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Stop codon readthrough

Lucile Pantel, Tanja Florin, Malgorzata Dobosz-Bartoszek, Emilie Racine, Matthieu Sarciaux, Marine Serri, Jessica Houard, Jean-Marc Campagne, Renata Marcia de Figueiredo, Camille Midrier, Sophie Gaudriault, Alain Givaudan, Anne Lanois, Steve Forst, André Aumelas, Christelle Cotteaux-Lautard, Jean-Michel Bolla, Carina Vingsbo Lundberg, Douglas L Huseby, Diarmaid Hughes, Philippe Villain-Guillot, Alexander S Mankin, Yury S Polikanov, Maxime Gualtieri
Growing resistance of pathogenic bacteria and shortage of antibiotic discovery platforms challenge the use of antibiotics in the clinic. This threat calls for exploration of unconventional sources of antibiotics and identification of inhibitors able to eradicate resistant bacteria. Here we describe a different class of antibiotics, odilorhabdins (ODLs), produced by the enzymes of the non-ribosomal peptide synthetase gene cluster of the nematode-symbiotic bacterium Xenorhabdus nematophila. ODLs show activity against Gram-positive and Gram-negative pathogens, including carbapenem-resistant Enterobacteriaceae, and can eradicate infections in animal models...
April 5, 2018: Molecular Cell
Yi Xu, Ho-Jong Ju, Stacy DeBlasio, Elizabeth J Carino, Richard Johnson, Michael J MacCoss, Michelle Heck, W Allen Miller, Stewart M Gray
Translational readthrough of the stop codon of the capsid protein (CP) open reading frame (ORF) is used by members of the Luteoviridae to produce their minor capsid protein as a readthrough protein (RTP). The elements regulating RTP expression are not well understood, but they involve long-distance interactions between RNA domains. Using high-resolution mass spectrometry, glutamine and tyrosine were identified as the primary amino acids inserted at the stop codon of Potato leafroll virus (PLRV) CP ORF. We characterized the contributions of a cytidine-rich domain immediately downstream and a branched stem-loop structure 600 to 700 nucleotides downstream of the CP stop codon...
June 1, 2018: Journal of Virology
Gary Loughran, Irwin Jungreis, Ioanna Tzani, Michael Power, Ruslan I Dmitriev, Ivaylo P Ivanov, Manolis Kellis, John F Atkins
Although stop codon readthrough is used extensively by viruses to expand their gene expression, verified instances of mammalian readthrough have only recently been uncovered by systems biology and comparative genomics approaches. Previously, our analysis of conserved protein coding signatures that extend beyond annotated stop codons predicted stop codon readthrough of several mammalian genes, all of which have been validated experimentally. Four mRNAs display highly efficient stop codon readthrough, and these mRNAs have a UGA stop codon immediately followed by CUAG (UGA_CUAG) that is conserved throughout vertebrates...
March 23, 2018: Journal of Biological Chemistry
Nerea Irigoyen, Adam M Dinan, Ian Brierley, Andrew E Firth
BACKGROUND: The retrovirus murine leukemia virus (MuLV) has an 8.3 kb RNA genome with a simple 5'-gag-pol-env-3' architecture. Translation of the pol gene is dependent upon readthrough of the gag UAG stop codon; whereas the env gene is translated from spliced mRNA transcripts. Here, we report the first high resolution analysis of retrovirus gene expression through tandem ribosome profiling (RiboSeq) and RNA sequencing (RNASeq) of MuLV-infected cells. RESULTS: Ribosome profiling of MuLV-infected cells was performed, using the translational inhibitors harringtonine and cycloheximide to distinguish initiating and elongating ribosomes, respectively...
January 22, 2018: Retrovirology
Andrew G Cridge, Caillan Crowe-McAuliffe, Suneeth F Mathew, Warren P Tate
When a stop codon is at the 80S ribosomal A site, there are six nucleotides (+4 to +9) downstream that are inferred to be occupying the mRNA channel. We examined the influence of these downstream nucleotides on translation termination success or failure in mammalian cells at the three stop codons. The expected hierarchy in the intrinsic fidelity of the stop codons (UAA>UAG>UGA) was observed, with highly influential effects on termination readthrough mediated by nucleotides at position +4 and position +8...
February 28, 2018: Nucleic Acids Research
Martina M Yordanova, Gary Loughran, Alexander V Zhdanov, Marco Mariotti, Stephen J Kiniry, Patrick B F O'Connor, Dmitry E Andreev, Ioanna Tzani, Paul Saffert, Audrey M Michel, Vadim N Gladyshev, Dmitry B Papkovsky, John F Atkins, Pavel V Baranov
In addition to acting as template for protein synthesis, messenger RNA (mRNA) often contains sensory sequence elements that regulate this process. Here we report a new mechanism that limits the number of complete protein molecules that can be synthesized from a single mRNA molecule of the human AMD1 gene encoding adenosylmethionine decarboxylase 1 (AdoMetDC). A small proportion of ribosomes translating AMD1 mRNA stochastically read through the stop codon of the main coding region. These readthrough ribosomes then stall close to the next in-frame stop codon, eventually forming a ribosome queue, the length of which is proportional to the number of AdoMetDC molecules that were synthesized from the same AMD1 mRNA...
January 18, 2018: Nature
H M Chowdhury, M A Siddiqui, S Kanneganti, N Sharmin, M W Chowdhury, M Talat Nasim
Attempts have been made to treat nonsense-associated genetic disorders by chemical agents and hence an improved mechanistic insight into the decoding of readthrough signals is essential for the identification and characterisation of factors for the treatment of these disorders. To identify either novel compounds or genes that modulate translation readthrough, we have employed dual reporter-based high-throughput screens that use enzymatic and fluorescence activities and screened bioactive National Institute of Neurological Disease Syndrome (NINDS) compounds (n = 1000) and siRNA (n = 288) libraries...
January 15, 2018: Human Molecular Genetics
Nachelli Malpica-López, Rajendran Rajeswaran, Daria Beknazariants, Jonathan Seguin, Victor Golyaev, Laurent Farinelli, Mikhail M Pooggin
Tobamoviral replicase possesses an RNA-dependent RNA polymerase (RDR) domain and is translated from genomic (g)RNA via a stop codon readthrough mechanism at a one-to-ten ratio relative to a shorter protein lacking the RDR domain. The two proteins share methyltransferase and helicase domains and form a heterodimer implicated in gRNA replication. The shorter protein is also implicated in suppressing RNA silencing-based antiviral defenses. Using a stop codon mutant of Oilseed rape mosaic tobamovirus (ORMV), we demonstrate that the readthrough replicase (p182) is sufficient for gRNA replication and for subgenomic RNA transcription during systemic infection in Nicotiana benthamiana and Arabidopsis thaliana...
January 2018: Molecular Plant-microbe Interactions: MPMI
Yoshihide Yamaguchi, Hiroko Baba
Myelin protein zero (P0, MPZ) is the main cell adhesion molecule in peripheral myelin, the sequence of which is evolutionarily highly conserved. Large myelin protein zero (L-MPZ) is a novel translational readthrough molecule in mammals in a physiological status and is encoded by the P0 mRNA with an extra domain. The sequence similarities in the L-MPZ-specific region are found in humans and frogs but not in fish P0 cDNA. Actual synthesis of L-MPZ has been detected in rat and mouse sciatic nerve but not yet evaluated in frogs and humans...
January 2018: Neurochemical Research
Leoš Shivaya Valášek, Jakub Zeman, Susan Wagner, Petra Beznosková, Zuzana Pavlíková, Mahabub Pasha Mohammad, Vladislava Hronová, Anna Herrmannová, Yaser Hashem, Stanislava Gunišová
Protein synthesis is mediated via numerous molecules including the ribosome, mRNA, tRNAs, as well as translation initiation, elongation and release factors. Some of these factors play several roles throughout the entire process to ensure proper assembly of the preinitiation complex on the right mRNA, accurate selection of the initiation codon, errorless production of the encoded polypeptide and its proper termination. Perhaps, the most intriguing of these multitasking factors is the eukaryotic initiation factor eIF3...
November 2, 2017: Nucleic Acids Research
Yongqiang Fan, Christopher R Evans, Karl W Barber, Kinshuk Banerjee, Kalyn J Weiss, William Margolin, Oleg A Igoshin, Jesse Rinehart, Jiqiang Ling
Gene expression noise (heterogeneity) leads to phenotypic diversity among isogenic individual cells. Our current understanding of gene expression noise is mostly limited to transcription, as separating translational noise from transcriptional noise has been challenging. It also remains unclear how translational heterogeneity originates. Using a transcription-normalized reporter system, we discovered that stop codon readthrough is heterogeneous among single cells, and individual cells with higher UGA readthrough grow faster from stationary phase...
September 7, 2017: Molecular Cell
Mary E M Larkin, Allen R Place
The UAG termination codon is generally recognized as the least efficient and least frequently used of the three universal stop codons. This is substantiated by numerous studies in an array of organisms. We present here evidence of a translational readthrough of a mutant nonsense UAG codon in the transcript from the cysteine sulfinic acid decarboxylase ( csad ) gene (ENSDARG00000026348) in zebrafish. The csad gene encodes the terminal enzyme in the taurine biosynthetic pathway. Taurine is a critical amino acid for all animals, playing several essential roles throughout the body, including modulation of the immune system...
June 3, 2017: Marine Drugs
Ziwei Zhang, Huan Xu, Longlong Si, Yi Chen, Bo Zhang, Yan Wang, Yiming Wu, Xueying Zhou, Lihe Zhang, Demin Zhou
The genetic incorporation of unnatural amino acids (Uaas) with defined properties into proteins at designated sites represents an extremely powerful tool for protein engineering. However, the efficient incorporation of Uaas in response to the amber stop codon in mammalian cells remains a substantial challenge due to the competition from release factor 1(RF1). Addressing this challenge will greatly broaden the power and scope of this technology. Here, we chose the eRF1 mutant, which can selectively enhance Uaa incorporation in response to the amber codon without increasing the readthrough of the opal and ochre codons...
August 5, 2017: Biochemical and Biophysical Research Communications
Luca Bello, Elena Pegoraro
Accurate definition of genetic mutations causing Duchenne muscular dystrophy (DMD) has always been relevant in order to provide genetic counseling to patients and families, and helps to establish the prognosis in the case where the distinction between Duchenne, Becker, or intermediate muscular dystrophy is not obvious. As molecular treatments aimed at dystrophin restoration in DMD are increasingly available as commercialized drugs or within clinical trials, genetic diagnosis has become an indispensable tool in order to determine eligibility for these treatments...
December 2016: Acta Myologica: Myopathies and Cardiomyopathies: Official Journal of the Mediterranean Society of Myology
Valery N Urakov, Olga V Mitkevich, Irina V Safenkova, Michael D Ter-Avanesyan
In eukaryotes, termination of translation is controlled by polypeptide chain release factors eRF1 and eRF3, of which the former recognizes nonsense codons, while the latter interacts with eRF1 and stimulates polypeptide release from the ribosome in a GTP- dependent manner, and ABCE1, which facilitates ribosome recycling. In this work, we demonstrate that Pub1, a yeast protein known to be involved in stress granule formation, regulation of gene expression, and organization of the tubulin cytoskeleton, also plays a role in translation termination...
June 2017: FEBS Journal
Gary Loughran, Michael T Howard, Andrew E Firth, John F Atkins
Positioning test sequences between fused reporters permits monitoring of both translation levels and framing, before and after the test sequence. Many studies, including those on recoding such as productive ribosomal frameshifting and stop codon readthrough, use distinguishable luciferases or fluorescent proteins as reporters. Occasional distortions, due to test sequence product interference with the individual reporter activities or stabilities, are here shown to be avoidable by the introduction of tandem StopGo sequences (2A) flanking the test sequence...
August 2017: RNA
Manuel Miras, W Allen Miller, Verónica Truniger, Miguel A Aranda
Viral protein synthesis is completely dependent upon the host cell's translational machinery. Canonical translation of host mRNAs depends on structural elements such as the 5' cap structure and/or the 3' poly(A) tail of the mRNAs. Although many viral mRNAs are devoid of one or both of these structures, they can still translate efficiently using non-canonical mechanisms. Here, we review the tools utilized by positive-sense single-stranded (+ss) RNA plant viruses to initiate non-canonical translation, focusing on cis-acting sequences present in viral mRNAs...
2017: Frontiers in Plant Science
Julia Hofhuis, Severin Dieterle, Rosemol George, Fabian Schueren, Sven Thoms
Translational readthrough, the decoding of stop codons as sense codons, leads to C-terminal extension of proteins which may lead to the formation of protein isoforms with distinct properties from the original protein. Two proteins have recently been identified that are targeted to the peroxisome via hidden peroxisomal targeting signals in their readthrough extensions. This noninduced basal translational readthrough can be distinguished from pharmacological induction of readthrough by aminoglycosides or other small molecules, which can be used for the treatment of diseases caused by premature stop (termination) codons (PTCs)...
2017: Methods in Molecular Biology
Natalie E Baggett, Yan Zhang, Carol A Gross
Terminating protein translation accurately and efficiently is critical for both protein fidelity and ribosome recycling for continued translation. The three bacterial release factors (RFs) play key roles: RF1 and 2 recognize stop codons and terminate translation; and RF3 promotes disassociation of bound release factors. Probing release factors mutations with reporter constructs containing programmed frameshifting sequences or premature stop codons had revealed a propensity for readthrough or frameshifting at these specific sites, but their effects on translation genome-wide have not been examined...
March 2017: PLoS Genetics
Alessio Branchini, Mattia Ferrarese, Matteo Campioni, Giancarlo Castaman, Rosella Mari, Francesco Bernardi, Mirko Pinotti
Drug-induced readthrough over premature stop codons (PTCs) is a potentially attractive therapy for genetic disorders, but a wide outcome variability has been observed. Through expression studies, we investigated the responsiveness to the readthrough-inducing drug geneticin of 11 rationally selected factor IX (FIX) nonsense mutations, present in 70% (324/469) of hemophilia B (HB) patients with PTCs. Among the predicted readthrough-permissive TGA variants, only 2 (p.W240X and p.R384X) responded with a remarkable rescue of FIX activity...
April 20, 2017: Blood
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