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nonsense-mediated degradation

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https://www.readbyqxmd.com/read/29348139/dissecting-the-functions-of-smg5-smg7-and-pnrc2-in-nonsense-mediated-mrna-decay-of-human-cells
#1
Pamela Nicholson, Asimina Gkratsou, Christoph Josi, Martino Colombo, Oliver Mühlemann
The term "nonsense-mediated mRNA decay" (NMD) originally described the degradation of mRNAs with premature translation-termination codons (PTCs), but its meaning has recently been extended to be a translation-dependent post-transcriptional regulator of gene expression affecting 3-10 % of all mRNAs. The degradation of NMD target mRNAs involves both exonucleolytic and endonucleolytic pathways in mammalian cells. While the latter is mediated by the endonuclease SMG6, the former pathway has been reported to require a complex of SMG5-SMG7 or SMG5-PNRC2 binding to UPF1...
January 18, 2018: RNA
https://www.readbyqxmd.com/read/29282598/upf-proteins-highly-conserved-factors-involved-in-nonsense-mrna-mediated-decay
#2
REVIEW
Puneet Gupta, Yan-Ruide Li
Over 10% of genetic diseases are caused by mutations that introduce a premature termination codon in protein-coding mRNA. Nonsense-mediated mRNA decay (NMD) is an essential cellular pathway that degrades these mRNAs to prevent the accumulation of harmful partial protein products. NMD machinery is also increasingly appreciated to play a role in other essential cellular functions, including telomere homeostasis and the regulation of normal mRNA turnover, and is misregulated in numerous cancers. Hence, understanding and designing therapeutics targeting NMD is an important goal in biomedical science...
December 27, 2017: Molecular Biology Reports
https://www.readbyqxmd.com/read/29247835/amlexanox-provides-a-potential-therapy-for-nonsense-mutations-in-the-lysosomal-storage-disorder-aspartylglucosaminuria
#3
Antje Banning, Manuel Schiff, Ritva Tikkanen
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by mutations in the gene for aspartylglucosaminidase (AGA). This enzyme participates in glycoprotein degradation in lysosomes. AGU results in progressive mental retardation, and no curative therapy is currently available. We have here characterized the consequences of AGA gene mutations in a compound heterozygous patient who exhibits a missense mutation producing a Ser72Pro substitution in one allele, and a nonsense mutation Trp168X in the other...
December 13, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29236262/studying-nonsense-mediated-mrna-decay-in-mammalian-cells-using-a-multicolored-bioluminescence-based-reporter-system
#4
Andrew Nickless, Zhongsheng You
The nonsense-mediated mRNA decay (NMD) pathway degrades aberrant transcripts containing premature translation termination codons (PTCs) and also regulates the levels of many normal mRNAs containing NMD-inducing features. The activity of this pathway varies considerably in different cell types and can change in response to developmental and environmental cues. Modulating NMD activity represents a potential therapeutic avenue for certain genetic disorders and cancers. Simple reporter systems capable of faithfully assessing NMD activity in mammalian cells greatly facilitate both basic and translational research on NMD...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29167381/crispr-trap-a-clean-approach-for-the-generation-of-gene-knockouts-and-gene-replacements-in-human-cells
#5
Stefan Reber, Jonas Mechtersheimer, Sofia Nasif, Julio Aguila Benitez, Martino Colombo, Michal Domanski, Daniel Jutzi, Eva Hedlund, Marc-David Ruepp
CRISPR/Cas9-based genome editing offers the possibility to knock out (KO) almost any gene of interest in an affordable and simple manner. The most common strategy is the introduction of a frameshift into the open reading frame (ORF) of the target gene which truncates the coding sequence (CDS) and targets the corresponding transcript for degradation by nonsense-mediated mRNA decay (NMD). However, we show that transcripts containing premature termination codons (PTCs) are not always degraded efficiently and can generate C-terminally truncated proteins which might have residual or dominant negative functions...
November 22, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29162348/human-aniridia-limbal-epithelial-cells-lack-expression-of-keratins-k3-and-k12
#6
Lorenz Latta, Arne Viestenz, Tanja Stachon, Sarah Colanesi, Nóra Szentmáry, Berthold Seitz, Barbara Käsmann-Kellner
Patients with aniridia often develop aniridia-related keratopathy (ARK), due to limbal stem cell insufficiency. This study aimed to determine the proliferative capacity and differentiation status of limbal epithelial cells (LECs) in patients with ARK. We also investigated the influences of PAX6 genotype on PAX6-transcript and protein level. Here two patients with aniridia underwent keratoplasty were examined. During the surgery, small limbal biopsies and pannus tissue were excised and processed for cell culture...
November 18, 2017: Experimental Eye Research
https://www.readbyqxmd.com/read/29158530/mrnas-containing-nmd-competent-premature-termination-codons-are-stabilized-and-translated-under-upf1-depletion
#7
Won Kyu Kim, SeongJu Yun, Yujin Kwon, Kwon Tae You, Nara Shin, Jiyoon Kim, Hoguen Kim
mRNAs containing premature termination codons (PTCs) are rapidly degraded through nonsense-mediated mRNA decay (NMD). However, some PTC-containing mRNAs evade NMD, and might generate mutant proteins responsible for various diseases, including cancers. Using PTC-containing human genomic β-globin constructs, we show that a fraction (~30%) of PTC-containing mRNAs expressed from NMD-competent PTC-containing constructs were as stable as their PTC-free counterparts in a steady state. These PTC-containing mRNAs were monosome-enriched and rarely contributed to expression of mutant proteins...
November 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29128743/the-suppression-of-premature-termination-codons-and-the-repair-of-splicing-mutations-in-cftr
#8
REVIEW
Yifat S Oren, Iwona M Pranke, Batsheva Kerem, Isabelle Sermet-Gaudelus
Premature termination codons (PTC) originate from nucleotide substitution introducing an in-frame PTC. They induce truncated, usually non-functional, proteins, degradation of the PTC containing transcripts by the nonsense-mediated decay (NMD) pathway and abnormal exon skipping. Readthrough compounds facilitate near cognate amino-acyl-tRNA incorporation, leading potentially to restoration of a functional full-length protein. Splicing mutations can lead to aberrantly spliced transcripts by creating a cryptic splice site or destroying a normal site...
November 10, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29122854/the-substrates-of-nonsense-mediated-mrna-decay-in-caenorhabditis-elegans
#9
Virginia S Muir, Audrey P Gasch, Philip Anderson
Nonsense-mediated mRNA decay (NMD) is a conserved pathway that strongly influences eukaryotic gene expression.  Inactivating or inhibiting NMD affects the abundance of a substantial fraction of the transcriptome in numerous species.  Transcripts whose abundance is altered in NMD-deficient cells may represent either direct substrates of NMD or indirect effects of inhibiting NMD.  We present a genome-wide investigation of the direct substrates of NMD in Caenorhabditis elegans  Our goals were (i) to identify mRNA substrates of NMD and (ii) to distinguish those mRNAs from others whose abundance is indirectly influenced by the absence of NMD...
November 9, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29106929/gentamicin-induced-readthrough-and-nonsense-mediated-mrna-decay-of-serpinb7-nonsense-mutant-transcripts
#10
Yuka Ohguchi, Toshifumi Nomura, Shotaro Suzuki, Masae Takeda, Toshinari Miyauchi, Osamu Mizuno, Satoru Shinkuma, Yasuyuki Fujita, Osamu Nemoto, Kota Ono, W H Irwin McLean, Hiroshi Shimizu
Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive skin disorder with a high, unmet medical need that is caused by mutations in SERPINB7. Almost all NPPK patients carry the founder nonsense mutation c.796C>T (p.Arg266Ter) in the last exon of SERPINB7. Here we sought to determine whether topical "nonsense-suppression (readthrough)" therapy using gentamicin is applicable to NPPK. First, we demonstrated that gentamicin enhanced readthrough activity in cells transfected with SERPINB7 cDNA carrying the mutation and promoted full-length SERPINB7 protein synthesis in NPPK keratinocytes...
October 26, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29080838/the-smn1-common-variant-c-22-dupa-in-chinese-patients-causes-spinal-muscular-atrophy-by-nonsense-mediated-mrna-decay-in-humans
#11
Bai JinLi, Qu YuJin, Cao YanYan, Yang Lan, Ge Lin, Jin YuWei, Wang Hong, Song Fang
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is mostly caused by homozygous deletion of the SMN1 gene. Approximately 5%-10% of SMA patients are believed to have SMN1 variants. c.22 dupA (p.Ser8lysfs*23) has been identified as the most frequent variant in the Chinese SMA population and to be associated with a severe phenotype. However, the exact molecular mechanism of the variant on the pathogenesis of SMA is unclear. We observed that SMN1 mRNA and the SMN protein in the peripheral blood cells of a patient with c...
October 25, 2017: Gene
https://www.readbyqxmd.com/read/29077258/whole-exome-sequencing-identifies-a-novel-mutation-of-gpd1l-r189x-associated-with-familial-conduction-disease-and-sudden-death
#12
Hao Huang, Ya-Qin Chen, Liang-Liang Fan, Shuai Guo, Jing-Jing Li, Jie-Yuan Jin, Rong Xiang
Cardiac conduction disease (CCD) is a serious disorder and the leading cause of mortality worldwide. It is characterized by arrhythmia, syncope or even sudden cardiac death caused by the dysfunction of cardiac voltage-gated channel. Previous study has demonstrated that mutations in genes encoding voltage-gated channel and related proteins were the crucial genetic lesion of CCD. In this study, we employed whole-exome sequencing to explore the potential causative genes in a Chinese family with ventricular tachycardia and syncope...
October 27, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29058182/nonsense-mediated-mrna-decay-of-herg-mutations-in-long-qt-syndrome
#13
Qiuming Gong, Zhengfeng Zhou
Long QT syndrome type 2 (LQT2) is caused by mutations in the human ether-à-go-go related gene (hERG), which encodes the Kv11.1 potassium channel in the heart. Over 30% of identified LQT2 mutations are nonsense or frameshift mutations that introduce premature termination codons (PTCs). Contrary to intuition, the predominant consequence of LQT2 nonsense and frameshift mutations is not the production of truncated proteins, but rather the degradation of mutant mRNA by nonsense-mediated mRNA decay (NMD), an RNA surveillance mechanism that selectively eliminates the mRNA transcripts that contain PTCs...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29046474/human-alternative-klotho-mrna-is-a-nonsense-mediated-mrna-decay-target-inefficiently-spliced-in-renal-disease
#14
Rik Mencke, Geert Harms, Jill Moser, Matijs van Meurs, Arjan Diepstra, Henri G Leuvenink, Jan-Luuk Hillebrands
Klotho is a renal protein involved in phosphate homeostasis, which is downregulated in renal disease. It has long been considered an antiaging factor. Two Klotho gene transcripts are thought to encode membrane-bound and secreted Klotho. Indeed, soluble Klotho is detectable in bodily fluids, but the relative contributions of Klotho secretion and of membrane-bound Klotho shedding are unknown. Recent advances in RNA surveillance reveal that premature termination codons, as present in alternative Klotho mRNA (for secreted Klotho), prime mRNAs for degradation by nonsense-mediated mRNA decay (NMD)...
October 19, 2017: JCI Insight
https://www.readbyqxmd.com/read/29038333/germ-granule-mediated-rna-regulation-in-male-germ-cells
#15
Tiina Lehtiniemi, Noora Kotaja
Germ cells have exceptionally diverse transcriptomes. Furthermore, the progress of spermatogenesis is accompanied by dramatic changes in gene expression patterns, the most drastic of them being near-to-complete transcriptional silencing during the final steps of differentiation. Therefore, accurate RNA regulatory mechanisms are critical for normal spermatogenesis. Cytoplasmic germ cell-specific ribonucleoprotein (RNP) granules, known as germ granules, participate in posttranscriptional regulation in developing male germ cells...
October 16, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/28984438/engineering-the-genetic-code-in-cells-and-animals-biological-considerations-and-impacts
#16
Lei Wang
Expansion of the genetic code allows unnatural amino acids (Uaas) to be site-specifically incorporated into proteins in live biological systems, thus enabling novel properties selectively introduced into target proteins in vivo for basic biological studies and for engineering of novel biological functions. Orthogonal components including tRNA and aminoacyl-tRNA synthetase (aaRS) are expressed in live cells to decode a unique codon (often the amber stop codon UAG) as the desired Uaa. Initially developed in E...
November 21, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28983119/the-gbap1-pseudogene-acts-as-a-cerna-for-the-glucocerebrosidase-gene-gba-by-sponging-mir-22-3p
#17
Letizia Straniero, Valeria Rimoldi, Maura Samarani, Stefano Goldwurm, Alessio Di Fonzo, Rejko Krüger, Michela Deleidi, Massimo Aureli, Giulia Soldà, Stefano Duga, Rosanna Asselta
Mutations in the GBA gene, encoding lysosomal glucocerebrosidase, represent the major predisposing factor for Parkinson's disease (PD), and modulation of the glucocerebrosidase activity is an emerging PD therapy. However, little is known about mechanisms regulating GBA expression. We explored the existence of a regulatory network involving GBA, its expressed pseudogene GBAP1, and microRNAs. The high level of sequence identity between GBA and GBAP1 makes the pseudogene a promising competing-endogenous RNA (ceRNA), functioning as a microRNA sponge...
October 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28950212/p-val19glyfs-21-and-p-leu228-variants-in-the-survival-of-motor-neuron-1-trigger-nonsense-mediated-mrna-decay-causing-the-smn1-ptc-transcripts-degradation
#18
Yu-Jin Qu, Lin Ge, Jin-Li Bai, Yan-Yan Cao, Yu-Wei Jin, Hong Wang, Lan Yang, Fang Song
Spinal Muscular Atrophy (SMA) results from loss-of-function mutations in the survival of motor neuron 1 (SMN1) gene. Our previous research showed that 40% of variants were nonsense or frameshift variants and SMN1 mRNA levels in the patients carrying these variants were significantly decreased. Here we selected one rare variant (p.Val19Glyfs*21) and one common variant (p.Leu228*) to explore the degradation mechanism of mutant transcripts. The levels of full-length (FL)-SMN1 transcripts and SMN protein in the cell lines from the patients with these variants were both significantly reduced (p<0...
September 15, 2017: Mutation Research
https://www.readbyqxmd.com/read/28948974/a-upf3b-mutant-mouse-model-with-behavioral-and-neurogenesis-defects
#19
L Huang, E Y Shum, S H Jones, C-H Lou, J Dumdie, H Kim, A J Roberts, L A Jolly, J L Espinoza, D M Skarbrevik, M H Phan, H Cook-Andersen, N R Swerdlow, J Gecz, M F Wilkinson
Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, cause intellectual disability (ID) and are strongly associated with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ)...
September 26, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28929622/endonuclease-regnase-1-monocyte-chemotactic-protein-1-induced-protein-1-mcpip1-in-controlling-immune-responses-and-beyond
#20
REVIEW
Osamu Takeuchi
The activation of inflammatory cells is controlled at transcriptional and posttranscriptional levels. Posttranscriptional regulation modifies mRNA stability and translation, allowing for elaborate control of proteins required for inflammation, such as proinflammatory cytokines, prostaglandin synthases, cell surface co-stimulatory molecules, and even transcriptional modifiers. Such regulation is important for coordinating the initiation and resolution of inflammation, and is mediated by a set of RNA-binding proteins (RBPs), including Regnase-1, Roquin, Tristetraprolin (TTP), and AU-rich elements/poly(U)-binding/degradation factor 1 (AUF1)...
September 20, 2017: Wiley Interdisciplinary Reviews. RNA
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