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Nonsense suppression

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https://www.readbyqxmd.com/read/28765281/p38-mapk-inhibits-nonsense-mediated-rna-decay-in-response-to-persistent-dna-damage-in-non-cycling-cells
#1
Andrew Nickless, Abigael Cheruiyot, Kevin C Flanagan, David Piwnica-Worms, Sheila A Stewart, Zhongsheng You
Persistent DNA damage induces profound alterations in gene expression, which in turn influence tissue homeostasis, tumorigenesis, and cancer treatment outcome. However, the underlying mechanism for the gene expression reprogramming induced by persistent DNA damage remains poorly understood. Here, using a highly effective bioluminescence-based reporter system and other tools, we report that persistent DNA damage inhibits nonsense-mediated RNA decay (NMD), an RNA surveillance and gene-regulatory pathway, in noncycling cells...
August 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28754723/a-functional-link-between-bir1-and-the-saccharomyces-cerevisiae-ctf19-kinetochore-complex-revealed-through-quantitative-fitness-analysis
#2
Vasso Makrantoni, Adam Ciesiolka, Conor Lawless, Josefin Fernius, Adele Marston, David Lydall, Michael J R Stark
The chromosomal passenger complex (CPC) is a key regulator of eukaryotic cell division, consisting of the protein kinase Aurora B/Ipl1 in association with its activator (INCENP/Sli15) and two additional proteins (Survivin/Bir1 and Borealin/Nbl1). Here we report a genome-wide genetic interaction screen in Saccharomyces cerevisiae using the bir1-17 mutant, identifying through quantitative fitness analysis deletion mutations that act as enhancers and suppressors. Gene knockouts affecting the Ctf19 kinetochore complex were identified as the strongest enhancers of bir1-17, while mutations affecting the large ribosomal subunit or the mRNA nonsense-mediated decay (NMD) pathway caused strong phenotypic suppression...
July 28, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28716950/analysis-of-small-critical-regions-of-swi1-conferring-prion-formation-maintenance-and-transmission
#3
Stephanie Valtierra, Zhiqiang Du, Liming Li
Saccharomyces cerevisiae contains several prion elements, which are epigenetically transmitted as self-perpetuating protein conformations. One such prion is [SWI(+) ], whose protein determinant is Swi1, a subunit of the SWI/SNF chromatin-remodeling complex. We previously reported that [SWI(+) ] formation results in a partial loss-of-function phenotype of poor growth in non-glucose media and abolishment of multicellularity. We also showed that the first 38 amino acids of Swi1 propagated [SWI(+)]. We show here that a region as small as the first 32 amino acids of Swi1 (Swi11-32) can decorate [SWI(+)] aggregation and stably maintain and transmit [SWI(+)] independently of full-length Swi1...
July 17, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28715844/effects-of-pathogenic-variations-in-the-human-rhodopsin-gene-hrho-on-the-predicted-accessibility-for-a-lead-candidate-ribozyme
#4
Beau R Froebel, Alexandria J Trujillo, Jack M Sullivan
Purpose: The mutation-independent strategy for hammerhead ribozyme (hhRz) or RNA interference (RNAi)-based gene therapeutics to treat autosomal dominant diseases is predicated on the hypothesis that a single therapeutic would equivalently suppress all/most of the diverse mutant mRNAs in patients with the disease phenotype. However, the hypothesis has not been formally tested. We address this through a comprehensive bioinformatics study of how mutations affect target mRNA structure accessibility for a single lead hhRz therapeutic (725GUC↓), designed against human rod rhodopsin mRNA (hRHO), for patients with hRHO mutations that cause autosomal dominant retinitis pigmentosa...
July 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28691931/gentamicin-induces-functional-type-vii-collagen-in-recessive-dystrophic-epidermolysis-bullosa-patients
#5
David T Woodley, Jon Cogan, Yingping Hou, Chao Lyu, M Peter Marinkovich, Douglas Keene, Mei Chen
BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease caused by mutations in the gene encoding type VII collagen, the major component of anchoring fibrils (AF). We previously demonstrated that gentamicin produced functional type VII collagen in RDEB cells harboring nonsense mutations. Herein, we determined whether topical or intradermal gentamicin administration induces type VII collagen and AFs in RDEB patients. METHODS: A double-blind, placebo-controlled pilot trial assessed safety and efficacy of topical and intradermal gentamicin in 5 RDEB patients with nonsense mutations...
August 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28688851/characterization-of-the-dominant-inheritance-mechanism-of-episodic-ataxia-type-2
#6
Kevin Dorgans, Julie Salvi, Federica Bertaso, Ludivine Bernard, Philippe Lory, Frederic Doussau, Alexandre Mezghrani
Episodic Ataxia type 2 (EA2) is an autosomal dominant neuronal disorder linked to mutations in the Cav2.1 subunit of P/Q-type calcium channels. In vitro studies have established that EA2 mutations induce loss of channel activity and that EA2 mutants can exert a dominant negative effect, suppressing normal Cav2.1 activity through protein misfolding and trafficking defects. To date, the role of this mechanism in the disease pathogenesis is unknown because no animal model exists. To address this issue, we have generated a mouse bearing the R1497X nonsense mutation in Cav2...
July 5, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28669802/the-rna-surveillance-factor-upf1-represses-myogenesis-via-its-e3%C3%A2-ubiquitin-ligase-activity
#7
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/28663100/a-new-aav10-u7-mediated-gene-therapy-prolongs-survival-and-restores-function-in-an-als-mouse-model
#8
Maria Grazia Biferi, Mathilde Cohen-Tannoudji, Ambra Cappelletto, Benoit Giroux, Marianne Roda, Stéphanie Astord, Thibaut Marais, Corinne Bos, Thomas Voit, Arnaud Ferry, Martine Barkats
One of the most promising therapeutic approaches for familial amyotrophic lateral sclerosis linked to superoxide dismutase 1 (SOD1) is the suppression of toxic mutant SOD1 in the affected tissues. Here, we report an innovative molecular strategy for inducing substantial, widespread, and sustained reduction of mutant human SOD1 (hSOD1) levels throughout the body of SOD1(G93A) mice, leading to therapeutic effects in animals. Adeno-associated virus serotype rh10 vectors (AAV10) were used to mediate exon skipping of the hSOD1 pre-mRNA by expression of exon-2-targeted antisense sequences embedded in a modified U7 small-nuclear RNA (AAV10-U7-hSOD)...
June 26, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28652967/neural-circuit-of-verbal-humor-comprehension-in-schizophrenia-an-fmri-study
#9
Przemysław Adamczyk, Miroslaw Wyczesany, Aleksandra Domagalik, Artur Daren, Kamil Cepuch, Piotr Błądziński, Andrzej Cechnicki, Tadeusz Marek
Individuals with schizophrenia exhibit problems with understanding the figurative meaning of language. This study evaluates neural correlates of diminished humor comprehension observed in schizophrenia. The study included chronic schizophrenia (SCH) outpatients (n = 20), and sex, age and education level matched healthy controls (n = 20). The fMRI punchline based humor comprehension task consisted of 60 stories of which 20 had funny, 20 nonsensical and 20 neutral (not funny) punchlines. After the punchlines were presented, the participants were asked to indicate whether the story was comprehensible and how funny it was...
2017: NeuroImage: Clinical
https://www.readbyqxmd.com/read/28624217/efficacy-of-postnatal-in%C3%A2-vivo-nonsense-suppression-therapy-in-a-pax6-mouse-model-of-aniridia
#10
Xia Wang, Kevin Gregory-Evans, Kishor M Wasan, Olena Sivak, Xianghong Shan, Cheryl Y Gregory-Evans
Nonsense mutations leading to premature stop codons are common occurring in approximately 12% of all human genetic diseases. Thus, pharmacological nonsense mutation suppression strategies would be beneficial to a large number of patients if the drugs could be targeted to the affected tissues at the appropriate time. Here, we used nonsense suppression to manipulate Pax6 dosage at different developmental times in the eye of the small eye (Pax6(Sey/+); G194X) mouse model of aniridia. Efficacy was assessed by functional assays for visual capacity, including electroretinography and optokinetic tracking (OKT), in addition to histological and biochemical studies...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28598868/pax6-aniridia-syndrome-clinics-genetics-and-therapeutics
#11
Hyun Taek Lim, Dae Hee Kim, Hyuna Kim
PURPOSE OF REVIEW: Aniridia is a rare and panocular disorder affecting most of the ocular structures which may have significant impact on vision. The purpose of this review is to describe the clinical features, genetics, and therapeutic options for this disease and to provide an update of current knowledge and latest research findings. RECENT FINDINGS: Aside from the ocular features, a variety of associated systemic abnormalities, including hormonal, metabolic, gastrointestinal, genitourinary, and neurologic pathologies have been reported in children with aniridia...
September 2017: Current Opinion in Ophthalmology
https://www.readbyqxmd.com/read/28575328/identification-of-the-amino-acids-inserted-during-suppression-of-cftr-nonsense-mutations-and-determination-of-their-functional-consequences
#12
Xiaojiao Xue, Venkateshwar Mutyam, Amita Thakerar, James Mobley, Robert J Bridges, Steven M Rowe, Kim M Keeling, David M Bedwell
In-frame premature termination codons (PTCs) account for ∼11% of all disease-associated mutations. PTC suppression therapy utilizes small molecules that suppress translation termination at a PTC to restore synthesis of a full-length protein. PTC suppression is mediated by the base pairing of a near-cognate aminoacyl-tRNA with a PTC and subsequently, the amino acid becomes incorporated into the nascent polypeptide at the site of the PTC. However, little is known about the identity of the amino acid(s) inserted at a PTC during this process in mammalian cells, or how the surrounding sequence context influences amino acid incorporation...
May 31, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28554132/the-human-rna-surveillance-factor-up-frameshift-1-inhibits-hepatic-cancer-progression-by-targeting-mrp2-abcc2
#13
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/28552050/readthrough-of-scn5a-nonsense-mutations-r1623x-and-s1812x-question-gene-therapy-in-brugada-syndrome
#14
Siyong Teng, Jian Huang, Zhan Gao, Jie Hao, Yuejin Yang, Shu Zhang, Jielin Pu, Rutai Hui, Yongjian Wu, Zheng Fan
PURPOSE: Readthrough of nonsense mutation are used as gene-specific treatment in some genetic disease. Response to readthrough treatment is determined by readthrough efficiency of various nonsense mutations. In this manuscript, we aimed to explore the harmful effect of nonsense mutation suppressions. METHODS: HEK293 cells were transfected with two SCN5A (encode cardiac Na+ channel) nonsense mutations, p.R1623X and p.S1812X. We applied two readthrough-enhancing methods (either aminoglycosides or by a siRNA targeting eukaryotic release factor eRF3a (a GTPase that binds eRF1)) to suppress these SCN5A nonsense mutations...
May 28, 2017: Current Gene Therapy
https://www.readbyqxmd.com/read/28539829/multifaceted-regulation-of-gene-expression-by-the-apoptosis-and-splicing-associated-protein-complex-and-its-components
#15
REVIEW
Bhagyashree Deka, Kusum Kumari Singh
The differential deposition of RNA-binding proteins (RBPs) on pre-mRNA mediates the processes of gene expression. One of the complexes containing RBPs that play a crucial part in RNA metabolism is the apoptosis-and splicing-associated protein (ASAP) complex. In this review, we present a summary of the structure of ASAP complex and its localization. Also, we discuss the findings by different groups on various functions of the subunits of the ASAP complex in RNA metabolism. The subunits of the ASAP complex are RNPS1, Acinus and SAP18...
2017: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/28464005/a-tailored-mouse-model-of-cln2-disease-a-nonsense-mutant-for-testing-personalized-therapies
#16
Ryan D Geraets, Logan M Langin, Jacob T Cain, Camille M Parker, Rosanna Beraldi, Attila D Kovacs, Jill M Weimer, David A Pearce
The Neuronal Ceroid Lipofuscinoses (NCLs), also known as Batten disease, result from mutations in over a dozen genes. Although, adults are susceptible, the NCLs are frequently classified as pediatric neurodegenerative diseases due to their greater pediatric prevalence. Initial clinical presentation usually consists of either seizures or retinopathy but develops to encompass both in conjunction with declining motor and cognitive function. The NCLs result in premature death due to the absence of curative therapies...
2017: PloS One
https://www.readbyqxmd.com/read/28440616/discovery-and-characterization-of-a-eukaryotic-initiation-factor-4a-3-selective-inhibitor-that-suppresses-nonsense-mediated-mrna-decay
#17
Misa Iwatani-Yoshihara, Masahiro Ito, Yoshihiro Ishibashi, Hideyuki Oki, Toshio Tanaka, Daisuke Morishita, Takashi Ito, Hiromichi Kimura, Yasuhiro Imaeda, Samuel Aparicio, Atsushi Nakanishi, Tomohiro Kawamoto
Eukaryotic initiation factor 4A-3 (eIF4A3) is an Asp-Glu-Ala-Asp (DEAD) box-family adenosine triphosphate (ATP)-dependent RNA helicase. Subtypes eIF4A1 and eIF4A2 are required for translation initiation, but eIF4A3 participates in the exon junction complex (EJC) and functions in RNA metabolism including nonsense-mediated RNA decay (NMD). No small molecules for NMD inhibition via selective inhibition of eIF4A3 have been discovered. Here, we identified allosteric eIF4A3 inhibitors from a high-throughput screening campaign...
May 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28432296/aminoglycosides-but-not-ptc124-ataluren-rescue-nonsense-mutations-in-the-leptin-receptor-and-in-luciferase-reporter-genes
#18
Florian Bolze, Sabine Mocek, Anika Zimmermann, Martin Klingenspor
In rare cases, monogenetic obesity is caused by nonsense mutations in genes regulating energy balance. A key factor herein is the leptin receptor. Here, we focus on leptin receptor nonsense variants causing obesity, namely the human W31X, murine Y333X and rat Y763X mutations, and explored their susceptibilities to aminoglycoside and PTC124 mediated translational read-through in vitro. In a luciferase based assay, all mutations - when analysed within the mouse receptor - were prone to aminoglycoside mediated nonsense suppression with the highest susceptibility for W31X, followed by Y763X and Y333X...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28390174/suppression-of-basic-fibroblast-growth-factor-expression-by-antisense-oligonucleotides-inhibits-neural-stem-cell-proliferation-and-differentiation-in-rat-models-with-focal-cerebral-infarction
#19
Chao Li, Li-He Che, Lei Shi, Jin-Lu Yu
This study is designed to investigate the role of basic fibroblast growth factor (bFGF) antisense oligonucleotide (ASODN) on the proliferation and differentiation of neural stem cells (NSCs) in rat models with focal cerebral infarction (CI). Seventy-five Sprague-Dawlay (SD) rats were randomly divided into the control, sham, middle cerebral artery occlusion (MCAO), MCAO + nonsense oligonucleotide (NODN), and MCAO + ASODN groups. Proliferation and differentiation of NSCs were detected by bromodeoxyuridine (BrdU) and immunofluorescence staining, respectively...
April 8, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28367323/nonsense-suppression-as-an-approach-to-treat-lysosomal-storage-diseases
#20
Kim M Keeling
In-frame premature termination codons (PTCs) (also referred to as nonsense mutations) comprise ~10% of all disease-associated gene lesions. PTCs reduce gene expression in two ways. First, PTCs prematurely terminate translation of an mRNA, leading to the production of a truncated polypeptide that often lacks normal function and/or is unstable. Second, PTCs trigger degradation of an mRNA by activating nonsense-mediated mRNA decay (NMD), a cellular pathway that recognizes and degrades mRNAs containing a PTC. Thus, translation termination and NMD are putative therapeutic targets for the development of treatments for genetic diseases caused by PTCs...
December 2016: Diseases (Basel)
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