol 3-kinase-related kinase family, is involved in nonsense-mediated mRNA decay (NMD). SMG1 phosphorylates Upf1, a key NMD factor. Subsequently, hyperphosphorylated Upf1 associates with SMG5-7 or proline-rich nuclear receptor coregulatory protein (PNRC2) to elicit rapid mRNA degradation. Upf1 is also known to be involved in staufen 1 (Stau1)-mediated mRNA decay (SMD), which is closely related to NMD. However, the biological and molecular roles of SMG1 in SMD remain unknown...
December 2013: Biochimica et Biophysica Acta
Belinda Loh, Stefanie Jonas, Elisa Izaurralde
Nonsense-mediated mRNA decay (NMD) is a eukaryotic quality control mechanism that detects aberrant mRNAs containing nonsense codons and induces their rapid degradation. This degradation is mediated by SMG6, an NMD-specific endonuclease, as well as the SMG5 and SMG7 proteins, which recruit general mRNA decay enzymes. However, it remains unknown which specific decay factors are recruited and whether this recruitment is direct. Here, we show that SMG7 binds directly to POP2, a catalytic subunit of the CCR4-NOT deadenylase complex, and elicits deadenylation-dependent decapping and 5'-to-3' decay of NMD targets...
October 1, 2013: Genes & Development
Stefanie Metze, Veronika A Herzog, Marc-David Ruepp, Oliver Mühlemann
Nonsense-mediated mRNA decay (NMD) is a eukaryotic post-transcriptional gene regulation mechanism that eliminates mRNAs with the termination codon (TC) located in an unfavorable environment for efficient translation termination. The best-studied NMD-targeted mRNAs contain premature termination codons (PTCs); however, NMD regulates even many physiological mRNAs. An exon-junction complex (EJC) located downstream from a TC acts as an NMD-enhancing signal, but is not generally required for NMD. Here, we compared these "EJC-enhanced" and "EJC-independent" modes of NMD with regard to their requirement for seven known NMD factors in human cells using two well-characterized NMD reporter genes (immunoglobulin μ and β-Globin) with or without an intron downstream from the PTC...
October 2013: RNA
Xianning Lai, Traude Beilharz, Wei-Chun Au, Andrew Hammet, Thomas Preiss, Munira A Basrai, Jörg Heierhorst
During its natural life cycle, budding yeast (Saccharomyces cerevisiae) has to adapt to drastically changing environments, but how environmental-sensing pathways are linked to adaptive gene expression changes remains incompletely understood. Here, we describe two closely related yeast hEST1A-B (SMG5-6)-like proteins termed Esl1 and Esl2 that contain a 14-3-3-like domain and a putative PilT N-terminus ribonuclease domain. We found that, unlike their metazoan orthologs, Esl1 and Esl2 were not involved in nonsense-mediated mRNA decay or telomere maintenance pathways...
October 2013: G3: Genes—Genomes—Genetics
Jianran Hu, Yu Li, Ping Li
We have observed low expression levels of MARVELD1, a novel tumor repressor, in multiple tumors; however, its function in normal cells has not been explored. We recently reported that MARVELD1 interacts with importin β1, which plays an important role in nonsense-mediated RNA decay(NMD). Here, we demonstrate that MARVELD1 substantially inhibits nonsense-mediated RNA decay by decreasing the pioneer round of translation but not steady-state translation, and we identify MARVELD1 as an important component of the molecular machinery containing UPF1 and Y14...
2013: PloS One
Verena Geißler, Simone Altmeyer, Benjamin Stein, Heike Uhlmann-Schiffler, Hans Stahl
Non-sense-mediated mRNA decay (NMD) is a mechanism of translation-dependent mRNA surveillance in eukaryotes: it degrades mRNAs with premature termination codons (PTCs) and contributes to cellular homeostasis by downregulating a number of physiologically important mRNAs. In the NMD pathway, Upf proteins, a set of conserved factors of which Upf1 is the central regulator, recruit decay enzymes to promote RNA cleavage. In mammals, the degradation of PTC-containing mRNAs is triggered by the exon-junction complex (EJC) through binding of its constituents Upf2 and Upf3 to Upf1...
September 2013: Nucleic Acids Research
Christoph Schweingruber, Simone C Rufener, David Zünd, Akio Yamashita, Oliver Mühlemann
The nonsense-mediated mRNA decay (NMD) pathway is well known as a translation-coupled quality control system that recognizes and degrades aberrant mRNAs with truncated open reading frames (ORF) due to the presence of a premature termination codon (PTC). However, a more general role of NMD in posttranscriptional regulation of gene expression is indicated by transcriptome-wide mRNA profilings that identified a plethora of physiological mRNAs as NMD targets. In this review, we focus on mechanistic aspects of target mRNA identification and degradation in mammalian cells, based on the available biochemical and genetic data, and point out knowledge gaps...
June 2013: Biochimica et Biophysica Acta
Stefanie Jonas, Oliver Weichenrieder, Elisa Izaurralde
The nonsense-mediated mRNA decay (NMD) pathway triggers the rapid degradation of aberrant mRNAs containing premature translation termination codons (PTCs). In metazoans, NMD requires three 14-3-3-like proteins: SMG5, SMG6, and SMG7. These proteins are recruited to PTC-containing mRNAs through the interaction of their 14-3-3-like domains with phosphorylated UPF1, the central NMD effector. Recruitment of SMG5, SMG6, and SMG7 causes NMD target degradation. In this study, we report the crystal structure of the Caenorhabditis elegans SMG5-SMG7 complex...
January 15, 2013: Genes & Development
Hana Cho, Sisu Han, Junho Choe, Seung Gu Park, Sun Shim Choi, Yoon Ki Kim
In mammals, nonsense-mediated mRNA decay (NMD) functions in post-transcriptional gene regulation as well as mRNA surveillance. A key NMD factor, Upf1, becomes hyperphosphorylated by SMG1 kinase during the recognition of NMD substrates. Hyperphosphorylated Upf1 interacts with several factors including SMG5, SMG6, SMG7 and PNRC2 to trigger rapid mRNA degradation. However, the possible cross-talk among these factors and their selective use during NMD remain unknown. Here, we show that PNRC2 is preferentially complexed with SMG5, but not with SMG6 or SMG7, and that downregulation of PNRC2 abolishes the interaction between SMG5 and Dcp1a, a component of the decapping complex...
January 2013: Nucleic Acids Research
Hasmik Yepiskoposyan, Florian Aeschimann, Daniel Nilsson, Michal Okoniewski, Oliver Mühlemann
Nonsense-mediated mRNA decay (NMD) is traditionally portrayed as a quality-control mechanism that degrades mRNAs with truncated open reading frames (ORFs). However, it is meanwhile clear that NMD also contributes to the post-transcriptional gene regulation of numerous physiological mRNAs. To identify endogenous NMD substrate mRNAs and analyze the features that render them sensitive to NMD, we performed transcriptome profiling of human cells depleted of the NMD factors UPF1, SMG6, or SMG7. It revealed that mRNAs up-regulated by NMD abrogation had a greater median 3'-UTR length compared with that of the human mRNAome and were also enriched for 3'-UTR introns and uORFs...
December 2011: RNA
Kalpana Kannan, Liguo Wang, Jianghua Wang, Michael M Ittmann, Wei Li, Laising Yen
Transcription-induced chimeric RNAs, possessing sequences from different genes, are expected to increase the proteomic diversity through chimeric proteins or altered regulation. Despite their importance, few studies have focused on chimeric RNAs especially regarding their presence/roles in human cancers. By deep sequencing the transcriptome of 20 human prostate cancer and 10 matched benign prostate tissues, we obtained 1.3 billion sequence reads, which led to the identification of 2,369 chimeric RNA candidates...
May 31, 2011: Proceedings of the National Academy of Sciences of the United States of America
Anna Hangyáné Benkovics, Tünde Nyikó, Zsuzsanna Mérai, Dániel Silhavy, György Dénes Bisztray
Nonsense-mediated mRNA decay (NMD) is a eukaryotic quality control system that identifies and eliminates transcripts having a premature translation termination codon (PTC). NMD is also involved in the control of several wild-type mRNAs. The NMD core machinery consists of three highly conserved NMD factors (UPF1, UPF2 and UPF3) and at least one less conserved 14-3-3-like domain containing protein (SMG7). A PTC is identified by UPF factors, and then SMG7 triggers rapid transcript decay. UPF factors are generally encoded by a single gene, whereas SMG7 has duplicated several times during evolution...
February 2011: Plant Molecular Biology
Pamela Nicholson, Oliver Mühlemann
In eukaryotes, mRNAs harbouring PTCs (premature translation-termination codons) are recognized and eliminated by NMD (nonsense-mediated mRNA decay). In addition to its quality-control function, NMD constitutes a translation-dependent post-transcriptional pathway to regulate the expression levels of physiological mRNAs. In contrast with PTC recognition, little is known about the mechanisms that trigger the rapid degradation of mammalian nonsense mRNA. Studies have shown that mammalian NMD targets can be degraded via both an SMG6 (where SMG is suppressor of morphological defects on genitalia)-dependent endonucleolytic pathway and a deadenylation and decapping-dependent exonucleolytic pathway, with the possible involvement of SMG5 and SMG7...
December 2010: Biochemical Society Transactions
Nadine Wittkopp, Eric Huntzinger, Catrin Weiler, Jérôme Saulière, Steffen Schmidt, Mahendra Sonawane, Elisa Izaurralde
The nonsense-mediated mRNA decay (NMD) pathway promotes rapid degradation of mRNAs containing premature translation termination codons (PTCs or nonsense codons), preventing accumulation of potentially detrimental truncated proteins. In metazoa, seven genes (upf1, upf2, upf3, smg1, smg5, smg6, and smg7) have been identified as essential for NMD; here we show that the zebrafish genome encodes orthologs of upf1, upf2, smg1, and smg5 to smg7 and two upf3 paralogs. We also show that Upf1 is required for degradation of PTC-containing mRNAs in zebrafish embryos...
July 2009: Molecular and Cellular Biology
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