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https://www.readbyqxmd.com/read/28536849/nmd-monitors-translational-fidelity-24-7
#1
REVIEW
Alper Celik, Feng He, Allan Jacobson
Nonsense-mediated mRNA decay (NMD) is generally thought to be a eukaryotic mRNA surveillance pathway tasked with the elimination of transcripts harboring an in-frame premature termination codon (PTC). As presently conceived, NMD acting in this manner minimizes the likelihood that potentially toxic polypeptide fragments would accumulate in the cytoplasm. This notion is to be contrasted to the results of systematic RNA-Seq and microarray analyses of NMD substrates in multiple model systems, two different experimental approaches which have shown that many mRNAs identified as NMD substrates fail to contain a PTC...
May 23, 2017: Current Genetics
https://www.readbyqxmd.com/read/28444146/nonsense-in-the-testis-multiple-roles-for-nonsense-mediated-decay-revealed-in-male-reproduction
#2
Clinton C MacDonald, Petar N Grozdanov
Nonsense-mediated mRNA decay, or NMD, is a quality control mechanism that identifies cytoplasmic mRNAs containing translational termination (stop) codons in specific contexts - either premature termination codons or unusually long 3΄ untranslated regions - and targets them for degradation. In recent studies, researchers in different labs have knocked out important genes involved in NMD, Upf2 and Upf3a, and one component of chromatoid bodies, Tdrd6, and examined the consequences for spermatogenesis. Disruption of Upf2 during early stages of spermatogenesis resulted in disappearance of nearly all spermatogenic cells through loss of NMD...
April 22, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28402567/nonsense-mediated-mrna-decay-in-tetrahymena-is-ejc-independent-and-requires-a-protozoa-specific-nuclease
#3
Miao Tian, Wentao Yang, Jing Zhang, Huai Dang, Xingyi Lu, Chengjie Fu, Wei Miao
Nonsense-mediated mRNA decay (NMD) is essential for removing premature termination codon-containing transcripts from cells. Studying the NMD pathway in model organisms can help to elucidate the NMD mechanism in humans and improve our understanding of how this biologically important process has evolved. Ciliates are among the earliest branching eukaryotes; their NMD mechanism is poorly understood and may be primordial. We demonstrate that highly conserved Upf proteins (Upf1a, Upf2 and Upf3) are involved in the NMD pathway of the ciliate, Tetrahymena thermophila...
April 11, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28209632/high-resolution-profiling-of-nmd-targets-in-yeast-reveals-translational-fidelity-as-a-basis-for-substrate-selection
#4
Alper Celik, Richard Baker, Feng He, Allan Jacobson
Nonsense-mediated mRNA decay (NMD) plays an important role in eukaryotic gene expression, yet the scope and the defining features of NMD-targeted transcripts remain elusive. To address these issues, we reevaluated the genome-wide expression of annotated transcripts in yeast cells harboring deletions of the UPF1, UPF2, or UPF3 genes. Our new RNA-seq analyses confirm previous results of microarray studies, but also uncover hundreds of new NMD-regulated transcripts that had escaped previous detection, including many intron-containing pre-mRNAs and several noncoding RNAs...
May 2017: RNA
https://www.readbyqxmd.com/read/28008922/atp-hydrolysis-by-upf1-is-required-for-efficient-translation-termination-at-premature-stop-codons
#5
Lucas D Serdar, DaJuan L Whiteside, Kristian E Baker
Nonsense-mediated mRNA decay (NMD) represents a eukaryotic quality control pathway that recognizes and rapidly degrades transcripts harbouring nonsense mutations to limit accumulation of non-functional and potentially toxic truncated polypeptides. A critical component of the NMD machinery is UPF1, an RNA helicase whose ATPase activity is essential for NMD, but for which the precise function and site of action remain unclear. We provide evidence that ATP hydrolysis by UPF1 is required for efficient translation termination and ribosome release at a premature termination codon...
December 23, 2016: Nature Communications
https://www.readbyqxmd.com/read/27769252/genomic-copy-number-variation-association-study-in-caucasian-patients-with-nonsyndromic-cryptorchidism
#6
Yanping Wang, Jin Li, Thomas F Kolon, Alicia Olivant Fisher, T Ernesto Figueroa, Ahmad H BaniHani, Jennifer A Hagerty, Ricardo Gonzalez, Paul H Noh, Rosetta M Chiavacci, Kisha R Harden, Debra J Abrams, Deborah Stabley, Cecilia E Kim, Katia Sol-Church, Hakon Hakonarson, Marcella Devoto, Julia Spencer Barthold
BACKGROUND: Copy number variation (CNV) is a potential contributing factor to many genetic diseases. Here we investigated the potential association of CNV with nonsyndromic cryptorchidism, the most common male congenital genitourinary defect, in a Caucasian population. METHODS: Genome wide genotyping were performed in 559 cases and 1772 controls (Group 1) using Illumina HumanHap550 v1, HumanHap550 v3 or Human610-Quad platforms and in 353 cases and 1149 controls (Group 2) using the Illumina Human OmniExpress 12v1 or Human OmniExpress 12v1-1...
October 21, 2016: BMC Urology
https://www.readbyqxmd.com/read/27221324/nonsense-mediated-mrna-decay-factor-upf2-exists-in-both-the-nucleoplasm-and-the-cytoplasm
#7
Takanori Tatsuno, Yuka Nakamura, Shaofu Ma, Naohisa Tomosugi, Yasuhito Ishigaki
Upf2 protein predominantly localizes to the cytoplasmic fraction, and binds to the exon junction complex (EJC) on spliced mRNA. The present study aimed to determine the cellular site where the interaction between Upf2 and EJC occurs. First, the cell lysate was fractionated into the cytoplasm and nucleoplasm, and western blotting to detect levels of Upf2 protein was performed. Upf2 was clearly detected in the cytoplasm and in the nucleoplasm. Secondly, immunostaining was performed, and the majority of Upf2 was detected in the cytoplasmic perinuclear region; a small quantity of Upf2 was detected in the intranuclear region...
July 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27149259/upf2-dependent-nonsense-mediated-mrna-decay-pathway-is-essential-for-spermatogenesis-by-selectively-eliminating-longer-3-utr-transcripts
#8
Jianqiang Bao, Kristoffer Vitting-Seerup, Johannes Waage, Chong Tang, Ying Ge, Bo T Porse, Wei Yan
During transcription, most eukaryotic genes generate multiple alternative cleavage and polyadenylation (APA) sites, leading to the production of transcript isoforms with variable lengths in the 3' untranslated region (3'UTR). In contrast to somatic cells, male germ cells, especially pachytene spermatocytes and round spermatids, express a distinct reservoir of mRNAs with shorter 3'UTRs that are essential for spermatogenesis and male fertility. However, the mechanisms underlying the enrichment of shorter 3'UTR transcripts in the developing male germ cells remain unknown...
May 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27149095/chromatoid-body-protein-tdrd6-supports-long-3-utr-triggered-nonsense-mediated-mrna-decay
#9
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/26934103/identification-of-interactions-in-the-nmd-complex-using-proximity-dependent-biotinylation-bioid
#10
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
#11
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/26492277/hiv-1-recruits-upf1-but-excludes-upf2-to-promote-nucleocytoplasmic-export-of-the-genomic-rna
#12
Lara Ajamian, Karen Abel, Shringar Rao, Kishanda Vyboh, Francisco García-de-Gracia, Ricardo Soto-Rifo, Andreas E Kulozik, Niels H Gehring, Andrew J Mouland
Unspliced, genomic HIV-1 RNA (vRNA) is a component of several ribonucleoprotein complexes (RNP) during the viral replication cycle. In earlier work, we demonstrated that the host upframeshift protein 1 (UPF1), a key factor in nonsense-mediated mRNA decay (NMD), colocalized and associated to the viral structural protein Gag during viral egress. In this work, we demonstrate a new function for UPF1 in the regulation of vRNA nuclear export. OPEN ACCESS Biomolecules 2015, 5 2809 We establish that the nucleocytoplasmic shuttling of UPF1 is required for this function and demonstrate that UPF1 exists in two essential viral RNPs during the late phase of HIV-1 replication: the first, in a nuclear export RNP that contains Rev, CRM1, DDX3 and the nucleoporin p62, and the second, which excludes these nuclear export markers but contains Gag in the cytoplasm...
October 20, 2015: Biomolecules
https://www.readbyqxmd.com/read/26459599/intranuclear-binding-in-space-and-time-of-exon-junction-complex-and-nxf1-to-premrnps-mrnps-in-vivo
#13
Petra Björk, Jan-Olov Persson, Lars Wieslander
Eukaryotic gene expression requires the ordered association of numerous factors with precursor messenger RNAs (premRNAs)/messenger RNAs (mRNAs) to achieve efficiency and regulation. Here, we use the Balbiani ring (BR) genes to demonstrate the temporal and spatial association of the exon junction complex (EJC) core with gene-specific endogenous premRNAs and mRNAs. The EJC core components bind cotranscriptionally to BR premRNAs during or very rapidly after splicing. The EJC core does not recruit the nonsense-mediated decay mediaters UPF2 and UPF3 until the BR messenger RNA protein complexes (mRNPs) enter the interchromatin...
October 12, 2015: Journal of Cell Biology
https://www.readbyqxmd.com/read/26436458/nonsense-mediated-mrna-decay-degradation-of-defective-transcripts-is-only-part-of-the-story
#14
REVIEW
Feng He, Allan Jacobson
Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance mechanism that monitors cytoplasmic mRNA translation and targets mRNAs undergoing premature translation termination for rapid degradation. From yeasts to humans, activation of NMD requires the function of the three conserved Upf factors: Upf1, Upf2, and Upf3. Here, we summarize the progress in our understanding of the molecular mechanisms of NMD in several model systems and discuss recent experiments that address the roles of Upf1, the principal regulator of NMD, in the initial targeting and final degradation of NMD-susceptible mRNAs...
2015: Annual Review of Genetics
https://www.readbyqxmd.com/read/26130714/a-network-of-smg-8-smg-9-and-smg-1-c-terminal-insertion-domain-regulates-upf1-substrate-recruitment-and-phosphorylation
#15
Aurélien Deniaud, Manikandan Karuppasamy, Thomas Bock, Simonas Masiulis, Karine Huard, Frédéric Garzoni, Kathrin Kerschgens, Matthias W Hentze, Andreas E Kulozik, Martin Beck, Gabriele Neu-Yilik, Christiane Schaffitzel
Mammalian nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance mechanism that degrades mRNAs containing premature translation termination codons. Phosphorylation of the essential NMD effector UPF1 by the phosphoinositide-3-kinase-like kinase (PIKK) SMG-1 is a key step in NMD and occurs when SMG-1, its two regulatory factors SMG-8 and SMG-9, and UPF1 form a complex at a terminating ribosome. Electron cryo-microscopy of the SMG-1-8-9-UPF1 complex shows the head and arm architecture characteristic of PIKKs and reveals different states of UPF1 docking...
September 3, 2015: Nucleic Acids Research
https://www.readbyqxmd.com/read/25744026/caspases-shutdown-nonsense-mediated-mrna-decay-during-apoptosis
#16
J Jia, A Furlan, S Gonzalez-Hilarion, C Leroy, D C Gruenert, D Tulasne, F Lejeune
Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that plays integral roles in eliminating mRNAs with premature termination codons to prevent the synthesis of truncated proteins that could be pathogenic. One response to the accumulation of detrimental proteins is apoptosis, which involves the activation of enzymatic pathways leading to protein and nucleic acid cleavage and culminating in cell death. It is not clear whether NMD is required to ensure the accurate expression of apoptosis genes or is no longer necessary since cytotoxic proteins are not an issue during cell death...
November 2015: Cell Death and Differentiation
https://www.readbyqxmd.com/read/25503407/upf2-a-nonsense-mediated-mrna-decay-factor-is-required-for-prepubertal-sertoli-cell-development-and-male-fertility-by-ensuring-fidelity-of-the-transcriptome
#17
Jianqiang Bao, Chong Tang, Shuiqiao Yuan, Bo T Porse, Wei Yan
Nonsense-mediated mRNA decay (NMD) represents a highly conserved RNA surveillance mechanism through which mRNA transcripts bearing premature termination codons (PTCs) are selectively degraded to maintain transcriptomic fidelity in the cell. Numerous in vitro studies have demonstrated the importance of the NMD pathway; however, evidence supporting its physiological necessity has only just started to emerge. Here, we report that ablation of Upf2, which encodes a core NMD factor, in murine embryonic Sertoli cells (SCs) leads to severe testicular atrophy and male sterility owing to rapid depletion of both SCs and germ cells during prepubertal testicular development...
January 15, 2015: Development
https://www.readbyqxmd.com/read/25446649/nmd-at-the-crossroads-between-translation-termination-and-ribosome-recycling
#18
REVIEW
Alper Celik, Stephanie Kervestin, Allan Jacobson
Nonsense-mediated mRNA decay (NMD) is one of three regulatory mechanisms that monitor the cytoplasm for aberrant mRNAs. NMD is usually triggered by premature translation termination codons that arise from mutations, transcription errors, or inefficient splicing, but which also occur in transcripts with alternately spliced isoforms or upstream open reading frames, or in the context of long 3'-UTRs. This surveillance pathway requires detection of the nonsense codon by the eukaryotic release factors (eRF1 and eRF3) and the activities of the Upf proteins, but the exact mechanism by which a nonsense codon is recognized as premature, and the individual roles of the Upf proteins, are poorly understood...
July 2015: Biochimie
https://www.readbyqxmd.com/read/25310981/3-utr-length-and-messenger-ribonucleoprotein-composition-determine-endocleavage-efficiencies-at-termination-codons
#19
Volker Boehm, Nejc Haberman, Franziska Ottens, Jernej Ule, Niels H Gehring
Nonsense-mediated mRNA decay (NMD) degrades different classes of mRNAs, including transcripts with premature termination codons (PTCs). The NMD factor SMG6 initiates degradation of substrate mRNAs by endonucleolytic cleavage. Here, we aim to delineate the cascade of NMD-activating events that culminate in endocleavage. We report that long 3' UTRs elicit SMG6-mediated endonucleolytic degradation. The presence of an exon-junction complex (EJC) within the 3' UTR strongly stimulates endocleavage in a distance-independent manner...
October 23, 2014: Cell Reports
https://www.readbyqxmd.com/read/25277656/a-highly-conserved-region-essential-for-nmd-in-the-upf2-n-terminal-domain
#20
Zaineb Fourati, Bijoyita Roy, Claudia Millan, Pierre-Damien Coureux, Stéphanie Kervestin, Herman van Tilbeurgh, Feng He, Isabel Usón, Allan Jacobson, Marc Graille
Upf1, Upf2, and Upf3 are the principal regulators of nonsense-mediated mRNA decay (NMD), a cytoplasmic surveillance pathway that accelerates the degradation of mRNAs undergoing premature translation termination. These three proteins interact with each other, the ribosome, the translation termination machinery, and multiple mRNA decay factors, but the precise mechanism allowing the selective detection and degradation of nonsense-containing transcripts remains elusive. Here, we have determined the crystal structure of the N-terminal mIF4G domain from Saccharomyces cerevisiae Upf2 and identified a highly conserved region in this domain that is essential for NMD and independent of Upf2's binding sites for Upf1 and Upf3...
November 11, 2014: Journal of Molecular Biology
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