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https://www.readbyqxmd.com/read/27899591/modulation-of-nonsense-mediated-decay-by-rapamycin
#1
Rocio T Martinez-Nunez, Andrew Wallace, Doyle Coyne, Linnea Jansson, Miles Rush, Hanane Ennajdaoui, Sol Katzman, Joanne Bailey, Katrin Deinhardt, Tilman Sanchez-Elsner, Jeremy R Sanford
Rapamycin is a naturally occurring macrolide whose target is at the core of nutrient and stress regulation in a wide range of species. Despite well-established roles as an inhibitor of cap-dependent mRNA translation, relatively little is known about its effects on other modes of RNA processing. Here, we characterize the landscape of rapamycin-induced post-transcriptional gene regulation. Transcriptome analysis of rapamycin-treated cells reveals genome-wide changes in alternative mRNA splicing and pronounced changes in NMD-sensitive isoforms...
November 28, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27886048/interactions-between-the-hiv-1-unspliced-mrna-and-host-mrna-decay-machineries
#2
REVIEW
Daniela Toro-Ascuy, Bárbara Rojas-Araya, Fernando Valiente-Echeverría, Ricardo Soto-Rifo
The human immunodeficiency virus type-1 (HIV-1) unspliced transcript is used both as mRNA for the synthesis of structural proteins and as the packaged genome. Given the presence of retained introns and instability AU-rich sequences, this viral transcript is normally retained and degraded in the nucleus of host cells unless the viral protein REV is present. As such, the stability of the HIV-1 unspliced mRNA must be particularly controlled in the nucleus and the cytoplasm in order to ensure proper levels of this viral mRNA for translation and viral particle formation...
November 23, 2016: Viruses
https://www.readbyqxmd.com/read/27864472/transcriptome-wide-identification-of-nmd-targeted-human-mrnas-reveals-extensive-redundancy-between-smg6-and-smg7-mediated-degradation-pathways
#3
Martino Colombo, Evangelos D Karousis, Joël Bourquin, Rémy Bruggmann, Oliver Mühlemann
Besides degrading aberrant mRNAs that harbor a premature translation termination codon (PTC), nonsense-mediated mRNA decay (NMD) also targets many seemingly "normal" mRNAs that encode for full-length proteins. To identify a bona fide set of such endogenous NMD targets in human cells, we applied a meta-analysis approach in which we combined transcriptome profiling of knockdowns and rescues of the three NMD factors UPF1, SMG6 and SMG7. We provide evidence that this combinatorial approach identifies NMD-targeted transcripts more reliably than previous attempts that focused on inactivation of single NMD factors...
November 18, 2016: RNA
https://www.readbyqxmd.com/read/27798850/identification-and-molecular-characterization-of-cellular-factors-required-for-glucocorticoid-receptor-mediated-mrna-decay
#4
Ok Hyun Park, Joori Park, Mira Yu, Hyoung-Tae An, Jesang Ko, Yoon Ki Kim
Glucocorticoid (GC) receptor (GR) has been shown recently to bind a subset of mRNAs and elicit rapid mRNA degradation. However, the molecular details of GR-mediated mRNA decay (GMD) remain unclear. Here, we demonstrate that GMD triggers rapid degradation of target mRNAs in a translation-independent and exon junction complex-independent manner, confirming that GMD is mechanistically distinct from nonsense-mediated mRNA decay (NMD). Efficient GMD requires PNRC2 (proline-rich nuclear receptor coregulatory protein 2) binding, helicase ability, and ATM-mediated phosphorylation of UPF1 (upstream frameshift 1)...
September 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/27702662/upregulation-of-snhg6-regulates-zeb1-expression-by-competitively-binding-mir-101-3p-and-interacting-with-upf1-in-hepatocellular-carcinoma
#5
Lei Chang, Yufeng Yuan, Cuicui Li, Tao Guo, Haolong Qi, Yusha Xiao, Xu Dong, Zhisu Liu, Quanyan Liu
Emerging evidence suggests that small nucleolar RNAs (snoRNAs) and their host genes (SNHGs) have malfunctioning roles in the development of human cancers. We globally investigated the molecular mechanisms by which snoRNA host gene 6 (SNHG6) promotes hepatocellular carcinoma (HCC) progression using human tissues and cell lines. We found that SNHG6 is overexpressed in HCC tissues and in hepatoma cell lines and is closely associated with histologic grade, hepatitis B virus DNA, Barcelona Clinic Liver Cancer stage and portal vein tumor thrombus in patients with HCC...
October 1, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27573788/upf1-regulates-myeloid-cell-functions-and-s100a9-expression-by-the-hnrnp-e2-mirna-328-balance
#6
Meike J Saul, Stefan Stein, Manuel Grez, Per-Johan Jakobsson, Dieter Steinhilber, Beatrix Suess
UPF1 is a key player in nonsense mediated mRNA decay (NMD) but also involved in posttranscriptional gene regulation. In this study we found that UPF1 regulates the expression of genes with functions in inflammation and myeloid cell differentiation via hnRNP E2. The majority of the UPF1-regulated genes identified in monocytic cells contain a binding site for hnRNP E2 within 5' UTR located introns with hnRNP E2 acting here as splicing regulator. We found that miRNA-328 which is significantly induced during monocytic cell differentiation acts independently from its gene silencing function as RNA decoy for hnRNP E2...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27563065/the-polyadenosine-rna-binding-protein-zinc-finger-cys3his-protein-14-zc3h14-regulates-the-pre-mrna-processing-of-a-key-atp-synthase-subunit-mrna
#7
Callie P Wigington, Kevin J Morris, Laura E Newman, Anita H Corbett
Polyadenosine RNA-binding proteins (Pabs) regulate multiple steps in gene expression. This protein family includes the well studied Pabs, PABPN1 and PABPC1, as well as the newly characterized Pab, zinc finger CCCH-type containing protein 14 (ZC3H14). Mutations in ZC3H14 are linked to a form of intellectual disability. To probe the function of ZC3H14, we performed a transcriptome-wide analysis of cells depleted of either ZC3H14 or the control Pab, PABPN1. Depletion of PABPN1 affected ∼17% of expressed transcripts, whereas ZC3H14 affected only ∼1% of expressed transcripts...
October 21, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27511142/hyperphosphorylation-amplifies-upf1-activity-to-resolve-stalls-in-nonsense-mediated-mrna-decay
#8
Sébastien Durand, Tobias M Franks, Jens Lykke-Andersen
Many gene expression factors contain repetitive phosphorylation sites for single kinases, but the functional significance is poorly understood. Here we present evidence for hyperphosphorylation as a mechanism allowing UPF1, the central factor in nonsense-mediated decay (NMD), to increasingly attract downstream machinery with time of residence on target mRNAs. Indeed, slowing NMD by inhibiting late-acting factors triggers UPF1 hyperphosphorylation, which in turn enhances affinity for factors linking UPF1 to decay machinery...
2016: Nature Communications
https://www.readbyqxmd.com/read/27401799/upf1-mutations-suppress-nonsense-mediated-rna-decay-in-imt
#9
(no author information available yet)
Inflammatory myofibroblastic tumors (IMT) harbor mutations in nonsense-mediated RNA decay gene UPF1.
August 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27348585/the-nonsense-mediated-rna-decay-pathway-is-disrupted-in-inflammatory-myofibroblastic-tumors
#10
JingWei Lu, Terra-Dawn Plank, Fang Su, XiuJuan Shi, Chen Liu, Yuan Ji, ShuaiJun Li, Andrew Huynh, Chao Shi, Bo Zhu, Guang Yang, YanMing Wu, Miles F Wilkinson, YanJun Lu
Inflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblast proliferation and an inflammatory cell infiltrate. Little is known about the molecular pathways that precipitate IMT formation. Here, we report the identification of somatic mutations in UPF1, a gene that encodes an essential component of the nonsense-mediated RNA decay (NMD) pathway, in 13 of 15 pulmonary IMT samples. The majority of mutations occurred in a specific region of UPF1 and triggered UPF1 alternative splicing. Several mRNA targets of the NMD pathway were upregulated in IMT samples, indicating that the UPF1 mutations led to reduced NMD magnitude...
August 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27208313/modeling-and-gene-knockdown-to-assess-the-contribution-of-nonsense-mediated-decay-premature-termination-and-selenocysteine-insertion-to-the-selenoprotein-hierarchy
#11
Anze Zupanic, Catherine Meplan, Grazielle V B Huguenin, John E Hesketh, Daryl P Shanley
The expression of selenoproteins, a specific group of proteins that incorporates selenocysteine, is hierarchically regulated by the availability of Se, with some, but not all selenoprotein mRNA transcripts decreasing in abundance with decreasing Se. Selenocysteine insertion into the peptide chain occurs during translation following recoding of an internal UGA stop codon. There is increasing evidence that this UGA recoding competes with premature translation termination, which is followed by nonsense-mediated decay (NMD) of the transcript...
July 2016: RNA
https://www.readbyqxmd.com/read/27149095/chromatoid-body-protein-tdrd6-supports-long-3-utr-triggered-nonsense-mediated-mrna-decay
#12
Grigorios Fanourgakis, Mathias Lesche, Müge Akpinar, Andreas Dahl, Rolf Jessberger
Chromatoid bodies (CBs) are spermiogenesis-specific organelles of largely unknown function. CBs harbor various RNA species, RNA-associated proteins and proteins of the tudor domain family like TDRD6, which is required for a proper CB architecture. Proteome analysis of purified CBs revealed components of the nonsense-mediated mRNA decay (NMD) machinery including UPF1. TDRD6 is essential for UPF1 localization to CBs, for UPF1-UPF2 and UPF1-MVH interactions. Upon removal of TDRD6, the association of several mRNAs with UPF1 and UPF2 is disturbed, and the long 3' UTR-stimulated but not the downstream exon-exon junction triggered pathway of NMD is impaired...
May 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27018474/mutations-in-smg9-encoding-an-essential-component-of-nonsense-mediated-decay-machinery-cause-a-multiple-congenital-anomaly-syndrome-in-humans-and-mice
#13
Ranad Shaheen, Shams Anazi, Tawfeg Ben-Omran, Mohammed Zain Seidahmed, L Brianna Caddle, Kristina Palmer, Rehab Ali, Tarfa Alshidi, Samya Hagos, Leslie Goodwin, Mais Hashem, Salma M Wakil, Mohamed Abouelhoda, Dilek Colak, Stephen A Murray, Fowzan S Alkuraya
Nonsense-mediated decay (NMD) is an important process that is best known for degrading transcripts that contain premature stop codons (PTCs) to mitigate their potentially harmful consequences, although its regulatory role encompasses other classes of transcripts as well. Despite the critical role of NMD at the cellular level, our knowledge about the consequences of deficiency of its components at the organismal level is largely limited to model organisms. In this study, we report two consanguineous families in which a similar pattern of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutations in SMG9, encoding an essential component of the SURF complex that generates phospho-UPF1, the single most important step in NMD...
April 7, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/26946399/polycistronic-trypanosome-mrnas-are-a-target-for-the-exosome
#14
Susanne Kramer, Sophie Piper, Antonio Estevez, Mark Carrington
Eukaryotic cells have several mRNA quality control checkpoints to avoid the production of aberrant proteins. Intron-containing mRNAs are actively degraded by the nuclear exosome, prevented from nuclear exit and, if these systems fail, degraded by the cytoplasmic NMD machinery. Trypanosomes have only two introns. However, they process mRNAs from long polycistronic precursors by trans-splicing and polycistronic mRNA molecules frequently arise from any missed splice site. Here, we show that RNAi depletion of the trypanosome exosome, but not of the cytoplasmic 5'-3' exoribonuclease XRNA or the NMD helicase UPF1, causes accumulation of oligocistronic mRNAs...
January 2016: Molecular and Biochemical Parasitology
https://www.readbyqxmd.com/read/26934103/identification-of-interactions-in-the-nmd-complex-using-proximity-dependent-biotinylation-bioid
#15
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
https://www.readbyqxmd.com/read/26863136/in-silico-analysis-of-the-structural-and-biochemical-features-of-the-nmd-factor-upf1-in-ustilago-maydis
#16
Nancy Martínez-Montiel, Laura Morales-Lara, Julio M Hernández-Pérez, Rebeca D Martínez-Contreras
The molecular mechanisms regulating the accuracy of gene expression are still not fully understood. Among these mechanisms, Nonsense-mediated Decay (NMD) is a quality control process that detects post-transcriptionally abnormal transcripts and leads them to degradation. The UPF1 protein lays at the heart of NMD as shown by several structural and functional features reported for this factor mainly for Homo sapiens and Saccharomyces cerevisiae. This process is highly conserved in eukaryotes but functional diversity can be observed in various species...
2016: PloS One
https://www.readbyqxmd.com/read/26841701/the-rna-helicase-dhx34-functions-as-a-scaffold-for-smg1-mediated-upf1-phosphorylation
#17
Roberto Melero, Nele Hug, Andrés López-Perrote, Akio Yamashita, Javier F Cáceres, Oscar Llorca
Nonsense-mediated decay (NMD) is a messenger RNA quality-control pathway triggered by SMG1-mediated phosphorylation of the NMD factor UPF1. In recent times, the RNA helicase DHX34 was found to promote mRNP remodelling, leading to activation of NMD. Here we demonstrate the mechanism by which DHX34 functions in concert with SMG1. DHX34 comprises two distinct structural units, a core that binds UPF1 and a protruding carboxy-terminal domain (CTD) that binds the SMG1 kinase, as shown using truncated forms of DHX34 and electron microscopy of the SMG1-DHX34 complex...
February 4, 2016: Nature Communications
https://www.readbyqxmd.com/read/26787741/nonsense-mediated-mrna-decay-in-humans-at-a-glance
#18
Tatsuaki Kurosaki, Lynne E Maquat
Nonsense-mediated mRNA decay (NMD) is an mRNA quality-control mechanism that typifies all eukaryotes examined to date. NMD surveys newly synthesized mRNAs and degrades those that harbor a premature termination codon (PTC), thereby preventing the production of truncated proteins that could result in disease in humans. This is evident from dominantly inherited diseases that are due to PTC-containing mRNAs that escape NMD. Although many cellular NMD targets derive from mistakes made during, for example, pre-mRNA splicing and, possibly, transcription initiation, NMD also targets ∼10% of normal physiological mRNAs so as to promote an appropriate cellular response to changing environmental milieus, including those that induce apoptosis, maturation or differentiation...
February 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/26708722/insulin-signaling-augments-eif4e-dependent-nonsense-mediated-mrna-decay-in-mammalian-cells
#19
Jungyun Park, Seyoung Ahn, Aravinth K Jayabalan, Takbum Ohn, Hyun Chul Koh, Jungwook Hwang
Nonsense-mediated mRNA decay (NMD) modulates the level of mRNA harboring a premature termination codon (PTC) in a translation-dependent manner. Inhibition of translation is known to impair NMD; however, few studies have investigated the correlation between enhanced translation and increased NMD. Here, we demonstrate that insulin signaling events increase translation, leading to an increase in NMD of eIF4E-bound transcripts. We provide evidence that (i) insulin-mediated enhancement of translation augments NMD and rapamycin abrogates this enhancement; (ii) an increase in AKT phosphorylation due to inhibition of PTEN facilitates NMD; (iii) insulin stimulation increases the binding of up-frameshift factor 1 (UPF1), most likely to eIF4E-bound PTC-containing transcripts; and (iv) insulin stimulation induces the colocalization of UPF1 and eIF4E in processing bodies...
July 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/26656492/a-novel-role-for-carm1-in-promoting-nonsense-mediated-mrna-decay-potential-implications-for-spinal-muscular-atrophy
#20
Gabriel Sanchez, Emma Bondy-Chorney, Janik Laframboise, Geneviève Paris, Andréanne Didillon, Bernard J Jasmin, Jocelyn Côté
Loss of 'Survival of Motor Neurons' (SMN) leads to spinal muscular atrophy (SMA), a disease characterized by degeneration of spinal cord alpha motor neurons, resulting in muscle weakness, paralysis and death during early childhood. SMN is required for assembly of the core splicing machinery, and splicing defects were documented in SMA. We previously uncovered that Coactivator-Associated Methyltransferase-1 (CARM1) is abnormally up-regulated in SMA, leading to mis-regulation of a number of transcriptional and alternative splicing events...
April 7, 2016: Nucleic Acids Research
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