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Stop codon readthrough

Kanghyun Lee, Ruchika Sharma, Om Kumar Shrestha, Craig A Bingman, Elizabeth A Craig
Ribosome-associated J protein-Hsp70 chaperones promote nascent-polypeptide folding and normal translational fidelity. The J protein Zuo1 is known to span the ribosomal subunits, but understanding of its function is limited. Here we present new structural and cross-linking data allowing more precise positioning of Saccharomyces cerevisiae Zuo1 near the 60S polypeptide-exit site and suggesting interactions of Zuo1 with the ribosomal protein eL31 and 25S rRNA helix 24. The junction between the 60S-interacting and subunit-spanning helices is a hinge that positions Zuo1 on the 40S yet accommodates subunit rotation...
September 26, 2016: Nature Structural & Molecular Biology
Sujatha Jagannathan, Robert K Bradley
Genetic variants that disrupt protein-coding DNA are ubiquitous in the human population, with ~100 such loss-of-function variants per individual. While most loss-of-function variants are rare, a subset have risen to high frequency and occur in a homozygous state in healthy individuals. It is unknown why these common variants are well-tolerated, even though some affect essential genes implicated in Mendelian disease. Here, we combine genomic, proteomic, and biochemical data to demonstrate that many common nonsense variants do not ablate protein production from their host genes...
September 19, 2016: Genome Research
Irwin Jungreis, Clara S Chan, Robert M Waterhouse, Gabriel Fields, Michael F Lin, Manolis Kellis
Translational stop codon readthrough emerged as a major regulatory mechanism affecting hundreds of genes in animal genomes, based on recent comparative genomics and ribosomal profiling evidence, but its evolutionary properties remain unknown. Here, we leverage comparative genomic evidence across 21 Anopheles mosquitoes to systematically annotate readthrough genes in the malaria vector Anopheles gambiae, and to provide the first study of abundant readthrough evolution, by comparison with 20 Drosophila species...
September 7, 2016: Molecular Biology and Evolution
Alessio Branchini, Mattia Ferrarese, Silvia Lombardi, Rosella Mari, Francesco Bernardi, Mirko Pinotti
BACKGROUND: Whereas the rare homozygous nonsense mutations causing factor VII (FVII) deficiency may predict null conditions that are virtually incompatible with life, they can be associated with both life as well as appreciable differences in hemorrhagic symptoms. The misrecognition of premature stop codons (readthrough) may account for variable levels of functional full-length proteins. OBJECTIVES: To experimentally evaluate the basal and drug-induced levels of FVII produced by the homozygous p...
August 11, 2016: Journal of Thrombosis and Haemostasis: JTH
Fabian Schueren, Sven Thoms
Translational readthrough (TR) has come into renewed focus because systems biology approaches have identified the first human genes undergoing functional translational readthrough (FTR). FTR creates functional extensions to proteins by continuing translation of the mRNA downstream of the stop codon. Here we review recent developments in TR research with a focus on the identification of FTR in humans and the systems biology methods that have spurred these discoveries.
August 2016: PLoS Genetics
John VanNice, Steven T Gregory, Divya Kamath, Michael O'Connor
Ribosomal protein L19 is an essential ribosomal protein and is a component of bridge B8, one of the protein-RNA bridges linking the large and small ribosomal subunits. Bridge B8 also contributes to the accuracy of translation by affecting GTPase activation by ribosome-bound aminoacyl tRNA-EF-Tu•GTP ternary complexes. Previous work has identified a limited number of accuracy-altering alterations in protein L19 of Salmonella enterica and Thermus thermophilus. Here, we have targeted the Escherichia coli rplS gene encoding L19 for mutagenesis and have screened for mutants with altered levels of miscoding...
September 2016: Biochimie
Estienne Carl Swart, Valentina Serra, Giulio Petroni, Mariusz Nowacki
The prevailing view of the nuclear genetic code is that it is largely frozen and unambiguous. Flexibility in the nuclear genetic code has been demonstrated in ciliates that reassign standard stop codons to amino acids, resulting in seven variant genetic codes, including three previously undescribed ones reported here. Surprisingly, in two of these species, we find efficient translation of all 64 codons as standard amino acids and recognition of either one or all three stop codons. How, therefore, does the translation machinery interpret a "stop" codon? We provide evidence, based on ribosomal profiling and "stop" codon depletion shortly before coding sequence ends, that mRNA 3' ends may contribute to distinguishing stop from sense in a context-dependent manner...
July 28, 2016: Cell
Ivana Pibiri, Laura Lentini, Marco Tutone, Raffaella Melfi, Andrea Pace, Aldo Di Leonardo
Ataluren, also known as PTC124, is a 5-(fluorophenyl)-1,2,4-oxadiazolyl-benzoic acid suggested to suppress nonsense mutations by readthrough of premature stop codons in the mRNA. Potential interaction of PTC124 with mRNA has been recently studied by molecular dynamics simulations highlighting the importance of H-bonding and stacking π-π interactions. A series of non-acidic analogues of PTC124 were selected from a large database via a ligand-based virtual screening approach. Eight of them were synthesized and tested for their readthrough activity using the Fluc reporter harboring the UGA premature stop codon...
October 21, 2016: European Journal of Medicinal Chemistry
Joshua A Arribere, Elif S Cenik, Nimit Jain, Gaelen T Hess, Cameron H Lee, Michael C Bassik, Andrew Z Fire
A fraction of ribosomes engaged in translation will fail to terminate when reaching a stop codon, yielding nascent proteins inappropriately extended on their C termini. Although such extended proteins can interfere with normal cellular processes, known mechanisms of translational surveillance are insufficient to protect cells from potential dominant consequences. Here, through a combination of transgenics and CRISPR–Cas9 gene editing in Caenorhabditis elegans, we demonstrate a consistent ability of cells to block accumulation of C-terminal-extended proteins that result from failure to terminate at stop codons...
June 30, 2016: Nature
Janine Martitz, Peter Josef Hofmann, Jörg Johannes, Josef Köhrle, Lutz Schomburg, Kostja Renko
Aminoglycosides (AG) are oligosaccharide antibiotics that interfere with the small ribosomal subunit in aerobic, Gram-negative bacteria, causing pathogen-destructing error rates in their protein biosynthesis. Aminoglycosides also induce mRNA misinterpretation in eukaryotic cells, especially of the UGA (Opal)-stop codon, albeit to a lower extent. UGA recoding is essentially required for the incorporation of selenocysteine (Sec) into growing selenoproteins during translation. Selenocysteine incorporation requires the presence of a selenoprotein-specific stem-loop structure within the 3'-untranslated region of the mRNA, the so-called Sec-insertion sequence (SECIS) element...
September 2016: Journal of Trace Elements in Medicine and Biology
Venkateshwar Mutyam, Ming Du, Xiaojiao Xue, Kim M Keeling, E Lucile White, J Robert Bostwick, Lynn Rasmussen, Bo Liu, Marina Mazur, Jeong S Hong, Emily Falk Libby, Feng Liang, Haibo Shang, Martin Mense, Mark J Suto, David M Bedwell, Steven M Rowe
RATIONALE: Premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis. A number of agents are known to suppress PTCs, but are poorly efficacious or toxic. OBJECTIVES: To determine whether there are clinically available agents that elicit translational readthrough and improve CFTR function sufficient to confer therapeutic benefit to CF patients with PTCs. METHODS: Two independent screens, firefly luciferase and CFTR-mediated transepithelial chloride conductance assay (TECC), were performed on a library of 1600 clinically approved compounds using fisher rat thyroid (FRT) cells stably transfected with stop codons...
April 22, 2016: American Journal of Respiratory and Critical Care Medicine
Qais Al-Hadid, Jonelle White, Steven Clarke
A significant percentage of the methyltransferasome in Saccharomyces cerevisiae and higher eukaryotes is devoted to methylation of the translational machinery. Methylation of the RNA components of the translational machinery has been studied extensively and is important for structure stability, ribosome biogenesis, and translational fidelity. However, the functional effects of ribosomal protein methylation by their cognate methyltransferases are still largely unknown. Previous work has shown that the ribosomal protein Rpl3 methyltransferase, histidine protein methyltransferase 1 (Hpm1), is important for ribosome biogenesis and translation elongation fidelity...
February 12, 2016: Biochemical and Biophysical Research Communications
Petra Beznosková, Stanislava Gunišová, Leoš Shivaya Valášek
The molecular mechanism of stop codon recognition by the release factor eRF1 in complex with eRF3 has been described in great detail; however, our understanding of what determines the difference in termination efficiencies among various stop codon tetranucleotides and how near-cognate (nc) tRNAs recode stop codons during programmed readthrough in Saccharomyces cerevisiae is still poor. Here, we show that UGA-C as the only tetranucleotide of all four possible combinations dramatically exacerbated the readthrough phenotype of the stop codon recognition-deficient mutants in eRF1...
March 2016: RNA
Rosanna E B Young, Saul Purton
There is a growing interest in the use of microalgae as low-cost hosts for the synthesis of recombinant products such as therapeutic proteins and bioactive metabolites. In particular, the chloroplast, with its small, genetically tractable genome (plastome) and elaborate metabolism, represents an attractive platform for genetic engineering. In Chlamydomonas reinhardtii, none of the 69 protein-coding genes in the plastome uses the stop codon UGA, therefore this spare codon can be exploited as a useful synthetic biology tool...
May 2016: Plant Biotechnology Journal
Lisa Green, Stephen P Goff
Translational readthrough-promoting drugs enhance the incorporation of amino acids at stop codons and can thus bypass premature termination during protein synthesis. The polymerase (Pol) proteins of Moloney murine leukemia virus (MoMLV) are synthesized as a large Gag–Pol fusion protein, formed by the readthrough of a stop codon at the end of the gag ORF. The downstream pol ORF lacks its own start codon, and Pol protein synthesis is wholly dependent on translation of the upstream gag gene and the readthrough event for expression...
November 2015: Journal of General Virology
Marta Gómez-Grau, Elena Garrido, Mónica Cozar, Víctor Rodriguez-Sureda, Carmen Domínguez, Concepción Arenas, Richard A Gatti, Bru Cormand, Daniel Grinberg, Lluïsa Vilageliu
Nonsense mutations are quite prevalent in inherited diseases. Readthrough drugs could provide a therapeutic option for any disease caused by this type of mutation. Geneticin (G418) and gentamicin were among the first to be described. Novel compounds have been generated, but only a few have shown improved results. PTC124 is the only compound to have reached clinical trials. Here we first investigated the readthrough effects of gentamicin on fibroblasts from one patient with Sanfilippo B, one with Sanfilippo C, and one with Maroteaux-Lamy...
2015: PloS One
Marco Mariotti, Didac Santesmasses, Salvador Capella-Gutierrez, Andrea Mateo, Carme Arnan, Rory Johnson, Salvatore D'Aniello, Sun Hee Yim, Vadim N Gladyshev, Florenci Serras, Montserrat Corominas, Toni Gabaldón, Roderic Guigó
Selenoproteins are proteins that incorporate selenocysteine (Sec), a nonstandard amino acid encoded by UGA, normally a stop codon. Sec synthesis requires the enzyme Selenophosphate synthetase (SPS or SelD), conserved in all prokaryotic and eukaryotic genomes encoding selenoproteins. Here, we study the evolutionary history of SPS genes, providing a map of selenoprotein function spanning the whole tree of life. SPS is itself a selenoprotein in many species, although functionally equivalent homologs that replace the Sec site with cysteine (Cys) are common...
September 2015: Genome Research
Maciej Dabrowski, Zuzanna Bukowy-Bieryllo, Ewa Zietkiewicz
Termination of protein synthesis is not 100% efficient. A number of natural mechanisms that suppress translation termination exist. One of them is STOP codon readthrough, the process that enables the ribosome to pass through the termination codon in mRNA and continue translation to the next STOP codon in the same reading frame. The efficiency of translational readthrough depends on a variety of factors, including the identity of the termination codon, the surrounding mRNA sequence context, and the presence of stimulating compounds...
2015: RNA Biology
Ivana Pibiri, Laura Lentini, Raffaella Melfi, Giulia Gallucci, Andrea Pace, Angelo Spinello, Giampaolo Barone, Aldo Di Leonardo
Premature stop codons are the result of nonsense mutations occurring within the coding sequence of a gene. These mutations lead to the synthesis of a truncated protein and are responsible for several genetic diseases. A potential pharmacological approach to treat these diseases is to promote the translational readthrough of premature stop codons by small molecules aiming to restore the full-length protein. The compound PTC124 (Ataluren) was reported to promote the readthrough of the premature UGA stop codon, although its activity was questioned...
August 28, 2015: European Journal of Medicinal Chemistry
Sandeepa M Eswarappa, Paul L Fox
The transcript of the angiogenic factor vascular endothelial growth factor A (VEGF-A) is subject to a multitude of stimulus-dependent, posttranscriptional regulatory events, consistent with its unusually long 3' untranslated region. We have recently reported translational readthrough of VEGFA mRNA whereby translating ribosomes traverse the canonical stop codon to a conserved, downstream stop codon, generating VEGF-Ax ("x" for extended), a novel, extended isoform with an additional 22 amino acids appended at the C-terminus...
July 15, 2015: Cancer Research
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