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https://www.readbyqxmd.com/read/28669802/the-rna-surveillance-factor-upf1-represses-myogenesis-via-its-e3%C3%A2-ubiquitin-ligase-activity
#1
Qing Feng, Sujatha Jagannathan, Robert K Bradley
UPF1 is an RNA helicase that orchestrates nonsense-mediated decay and other RNA surveillance pathways. While UPF1 is best known for its basal cytoprotective role in degrading aberrant RNAs, UPF1 also degrades specific, normally occurring mRNAs to regulate diverse cellular processes. Here we describe a role for UPF1 in regulated protein decay, wherein UPF1 acts as an E3 ubiquitin ligase to repress human skeletal muscle differentiation. Suppressing UPF1 accelerates myogenesis, while ectopically increasing UPF1 levels slows myogenesis...
July 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28651017/crystal-structure-of-middle-east-respiratory-syndrome-coronavirus-helicase
#2
Wei Hao, Justyna Aleksandra Wojdyla, Rong Zhao, Ruiyun Han, Rajat Das, Ivan Zlatev, Muthiah Manoharan, Meitian Wang, Sheng Cui
Middle East respiratory syndrome coronavirus (MERS-CoV) remains a threat to public health worldwide; however, effective vaccine or drug against CoVs remains unavailable. CoV helicase is one of the three evolutionary most conserved proteins in nidoviruses, thus making it an important target for drug development. We report here the first structure of full-length coronavirus helicase, MERS-CoV nsp13. MERS-CoV helicase has multiple domains, including an N-terminal Cys/His rich domain (CH) with three zinc atoms, a beta-barrel domain and a C-terminal SF1 helicase core with two RecA-like subdomains...
June 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28648842/pnrc2-regulates-3-utr-mediated-decay-of-segmentation-clock-associated-transcripts-during-zebrafish-segmentation
#3
Thomas L Gallagher, Kiel T Tietz, Zachary T Morrow, Jasmine M McCammon, Michael L Goldrich, Nicolas L Derr, Sharon L Amacher
Vertebrate segmentation is controlled by the segmentation clock, a molecular oscillator that regulates gene expression and cycles rapidly. The expression of many genes oscillates during segmentation, including hairy/Enhancer of split-related (her or Hes) genes, which encode transcriptional repressors that auto-inhibit their own expression, and deltaC (dlc), which encodes a Notch ligand. We previously identified the tortuga (tor) locus in a zebrafish forward genetic screen for genes involved in cyclic transcript regulation and showed that cyclic transcripts accumulate post-splicing in tor mutants...
June 23, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28600326/up-frameshift-protein-upf1-regulates-neurospora-crassa-circadian-and-diurnal-growth-rhythms
#4
Yilan Wu, Yin Zhang, Yunpeng Sun, Jiali Yu, Peiliang Wang, Huan Ma, Shijunyin Chen, Lizhen Ma, Dongyang Zhang, Qun He, Jinhu Guo
Nonsense-mediated RNA decay (NMD) is a crucial post-transcriptional regulatory mechanism that recognizes and eliminates aberrantly processed transcripts, and mediates the expression of normal gene transcripts. In this study, we report that in the filamentous fungus Neurospora crassa, the NMD factors play a conserved role in regulating the surveillance of NMD targets including PTC-containing transcripts and normal transcripts. The circadian rhythms in all of the upf1-3 knockout strains, which are principle NMD factors, were aberrant...
June 9, 2017: Genetics
https://www.readbyqxmd.com/read/28554132/the-human-rna-surveillance-factor-up-frameshift-1-inhibits-hepatic-cancer-progression-by-targeting-mrp2-abcc2
#5
Hai Zhang, Yina You, Zhongliang Zhu
Although the roles of Up-frameshift 1 (UPF1) in hepatocellular carcinoma (HCC) have been partly revealed, the detailed mechanisms remain poorly understood. Here, quantitative real-time PCR (qRT-PCR) and immunohistochemistry assays indicated that UPF1 expression was decreased in HCC tissues compared to the corresponding adjacent tissues, and was negatively correlated with MRP2/ABCC2 expression. Cell viability and apoptosis analyses showed that overexpression of UPF1 enhanced HCC cell sensitivity to sorafenib treatment, while knockdown of UPF1 decreased the sensitivity...
August 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28541562/dna-substrate-recognition-and-processing-by-the-full-length-human-upf1-helicase
#6
Saba Dehghani-Tafti, Cyril M Sanders
UPF1 is a conserved helicase required for nonsense-mediated decay (NMD) regulating mRNA stability in the cytoplasm. Human UPF1 (hUPF1) is also needed for nuclear DNA replication. While loss of NMD is tolerated, loss of hUPF1 induces a DNA damage response and cell cycle arrest. We have analysed nucleic acid (NA) binding and processing by full-length hUPF1. hUPF1 unwinds non-B and B-form DNA and RNA substrates in vitro. Unlike many helicases involved in genome stability no hUPF1 binding to DNA structures stabilized by inter-base-pair hydrogen bonding was observed...
May 24, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28539120/comprehensive-whole-genome-sequence-analyses-yields-novel-genetic-and-structural-insights-for-intellectual-disability
#7
Farah R Zahir, Jill C Mwenifumbo, Hye-Jung E Chun, Emilia L Lim, Clara D M Van Karnebeek, Madeline Couse, Karen L Mungall, Leora Lee, Nancy Makela, Linlea Armstrong, Cornelius F Boerkoel, Sylvie L Langlois, Barbara M McGillivray, Steven J M Jones, Jan M Friedman, Marco A Marra
BACKGROUND: Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients. METHODS: We conducted WGS on eight children with idiopathic ID and brain structural defects, and their normal parents; carrying out an extensive data analyses, using standard and discovery approaches...
May 24, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28536849/nmd-monitors-translational-fidelity-24-7
#8
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/28483531/crucial-role-of-atp-bound-sse1-in-upf1-dependent-degradation-of-the-truncated-product
#9
Takato Sugiyama, Risa Nobuta, Koji Ando, Yasuko Matsuki, Toshifumi Inada
Up-frameshift (Upf) complex facilitates the degradation of aberrant mRNAs containing a premature termination codon (PTC) and its products in yeast. Here we report that Sse1, a member of the Hsp110 family, and Hsp70 play a crucial role in Upf-dependent degradation of the truncated FLAG-Pgk1-300 protein derived from PGK1 mRNA harboring a PTC at codon position 300. Sse1 was required for Upf-dependent rapid degradation of the FLAG-Pgk1-300. FLAG-Pgk1-300 was significantly destabilized in ATP hydrolysis defective sse1-1 mutant cells than in wild type cells...
June 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28461625/transcript-specific-characteristics-determine-the-contribution-of-endo-and-exonucleolytic-decay-pathways-during-the-degradation-of-nonsense-mediated-decay-substrates
#10
Franziska Ottens, Volker Boehm, Christopher R Sibley, Jernej Ule, Niels H Gehring
Nonsense-mediated mRNA decay (NMD) controls gene expression by eliminating mRNAs with premature or aberrant translation termination. Degradation of NMD substrates is initiated by the central NMD factor UPF1, which recruits the endonuclease SMG6 and the deadenylation-promoting SMG5/7 complex. The extent to which SMG5/7 and SMG6 contribute to the degradation of individual substrates and their regulation by UPF1 remain elusive. Here we map transcriptome-wide sites of SMG6-mediated endocleavage via 3' fragment capture and degradome sequencing...
May 1, 2017: RNA
https://www.readbyqxmd.com/read/28444146/nonsense-in-the-testis-multiple-roles-for-nonsense-mediated-decay-revealed-in-male-reproduction
#11
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/28408439/sen1-has-unique-structural-features-grafted-on-the-architecture-of-the-upf1-like-helicase-family
#12
Bronislava Leonaitė, Zhong Han, Jérôme Basquin, Fabien Bonneau, Domenico Libri, Odil Porrua, Elena Conti
The superfamily 1B (SF1B) helicase Sen1 is an essential protein that plays a key role in the termination of non-coding transcription in yeast. Here, we identified the ~90 kDa helicase core of Saccharomyces cerevisiae Sen1 as sufficient for transcription termination in vitro and determined the corresponding structure at 1.8 Å resolution. In addition to the catalytic and auxiliary subdomains characteristic of the SF1B family, Sen1 has a distinct and evolutionarily conserved structural feature that "braces" the helicase core...
June 1, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28337468/comparative-analysis-data-of-sf1-and-sf2-helicases-from-three-domains-of-life
#13
Wafi Chaar, Hiba Ibrahim, Juliana Kozah, Hala Chamieh
SF1 and SF2 helicases are important molecular motors that use the energy of ATP to unwind nucleic acids or nucleic-acid protein complexes. They are ubiquitous enzymes and found in almost all organisms sequenced to date. This article provides a comparative analysis for SF1 and SF2 helicase families from three domains of life archaea, human, bacteria. Seven families are conserved in these three representatives and includes Upf1-like, UvrD-like, Rad3-like, DEAD-box, RecQ-like. Snf2 and Ski2-like. The data highlight conservation of the helicase core motifs for each of these families...
April 2017: Data in Brief
https://www.readbyqxmd.com/read/28276441/rna-surveillance-via-nonsense-mediated-mrna-decay-is-crucial-for-longevity-in-daf-2-insulin-igf-1-mutant-c-elegans
#14
Heehwa G Son, Mihwa Seo, Seokjin Ham, Wooseon Hwang, Dongyeop Lee, Seon Woo A An, Murat Artan, Keunhee Seo, Rachel Kaletsky, Rachel N Arey, Youngjae Ryu, Chang Man Ha, Yoon Ki Kim, Coleen T Murphy, Tae-Young Roh, Hong Gil Nam, Seung-Jae V Lee
Long-lived organisms often feature more stringent protein and DNA quality control. However, whether RNA quality control mechanisms, such as nonsense-mediated mRNA decay (NMD), which degrades both abnormal as well as some normal transcripts, have a role in organismal aging remains unexplored. Here we show that NMD mediates longevity in C. elegans strains with mutations in daf-2/insulin/insulin-like growth factor 1 receptor. We find that daf-2 mutants display enhanced NMD activity and reduced levels of potentially aberrant transcripts...
March 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28261246/possible-role-of-mads-affecting-flowering-3-and-b-box-domain-protein-19-in-flowering-time-regulation-of-arabidopsis-mutants-with-defects-in-nonsense-mediated-mrna-decay
#15
Zeeshan Nasim, Muhammad Fahim, Ji Hoon Ahn
Eukaryotic cells use nonsense-mediated mRNA decay (NMD) to clear aberrant mRNAs from the cell, thus preventing the accumulation of truncated proteins. In Arabidopsis, two UP-Frameshift (UPF) proteins, UPF1 and UPF3, play a critical role in NMD. Although deficiency of UPF1 and UPF3 leads to various developmental defects, little is known about the mechanism underlying the regulation of flowering time by NMD. Here, we showed that the upf1-5 and upf3-1 mutants had a late-flowering phenotype under long-day conditions and the upf1-5 upf3-1 double mutants had an additive effect in delaying flowering time...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28224650/androgen-receptor-splice-variants-are-not-substrates-of-nonsense-mediated-decay
#16
Atinuke S Ajiboye, David Esopi, Srinivasan Yegnasubramanian, Samuel R Denmeade
BACKGROUND: Androgen receptor (AR) splice variants have been clinically associated with progressive cancer, castration-resistance, and resistance to AR antagonists and androgen synthesis inhibitors. AR variants can be generated by genomic alterations and alternative splicing, and their expression is androgen-regulated. There has been a suggestion that AR variants bearing premature termination codons and coding for truncated proteins should be regulated by the nonsense-mediated decay (NMD) mRNA surveillance pathway, suggesting that either the NMD pathway is dysfunctional in variant-expressing cell lines or that variants are somehow able to evade degradation by NMD...
June 2017: Prostate
https://www.readbyqxmd.com/read/28209632/high-resolution-profiling-of-nmd-targets-in-yeast-reveals-translational-fidelity-as-a-basis-for-substrate-selection
#17
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/28194024/regnase-1-a-rapid-response-ribonuclease-regulating-inflammation-and-stress-responses
#18
REVIEW
Renfang Mao, Riyun Yang, Xia Chen, Edward W Harhaj, Xiaoying Wang, Yihui Fan
RNA-binding proteins (RBPs) are central players in post-transcriptional regulation and immune homeostasis. The ribonuclease and RBP Regnase-1 exerts critical roles in both immune cells and non-immune cells. Its expression is rapidly induced under diverse conditions including microbial infections, treatment with inflammatory cytokines and chemical or mechanical stimulation. Regnase-1 activation is transient and is subject to negative feedback mechanisms including proteasome-mediated degradation or mucosa-associated lymphoid tissue 1 (MALT1) mediated cleavage...
May 2017: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/28128343/rna-sequencing-of-synaptic-and-cytoplasmic-upf1-bound-transcripts-supports-contribution-of-nonsense-mediated-decay-to-epileptogenesis
#19
Claire M Mooney, Eva M Jimenez-Mateos, Tobias Engel, Catherine Mooney, Mairead Diviney, Morten T Venø, Jørgen Kjems, Michael A Farrell, Donncha F O'Brien, Norman Delanty, David C Henshall
The nonsense mediated decay (NMD) pathway is a critical surveillance mechanism for identifying aberrant mRNA transcripts. It is unknown, however, whether the NMD system is affected by seizures in vivo and whether changes confer beneficial or maladaptive responses that influence long-term outcomes such the network alterations that produce spontaneous recurrent seizures. Here we explored the responses of the NMD pathway to prolonged seizures (status epilepticus) and investigated the effects of NMD inhibition on epilepsy in mice...
January 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28008922/atp-hydrolysis-by-upf1-is-required-for-efficient-translation-termination-at-premature-stop-codons
#20
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
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