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Nonsense suppression

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https://www.readbyqxmd.com/read/29128743/the-suppression-of-premature-termination-codons-and-the-repair-of-splicing-mutations-in-cftr
#1
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 9, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29109183/mutation-and-suppressor-analysis-of-the-essential-lps-transport-protein-lpta-reveals-strategies-to-overcome-severe-outer-membrane-permeability-defects-in-escherichia-coli
#2
Federica A Falchi, Elisa A Maccagni, Simone Puccio, Clelia Peano, Cristina De Castro, Angelo Palmigiano, Domenico Garozzo, Alessandra M Martorana, Alessandra Polissi, Gianni Dehò, Paola Sperandeo
In Gram-negative bacteria, lipopolysaccharide (LPS) contributes to the robust permeability barrier of the outer membrane (OM), preventing the entry of toxic molecules such as detergents and antibiotics. LPS is transported from the inner membrane (IM) to the OM by the Lpt multiprotein machinery. Defects in LPS transport compromise LPS assembly at the OM and result in increased antibiotic sensitivity. LptA is a key component of the Lpt machine that interacts with the IM protein LptC and chaperons LPS through the periplasm...
November 6, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/29106929/gentamicin-induced-readthrough-and-nonsense-mediated-mrna-decay-of-serpinb7-nonsense-mutant-transcripts
#3
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/29081953/defining-the-current-scope-and-limitations-of-dual-noncanonical-amino-acid-mutagenesis-in-mammalian-cells
#4
Yunan Zheng, Partha Sarathi Addy, Raja Mukherjee, Abhishek Chatterjee
The ability to site-specifically incorporate two distinct noncanonical amino acids (ncAAs) into the proteome of a mammalian cell with high fidelity and efficiency will have many enabling applications. It would require the use of two different engineered aminoacyl-tRNA synthetase (aaRS)/tRNA pairs, each suppressing a distinct nonsense codon, and which cross-react neither with each other, nor with their counterparts from the host cell. Three different aaRS/tRNA pairs have been developed so far to expand the genetic code of mammalian cells, which can be potentially combined in three unique ways to drive site-specific incorporation of two distinct ncAAs...
October 1, 2017: Chemical Science
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
#5
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/29075151/sporadic-pcdh18-somatic-mutations-in-epcam-positive-hepatocellular-carcinoma
#6
Takehiro Hayashi, Taro Yamashita, Hikari Okada, Kouki Nio, Yasumasa Hara, Yoshimoto Nomura, Tomoyuki Hayashi, Yoshiro Asahina, Mariko Yoshida, Naoki Oishi, Hajime Sunagozaka, Hajime Takatori, Masao Honda, Shuichi Kaneko
BACKGROUND: The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive (EpCAM(+)) CSCs. METHODS: Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/29058101/dock8-deficiency-presenting-as-an-ipex-like-disorder
#7
Fayhan J Alroqi, Louis-Marie Charbonnier, Sevgi Keles, Fatima Ghandour, Pierre Mouawad, Rami Sabouneh, Reem Mohammed, Abduarahman Almutairi, Janet Chou, Michel J Massaad, Raif S Geha, Zeina Baz, Talal A Chatila
PURPOSE: The dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive-combined immunodeficiency whose clinical spectra include recurrent infections, autoimmunity, malignancies, elevated serum IgE, eczema, and food allergies. Here, we report on patients with loss of function DOCK8 mutations with profound immune dysregulation suggestive of an immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like disorder. METHODS: Immunophenotyping of lymphocyte subpopulations and analysis of DOCK8 protein expression were evaluated by flow cytometry...
November 2017: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/29037135/distinct-mechanisms-of-phenotypic-effects-of-inactivation-and-prionization-of-swi1-protein-in-saccharomyces-cerevisiae
#8
K S Antonets, S F Kliver, D E Polev, A R Shuvalova, E A Andreeva, S G Inge-Vechtomov, A A Nizhnikov
Prions are proteins that under the same conditions can exist in two or more conformations, and at least one of the conformations has infectious properties. The prionization of a protein is typically accompanied by its functional inactivation due to sequestration of monomers by the prion aggregates. The most of prions has been identified in the yeast Saccharomyces cerevisiae. One of them is [SWI(+)], a prion isoform of the Swi1 protein, which is a component of the evolutionarily conserved chromatin remodeling complex SWI/SNF...
October 2017: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/29034140/regulation-of-gene-expression-by-translation-factor-eif5a-hypusine-modified-eif5a-enhances-nonsense-mediated-mrna-decay-in-human-cells
#9
Mainul Hoque, Ji Yeon Park, Yun-Juan Chang, Augusto D Luchessi, Tavane D Cambiaghi, Raghavendra Shamanna, Hartmut M Hanauske-Abel, Bart Holland, Tsafi Pe'ery, Bin Tian, Michael B Mathews
Nonsense-mediated mRNA decay (NMD) couples protein synthesis to mRNA turnover. It eliminates defective transcripts and controls the abundance of certain normal mRNAs. Our study establishes a connection between NMD and the translation factor eIF5A (eukaryotic initiation factor 5A) in human cells. eIF5A modulates the synthesis of groups of proteins (the eIF5A regulon), and undergoes a distinctive two-step post-translational modification (hypusination) catalyzed by deoxyhypusine synthase and deoxyhypusine hydroxylase...
2017: Translation
https://www.readbyqxmd.com/read/29020934/transcriptome-analyses-reveal-sr45-to-be-a-neutral-splicing-regulator-and-a-suppressor-of-innate-immunity-in-arabidopsis-thaliana
#10
Xiao-Ning Zhang, Yifei Shi, Jordan J Powers, Nikhil B Gowda, Chong Zhang, Heba M M Ibrahim, Hannah B Ball, Samuel L Chen, Hua Lu, Stephen M Mount
BACKGROUND: Regulation of pre-mRNA splicing diversifies protein products and affects many biological processes. Arabidopsis thaliana Serine/Arginine-rich 45 (SR45), regulates pre-mRNA splicing by interacting with other regulatory proteins and spliceosomal subunits. Although SR45 has orthologs in diverse eukaryotes, including human RNPS1, the sr45-1 null mutant is viable. Narrow flower petals and reduced seed formation suggest that SR45 regulates genes involved in diverse processes, including reproduction...
October 11, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28984438/engineering-the-genetic-code-in-cells-and-animals-biological-considerations-and-impacts
#11
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...
October 6, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28983143/synthetic-biology-approach-for-the-development-of-conditionally-replicating-hiv-1-vaccine
#12
Nanxi Wang, Zhe Yuan, Wei Niu, Qingsheng Li, Jiantao Guo
While the combined antiretroviral therapy has resulted in a significant decrease in HIV-1 related morbidity and mortality, the HIV-1 pandemic has not been substantially averted. To curtail the 2.4 million new infections each year, a prophylactic HIV-1 vaccine is urgently needed. This review first summarizes four major completed clinical efficacy trials of prophylactic HIV-1 vaccine and their outcomes. Next, it discusses several other approaches that have not yet advanced to clinical efficacy trials, but provided valuable insights into vaccine design...
March 2017: Journal of Chemical Technology and Biotechnology
https://www.readbyqxmd.com/read/28974234/agonists-for-g-protein-coupled-receptor-84-gpr84-alter-cellular-morphology-and-motility-but-do-not-induce-pro-inflammatory-responses-in-microglia
#13
Li Wei, Kyohei Tokizane, Hiroyuki Konishi, Hua-Rong Yu, Hiroshi Kiyama
BACKGROUND: Several G-protein-coupled receptors (GPCRs) have been shown to be important signaling mediators between neurons and glia. In our previous screening for identification of nerve injury-associated GPCRs, G-protein-coupled receptor 84 (GPR84) mRNA showed the highest up-regulation by microglia after nerve injury. GPR84 is a pro-inflammatory receptor of macrophages in a neuropathic pain mouse model, yet its function in resident microglia in the central nervous system is poorly understood...
October 3, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28959040/endoplasmic-reticulum-stress-preconditioning-modifies-intracellular-mercury-content-by-upregulating-membrane-transporters
#14
Fusako Usuki, Masatake Fujimura, Akio Yamashita
Endoplasmic reticulum (ER) stress preconditioning protects cells against methylmercury (MeHg) cytotoxicity by inducing integrated stress responses such as eIF2α phosphorylation, ATF4 accumulation, and nonsense-mediated mRNA decay (NMD) suppression. Here we demonstrated that ER stress preconditioning results in the upregulation of membrane transporters, leading to a decrease in intracellular mercury content. Our analyses showed that ER stress preconditioning upregulated the expression of methionine transporters that affect the cellular influx of MeHg, LAT1, LAT3, and SNAT2; and a membrane transporter that affects the efflux of MeHg, ABCC4, in MeHg-susceptible myogenic cells...
September 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28910422/a-prolonged-chronological-lifespan-is-an-unexpected-benefit-of-the-psi-prion-in-yeast
#15
Kai Wang, Ronald Melki, Mehdi Kabani
Self-replicating 'proteinaceous infectious particles' or prions are responsible for complex heritable traits in the yeast Saccharomyces cerevisiae. Our current understanding of the biology of yeast prions stems from studies mostly done in the context of actively dividing cells in optimal laboratory growth conditions. Evidence suggest that fungal prions exist in the wild where most cells are in a non-dividing quiescent state, because of imperfect growth conditions, scarcity of nutrients and competition. We know little about the faithful transmission of yeast prions in such conditions and their physiological consequences throughout the lifespan of yeast cells...
2017: PloS One
https://www.readbyqxmd.com/read/28874147/assessing-the-activity-of-nonsense-mediated-mrna-decay-in-lung-cancer
#16
Meng Wang, Peiwei Zhang, Yufei Zhu, Xiangyin Kong, Zhenguo Zhang, Landian Hu
BACKGROUND: Inhibition of nonsense-mediated mRNA decay (NMD) in tumor cells can suppress tumor growth through expressing new antigens whose mRNAs otherwise are degraded by NMD. Thus NMD inhibition is a promising approach for developing cancer therapies. Apparently, the success of this approach relies on the basal NMD activity in cancer cells. If NMD is already strongly inhibited in tumors, the approach would not work. Therefore, it is crucial to assess NMD activity in cancers to forecast the efficacy of NMD-inhibition based therapy...
September 6, 2017: BMC Medical Genomics
https://www.readbyqxmd.com/read/28872616/use-of-a-yeast-trnase-killer-toxin-to-diagnose-kti12-motifs-required-for-trna-modification-by-elongator
#17
Constance Mehlgarten, Heike Prochaska, Alexander Hammermeister, Wael Abdel-Fattah, Melanie Wagner, Rościsław Krutyhołowa, Sang Eun Jun, Gyung-Tae Kim, Sebastian Glatt, Karin D Breunig, Michael J R Stark, Raffael Schaffrath
Saccharomyces cerevisiae cells are killed by zymocin, a tRNase ribotoxin complex from Kluyveromyces lactis, which cleaves anticodons and inhibits protein synthesis. Zymocin's action requires specific chemical modification of uridine bases in the anticodon wobble position (U34) by the Elongator complex (Elp1-Elp6). Hence, loss of anticodon modification in mutants lacking Elongator or related KTI (K. lactis Toxin Insensitive) genes protects against tRNA cleavage and confers resistance to the toxin. Here, we show that zymocin can be used as a tool to genetically analyse KTI12, a gene previously shown to code for an Elongator partner protein...
September 5, 2017: Toxins
https://www.readbyqxmd.com/read/28765281/p38-mapk-inhibits-nonsense-mediated-rna-decay-in-response-to-persistent-dna-damage-in-noncycling-cells
#18
COMPARATIVE STUDY
Andrew Nickless, Abigael Cheruiyot, Kevin C Flanagan, David Piwnica-Worms, Sheila A Stewart, Zhongsheng You
Persistent DNA damage induces profound alterations in gene expression that, in turn, influence tissue homeostasis, tumorigenesis, and cancer treatment outcome. However, the underlying mechanism for 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...
September 15, 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
#19
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 pathway caused strong phenotypic suppression...
September 7, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28716950/analysis-of-small-critical-regions-of-swi1-conferring-prion-formation-maintenance-and-transmission
#20
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 nonglucose medium and abolishment of multicellular features. 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...
October 15, 2017: Molecular and Cellular Biology
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