Journal articles: 'Premature termination codon'

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Zinshteyn, Boris, Niladri K. Sinha, Syed Usman Enam, Benjamin Koleske, and Rachel Green. "Translational repression of NMD targets by GIGYF2 and EIF4E2." PLOS Genetics 17, no. 10 (October 19, 2021): e1009813. http://dx.doi.org/10.1371/journal.pgen.1009813.

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Translation of messenger RNAs (mRNAs) with premature termination codons produces truncated proteins with potentially deleterious effects. This is prevented by nonsense-mediated mRNA decay (NMD) of these mRNAs. NMD is triggered by ribosomes terminating upstream of a splice site marked by an exon-junction complex (EJC), but also acts on many mRNAs lacking a splice junction after their termination codon. We developed a genome-wide CRISPR flow cytometry screen to identify regulators of mRNAs with premature termination codons in K562 cells. This screen recovered essentially all core NMD factors and suggested a role for EJC factors in degradation of PTCs without downstream splicing. Among the strongest hits were the translational repressors GIGYF2 and EIF4E2. GIGYF2 and EIF4E2 mediate translational repression but not mRNA decay of a subset of NMD targets and interact with NMD factors genetically and physically. Our results suggest a model wherein recognition of a stop codon as premature can lead to its translational repression through GIGYF2 and EIF4E2.

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Yang, Qian, Chien-Hung Yu, Fangzhou Zhao, Yunkun Dang, Cheng Wu, Pancheng Xie, Matthew S. Sachs, and Yi Liu. "eRF1 mediates codon usage effects on mRNA translation efficiency through premature termination at rare codons." Nucleic Acids Research 47, no. 17 (August 14, 2019): 9243–58. http://dx.doi.org/10.1093/nar/gkz710.

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Abstract Codon usage bias is a universal feature of eukaryotic and prokaryotic genomes and plays an important role in regulating gene expression levels. A major role of codon usage is thought to regulate protein expression levels by affecting mRNA translation efficiency, but the underlying mechanism is unclear. By analyzing ribosome profiling results, here we showed that codon usage regulates translation elongation rate and that rare codons are decoded more slowly than common codons in all codon families in Neurospora. Rare codons resulted in ribosome stalling in manners both dependent and independent of protein sequence context and caused premature translation termination. This mechanism was shown to be conserved in Drosophila cells. In both Neurospora and Drosophila cells, codon usage plays an important role in regulating mRNA translation efficiency. We found that the rare codon-dependent premature termination is mediated by the translation termination factor eRF1, which recognizes ribosomes stalled on rare sense codons. Silencing of eRF1 expression resulted in codon usage-dependent changes in protein expression. Together, these results establish a mechanism for how codon usage regulates mRNA translation efficiency.

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Morozov, Igor Y., Susana Negrete-Urtasun, Joan Tilburn, Christine A. Jansen, Mark X. Caddick, and Herbert N. Arst. "Nonsense-Mediated mRNA Decay Mutation in Aspergillus nidulans." Eukaryotic Cell 5, no. 11 (September 8, 2006): 1838–46. http://dx.doi.org/10.1128/ec.00220-06.

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ABSTRACT An Aspergillus nidulans mutation, designated nmdA1, has been selected as a partial suppressor of a frameshift mutation and shown to truncate the homologue of the Saccharomyces cerevisiae nonsense-mediated mRNA decay (NMD) surveillance component Nmd2p/Upf2p. nmdA1 elevates steady-state levels of premature termination codon-containing transcripts, as demonstrated using mutations in genes encoding xanthine dehydrogenase (hxA), urate oxidase (uaZ), the transcription factor mediating regulation of gene expression by ambient pH (pacC), and a protease involved in pH signal transduction (palB). nmdA1 can also stabilize pre-mRNA (unspliced) and wild-type transcripts of certain genes. Certain premature termination codon-containing transcripts which escape NMD are relatively stable, a feature more in common with certain nonsense codon-containing mammalian transcripts than with those in S. cerevisiae. As in S. cerevisiae, 5′ nonsense codons are more effective at triggering NMD than 3′ nonsense codons. Unlike the mammalian situation but in common with S. cerevisiae and other lower eukaryotes, A. nidulans is apparently impervious to the position of premature termination codons with respect to the 3′ exon-exon junction.

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Barker, G. F., and K. Beemon. "Rous sarcoma virus RNA stability requires an open reading frame in the gag gene and sequences downstream of the gag-pol junction." Molecular and Cellular Biology 14, no. 3 (March 1994): 1986–96. http://dx.doi.org/10.1128/mcb.14.3.1986-1996.1994.

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The intracellular accumulation of the unspliced RNA of Rous sarcoma virus was decreased when translation was prematurely terminated by the introduction of nonsense codons within its 5' proximal gene, the gag gene. Subcellular fractionation of transfected cells suggested that nonsense codon-mediated instability occurred in the cytoplasm. Analysis of constructs containing an in-frame deletion in the nucleocapsid domain of gag, which prevents interaction between the Gag protein and viral RNA, showed that an open reading frame extending to approximately 30 nucleotides from the natural gag termination codon was needed for RNA stability. Sequences at the gag-pol junction necessary for ribosomal frameshifting were not required for RNA stability; however, sequences located 100 to 200 nucleotides downstream of the natural gag termination codon were found to be necessary for stable RNA. The stability of RNAs lacking this downstream sequence was not markedly affected by premature termination codons. We propose that this downstream RNA sequence may interact with ribosomes translating gag to stabilize the RNA.

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Barker, G. F., and K. Beemon. "Rous sarcoma virus RNA stability requires an open reading frame in the gag gene and sequences downstream of the gag-pol junction." Molecular and Cellular Biology 14, no. 3 (March 1994): 1986–96. http://dx.doi.org/10.1128/mcb.14.3.1986.

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The intracellular accumulation of the unspliced RNA of Rous sarcoma virus was decreased when translation was prematurely terminated by the introduction of nonsense codons within its 5' proximal gene, the gag gene. Subcellular fractionation of transfected cells suggested that nonsense codon-mediated instability occurred in the cytoplasm. Analysis of constructs containing an in-frame deletion in the nucleocapsid domain of gag, which prevents interaction between the Gag protein and viral RNA, showed that an open reading frame extending to approximately 30 nucleotides from the natural gag termination codon was needed for RNA stability. Sequences at the gag-pol junction necessary for ribosomal frameshifting were not required for RNA stability; however, sequences located 100 to 200 nucleotides downstream of the natural gag termination codon were found to be necessary for stable RNA. The stability of RNAs lacking this downstream sequence was not markedly affected by premature termination codons. We propose that this downstream RNA sequence may interact with ribosomes translating gag to stabilize the RNA.

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Cohen, Sarit, Lior Kramarski, Shahar Levi, Noa Deshe, Oshrit Ben David, and Eyal Arbely. "Nonsense mutation-dependent reinitiation of translation in mammalian cells." Nucleic Acids Research 47, no. 12 (May 2, 2019): 6330–38. http://dx.doi.org/10.1093/nar/gkz319.

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AbstractIn-frame stop codons mark the termination of translation. However, post-termination ribosomes can reinitiate translation at downstream AUG codons. In mammals, reinitiation is most efficient when the termination codon is positioned close to the 5′-proximal initiation site and around 78 bases upstream of the reinitiation site. The phenomenon was studied mainly in the context of open reading frames (ORFs) found within the 5′-untranslated region, or polycicstronic viral mRNA. We hypothesized that reinitiation of translation following nonsense mutations within the main ORF of p53 can promote the expression of N-truncated p53 isoforms such as Δ40, Δ133 and Δ160p53. Here, we report that expression of all known N-truncated p53 isoforms by reinitiation is mechanistically feasible, including expression of the previously unidentified variant Δ66p53. Moreover, we found that significant reinitiation of translation can be promoted by nonsense mutations located even 126 codons downstream of the 5′-proximal initiation site, and observed when the reinitiation site is positioned between 6 and 243 bases downstream of the nonsense mutation. We also demonstrate that reinitiation can stabilise p53 mRNA transcripts with a premature termination codon, by allowing such transcripts to evade the nonsense mediated decay pathway. Our data suggest that the expression of N-truncated proteins from alleles carrying a premature termination codon is more prevalent than previously thought.

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Muhlrad, Denise, and Roy Parker. "Recognition of Yeast mRNAs as “Nonsense Containing” Leads to Both Inhibition of mRNA Translation and mRNA Degradation: Implications for the Control of mRNA Decapping." Molecular Biology of the Cell 10, no. 11 (November 1999): 3971–78. http://dx.doi.org/10.1091/mbc.10.11.3971.

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A critical step in the degradation of many eukaryotic mRNAs is a decapping reaction that exposes the transcript to 5′ to 3′ exonucleolytic degradation. The dual role of the cap structure as a target of mRNA degradation and as the site of assembly of translation initiation factors has led to the hypothesis that the rate of decapping would be specified by the status of the cap binding complex. This model makes the prediction that signals that promote mRNA decapping should also alter translation. To test this hypothesis, we examined the decapping triggered by premature termination codons to determine whether there is a down-regulation of translation when mRNAs were recognized as “nonsense containing.” We constructed an mRNA containing a premature stop codon in which we could measure the levels of both the mRNA and the polypeptide encoded upstream of the premature stop codon. Using this system, we analyzed the effects of premature stop codons on the levels of protein being produced per mRNA. In addition, by using alterations either in cis or intrans that inactivate different steps in the recognition and degradation of nonsense-containing mRNAs, we demonstrated that the recognition of a nonsense codon led to a decrease in the translational efficiency of the mRNA. These observations argue that the signal from a premature termination codon impinges on the translation machinery and suggest that decapping is a consequence of the change in translational status of the mRNA.

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Daar, I. O., and L. E. Maquat. "Premature translation termination mediates triosephosphate isomerase mRNA degradation." Molecular and Cellular Biology 8, no. 2 (February 1988): 802–13. http://dx.doi.org/10.1128/mcb.8.2.802-813.1988.

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We characterized an anemia-inducing mutation in the human gene for triosephosphate isomerase (TPI) that resulted in the production of prematurely terminated protein and mRNA with a reduced cytoplasmic half-life. The mutation converted a CGA arginine codon to a TGA nonsense codon and generated a protein of 188 amino acids, instead of the usual 248 amino acids. To determine how mRNA primary structure and translation influence mRNA stability, in vitro-mutagenized TPI alleles were introduced into cultured L cells and analyzed for their effect on TPI RNA metabolism. Results indicated that mRNA stability is decreased by all nonsense and frameshift mutations. To determine the relative contribution of the changes in mRNA structure and translation to the altered half-life, the effects of individual mutations were compared with the effects of second-site reversions that restored translation termination to normal. All mutations that resulted in premature translation termination reduced the mRNA half-life solely or mainly by altering the length of the mRNA that was translated. The only mutation that altered translation termination and that reduced the mRNA half-life mainly by affecting the mRNA structure was an insertion that shifted termination to a position downstream of the normal stop codon.

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Daar, I. O., and L. E. Maquat. "Premature translation termination mediates triosephosphate isomerase mRNA degradation." Molecular and Cellular Biology 8, no. 2 (February 1988): 802–13. http://dx.doi.org/10.1128/mcb.8.2.802.

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We characterized an anemia-inducing mutation in the human gene for triosephosphate isomerase (TPI) that resulted in the production of prematurely terminated protein and mRNA with a reduced cytoplasmic half-life. The mutation converted a CGA arginine codon to a TGA nonsense codon and generated a protein of 188 amino acids, instead of the usual 248 amino acids. To determine how mRNA primary structure and translation influence mRNA stability, in vitro-mutagenized TPI alleles were introduced into cultured L cells and analyzed for their effect on TPI RNA metabolism. Results indicated that mRNA stability is decreased by all nonsense and frameshift mutations. To determine the relative contribution of the changes in mRNA structure and translation to the altered half-life, the effects of individual mutations were compared with the effects of second-site reversions that restored translation termination to normal. All mutations that resulted in premature translation termination reduced the mRNA half-life solely or mainly by altering the length of the mRNA that was translated. The only mutation that altered translation termination and that reduced the mRNA half-life mainly by affecting the mRNA structure was an insertion that shifted termination to a position downstream of the normal stop codon.

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Hwang, Jungwook, and Yoon Ki Kim. "When a ribosome encounters a premature termination codon." BMB Reports 46, no. 1 (January 31, 2013): 9–16. http://dx.doi.org/10.5483/bmbrep.2013.46.1.002.

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Michorowska, Sylwia. "Ataluren—Promising Therapeutic Premature Termination Codon Readthrough Frontrunner." Pharmaceuticals 14, no. 8 (August 9, 2021): 785. http://dx.doi.org/10.3390/ph14080785.

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Around 12% of hereditary disease-causing mutations are in-frame nonsense mutations. The expression of genes containing nonsense mutations potentially leads to the production of truncated proteins with residual or virtually no function. However, the translation of transcripts containing premature stop codons resulting in full-length protein expression can be achieved using readthrough agents. Among them, only ataluren was approved in several countries to treat nonsense mutation Duchenne muscular dystrophy (DMD) patients. This review summarizes ataluren’s journey from its identification, via first in vitro activity experiments, to clinical trials in DMD, cystic fibrosis, and aniridia. Additionally, data on its pharmacokinetics and mechanism of action are presented. The range of diseases with underlying nonsense mutations is described for which ataluren therapy seems to be promising. What is more, experiments in which ataluren did not show its readthrough activity are also included, and reasons for their failures are discussed.

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Beißel, Christian, Sebastian Grosse, and Heike Krebber. "Dbp5/DDX19 between Translational Readthrough and Nonsense Mediated Decay." International Journal of Molecular Sciences 21, no. 3 (February 6, 2020): 1085. http://dx.doi.org/10.3390/ijms21031085.

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The DEAD-box protein Dbp5 (human DDX19) remodels RNA-protein complexes. Dbp5 functions in ribonucleoprotein export and translation termination. Termination occurs, when the ribosome has reached a stop codon through the Dbp5 mediated delivery of the eukaryotic termination factor eRF1. eRF1 contacts eRF3 upon dissociation of Dbp5, resulting in polypeptide chain release and subsequent ribosomal subunit splitting. Mutations in DBP5 lead to stop codon readthrough, because the eRF1 and eRF3 interaction is not controlled and occurs prematurely. This identifies Dbp5/DDX19 as a possible potent drug target for nonsense suppression therapy. Neurodegenerative diseases and cancer are caused in many cases by the loss of a gene product, because its mRNA contained a premature termination codon (PTC) and is thus eliminated through the nonsense mediated decay (NMD) pathway, which is described in the second half of this review. We discuss translation termination and NMD in the light of Dbp5/DDX19 and subsequently speculate on reducing Dbp5/DDX19 activity to allow readthrough of the PTC and production of a full-length protein to detract the RNA from NMD as a possible treatment for diseases.

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Pibiri, Ivana. "Molecular Approaches Fighting Nonsense." International Journal of Molecular Sciences 22, no. 21 (November 3, 2021): 11933. http://dx.doi.org/10.3390/ijms222111933.

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Nonsense mutations are the result of single nucleotide substitutions in the DNA that change a sense codon (coding for an amino acid) to a nonsense or premature termination codon (PTC) within the coding region of the mRNA [...]

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Tokuoka, Masafumi, Mizuki Tanaka, Kazuhisa Ono, Shinobu Takagi, Takahiro Shintani, and Katsuya Gomi. "Codon Optimization Increases Steady-State mRNA Levels in Aspergillus oryzae Heterologous Gene Expression." Applied and Environmental Microbiology 74, no. 21 (September 12, 2008): 6538–46. http://dx.doi.org/10.1128/aem.01354-08.

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ABSTRACT We investigated the effect of codon optimization on the expression levels of heterologous proteins in Aspergillus oryzae, using the mite allergen Der f 7 as a model protein. A codon-optimized Der f 7 gene was synthesized according to the frequency of codon usage in A. oryzae by recursive PCR. Both native and optimized Der f 7 genes were expressed under the control of a high-level-expression promoter with their own signal peptides or in a fusion construct with A. oryzae glucoamylase (GlaA). Codon optimization markedly increased protein and mRNA production levels in both nonfused and GlaA-fused Der f 7 constructs. For constructs with native codons, analysis by 3′ rapid amplification of cDNA ends revealed that poly(A) tracts tended to be added within the coding region, producing aberrant mRNAs that lack a termination codon. Insertion of a termination codon between the carrier GlaA and native Der f 7 proteins in the GlaA fusion construct resulted in increases in mRNA and secreted-carrier-GlaA levels. These results suggested that mRNAs without a termination codon as a result of premature polyadenylation are degraded, possibly through the nonstop mRNA decay pathway. We suggest that codon optimization in A. oryzae results in elimination of cryptic polyadenylation signals in native Der f 7, thereby circumventing the production of truncated transcripts and resulting in an increase in steady-state mRNA levels.

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Thamban Chandrika, Nishad, and Sylvie Garneau-Tsodikova. "Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities." Chemical Society Reviews 47, no. 4 (2018): 1189–249. http://dx.doi.org/10.1039/c7cs00407a.

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Terzano, Susanna, Ilaria Oliva, Francesca Forti, Claudia Sala, Francesca Magnoni, Gianni Dehò, and Daniela Ghisotti. "Bacteriophage P4 sut1: a mutation suppressing transcription termination." Journal of General Virology 88, no. 3 (March 1, 2007): 1041–47. http://dx.doi.org/10.1099/vir.0.82605-0.

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In the Escherichia coli satellite phage P4, transcription starting from PLE is prevalently controlled via premature termination at several termination sites. We identified a spontaneous mutation, P4 sut1 (suppression of termination), in the natural stop codon of P4 orf151 that, by elongating translation, suppresses transcription termination at the downstream t151 site. Both the translational and the transcriptional profile of P4 sut1 differed from those of P4 wild-type. First of all, P4 sut1 did not express Orf151, but a higher molecular mass protein, compatible with the 303 codon open reading frame generated by the fusion of orf151, cnr and the intervening 138 nt. Moreover, after infection of E. coli, the mutant expressed a very low amount of the 1.3 and 1.7 kb transcripts originating at PLE and PLL promoters, respectively, and terminating at the intracistronic t151 site, whereas correspondingly higher amounts of the 4.1 and 4.5 kb RNAs arising from the same promoters and covering the entire operon were detected. Thus the sut1 mutation converts a natural stop codon into a sense codon, suppresses a natural intracistronic termination site and leads to overexpression of the downstream cnr and α genes. This correlates with the inability of P4 sut1 to propagate in the plasmid state. By cloning different P4 DNA fragments, we mapped the t151 transcription termination site within the 7633–7361 region between orf151 and gene cnr. A potential stem–loop structure, resembling the structure of a Rho-independent termination site, was predicted by mfold sequence analysis at 7414–7385.

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Ma, Zhipeng, and Jun Chen. "Premature Termination Codon-Bearing mRNA Mediates Genetic Compensation Response." Zebrafish 17, no. 3 (June 1, 2020): 157–62. http://dx.doi.org/10.1089/zeb.2019.1824.

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Svidritskiy, Egor, Gabriel Demo, and Andrei A. Korostelev. "Mechanism of premature translation termination on a sense codon." Journal of Biological Chemistry 293, no. 32 (June 25, 2018): 12472–79. http://dx.doi.org/10.1074/jbc.aw118.003232.

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Amrani, N., S. Dong, F. He, R. Ganesan, S. Ghosh, S. Kervestin, C. Li, D. A. Mangus, P. Spatrick, and A. Jacobson. "Aberrant termination triggers nonsense-mediated mRNA decay." Biochemical Society Transactions 34, no. 1 (January 20, 2006): 39–42. http://dx.doi.org/10.1042/bst0340039.

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NMD (nonsense-mediated mRNA decay) is a cellular quality-control mechanism in which an otherwise stable mRNA is destabilized by the presence of a premature termination codon. We have defined the set of endogenous NMD substrates, demonstrated that they are available for NMD at every round of translation, and showed that premature termination and normal termination are not equivalent biochemical events. Premature termination is aberrant, and its NMD-stimulating defects can be reversed by the presence of tethered poly(A)-binding protein (Pab1p) or tethered eRF3 (eukaryotic release factor 3) (Sup35p). Thus NMD appears to be triggered by a ribosome's failure to terminate adjacent to a properly configured 3′-UTR (untranslated region), an event that may promote binding of the UPF/NMD factors to stimulate mRNA decapping.

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Halim, Danny, Michael P. Wilson, Daniel Oliver, Erwin Brosens, Joke B. G. M. Verheij, Yu Han, Vivek Nanda, et al. "Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice." Proceedings of the National Academy of Sciences 114, no. 13 (March 14, 2017): E2739—E2747. http://dx.doi.org/10.1073/pnas.1620507114.

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Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital visceral myopathy characterized by severe dilation of the urinary bladder and defective intestinal motility. The genetic basis of MMIHS has been ascribed to spontaneous and autosomal dominant mutations in actin gamma 2 (ACTG2), a smooth muscle contractile gene. However, evidence suggesting a recessive origin of the disease also exists. Using combined homozygosity mapping and whole exome sequencing, a genetically isolated family was found to carry a premature termination codon in Leiomodin1 (LMOD1), a gene preferentially expressed in vascular and visceral smooth muscle cells. Parents heterozygous for the mutation exhibited no abnormalities, but a child homozygous for the premature termination codon displayed symptoms consistent with MMIHS. We used CRISPR-Cas9 (CRISPR-associated protein) genome editing of Lmod1 to generate a similar premature termination codon. Mice homozygous for the mutation showed loss of LMOD1 protein and pathology consistent with MMIHS, including late gestation expansion of the bladder, hydronephrosis, and rapid demise after parturition. Loss of LMOD1 resulted in a reduction of filamentous actin, elongated cytoskeletal dense bodies, and impaired intestinal smooth muscle contractility. These results define LMOD1 as a disease gene for MMIHS and suggest its role in establishing normal smooth muscle cytoskeletal–contractile coupling.

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Schilff, Mirco, Yelena Sargsyan, Julia Hofhuis, and Sven Thoms. "Stop Codon Context-Specific Induction of Translational Readthrough." Biomolecules 11, no. 7 (July 9, 2021): 1006. http://dx.doi.org/10.3390/biom11071006.

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Premature termination codon (PTC) mutations account for approximately 10% of pathogenic variants in monogenic diseases. Stimulation of translational readthrough, also known as stop codon suppression, using translational readthrough-inducing drugs (TRIDs) may serve as a possible therapeutic strategy for the treatment of genetic PTC diseases. One important parameter governing readthrough is the stop codon context (SCC)—the stop codon itself and the nucleotides in the vicinity of the stop codon on the mRNA. However, the quantitative influence of the SCC on treatment outcome and on appropriate drug concentrations are largely unknown. Here, we analyze the readthrough-stimulatory effect of various readthrough-inducing drugs on the SCCs of five common premature termination codon mutations of PEX5 in a sensitive dual reporter system. Mutations in PEX5, encoding the peroxisomal targeting signal 1 receptor, can cause peroxisomal biogenesis disorders of the Zellweger spectrum. We show that the stop context has a strong influence on the levels of readthrough stimulation and impacts the choice of the most effective drug and its concentration. These results highlight potential advantages and the personalized medicine nature of an SCC-based strategy in the therapy of rare diseases.

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Powers, Kyle T., Flint Stevenson-Jones, Sathish K. N. Yadav, Beate Amthor, Joshua C. Bufton, Ufuk Borucu, Dakang Shen, et al. "Blasticidin S inhibits mammalian translation and enhances production of protein encoded by nonsense mRNA." Nucleic Acids Research 49, no. 13 (June 22, 2021): 7665–79. http://dx.doi.org/10.1093/nar/gkab532.

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Abstract Deciphering translation is of paramount importance for the understanding of many diseases, and antibiotics played a pivotal role in this endeavour. Blasticidin S (BlaS) targets translation by binding to the peptidyl transferase center of the large ribosomal subunit. Using biochemical, structural and cellular approaches, we show here that BlaS inhibits both translation elongation and termination in Mammalia. Bound to mammalian terminating ribosomes, BlaS distorts the 3′CCA tail of the P-site tRNA to a larger extent than previously reported for bacterial ribosomes, thus delaying both, peptide bond formation and peptidyl-tRNA hydrolysis. While BlaS does not inhibit stop codon recognition by the eukaryotic release factor 1 (eRF1), it interferes with eRF1’s accommodation into the peptidyl transferase center and subsequent peptide release. In human cells, BlaS inhibits nonsense-mediated mRNA decay and, at subinhibitory concentrations, modulates translation dynamics at premature termination codons leading to enhanced protein production.

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Ghelfi, Mikel D., Saleem Y. Bhat, Hong Li, and Barry S. Cooperman. "A High-Throughput Assay for In Vitro Determination of Release Factor-Dependent Peptide Release from a Pretermination Complex by Fluorescence Anisotropy—Application to Nonsense Suppressor Screening and Mechanistic Studies." Biomolecules 13, no. 2 (January 27, 2023): 242. http://dx.doi.org/10.3390/biom13020242.

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Premature termination codons (PTCs) account for ~12% of all human disease mutations. Translation readthrough-inducing drugs (TRIDs) are prominent among the several therapeutic approaches being used to overcome PTCs. Ataluren is the only TRID that has been approved for treating patients suffering from a PTC disease, Duchenne muscular dystrophy, but it gives variable readthrough results in cells isolated from patients suffering from other PTC diseases. We recently elucidated ataluren’s mechanism of action as a competitive inhibitor of release factor complex (RFC) catalysis of premature termination and identified ataluren’s binding sites on the ribosome responsible for such an inhibition. These results suggest the possibility of discovering new TRIDs, which would retain ataluren’s low toxicity while displaying greater potency and generality in stimulating readthrough via the inhibition of termination. Here we present a detailed description of a new in vitro plate reader assay that we are using both to screen small compound libraries for the inhibition of RFC-dependent peptide release and to better understand the influence of termination codon identity and sequence context on RFC activity.

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Hart, Thomas C., P. Suzanne Hart, Donald W. Bowden, Michael D. Michalec, Scott A. Callison, Steve J. Walker, Yingze Zhang, and Erhan Firatli. "Mutations of the cathepsin C gene are responsible for Papillon-Lefèvre syndrome." Journal of Medical Genetics 36, no. 12 (December 1, 1999): 881–87. http://dx.doi.org/10.1136/jmg.36.12.881.

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Papillon-Lefèvre syndrome (PLS) is an autosomal recessive disorder characterised by palmoplantar hyperkeratosis and severe early onset periodontitis that results in the premature loss of the primary and secondary dentitions. A major gene locus for PLS has been mapped to a 2.8 cM interval on chromosome 11q14. Correlation of physical and genetic maps of this interval indicate it includes at least 40 ESTs and six known genes including the lysosomal protease cathepsin C gene (CTSC). The CTSCmessage is expressed at high levels in a variety of immune cells including polymorphonuclear leucocytes, macrophages, and their precursors. By RT-PCR, we found CTSC is also expressed in epithelial regions commonly affected by PLS, including the palms, soles, knees, and oral keratinised gingiva. The 4.7 kbCTSC gene consists of two exons. Sequence analysis of CTSC from subjects affected with PLS from five consanguineous Turkish families identified four different mutations. An exon 1 nonsense mutation (856C→T) introduces a premature stop codon at amino acid 286. Three exon 2 mutations were identified, including a single nucleotide deletion (2692delA) of codon 349 introducing a frameshift and premature termination codon, a 2 bp deletion (2673-2674delCT) that results in introduction of a stop codon at amino acid 343, and a G→A substitution in codon 429 (2931G→A) introducing a premature termination codon. All PLS patients were homozygous for cathepsin C mutations inherited from a common ancestor. Parents and sibs heterozygous for cathepsin C mutations do not show either the palmoplantar hyperkeratosis or severe early onset periodontitis characteristic of PLS. A more complete understanding of the functional physiology of cathepsin C carries significant implications for understanding normal and abnormal skin development and periodontal disease susceptibility.

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Baradaran-Heravi, Alireza, Aruna D. Balgi, Carla Zimmerman, Kunho Choi, Fahimeh S. Shidmoossavee, Jason S. Tan, Célia Bergeaud, et al. "Novel small molecules potentiate premature termination codon readthrough by aminoglycosides." Nucleic Acids Research 44, no. 14 (July 12, 2016): 6583–98. http://dx.doi.org/10.1093/nar/gkw638.

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Michorowska, Sylwia, Joanna Giebułtowicz, Renata Wolinowska, Anna Konopka, Anna Wilkaniec, Paweł Krajewski, Ewa Bulska, and Piotr Wroczyński. "Detection of ALDH3B2 in Human Placenta." International Journal of Molecular Sciences 20, no. 24 (December 13, 2019): 6292. http://dx.doi.org/10.3390/ijms20246292.

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Aldehyde dehydrogenase 3B2 (ALDH3B2) gene contains a premature termination codon, which can be skipped or suppressed resulting in full-length protein expression. Alternatively, the longest putative open reading frame starting with the second in-frame start codon would encode short isoform. No unequivocal evidence of ALDH3B2 expression in healthy human tissues is available. The aim of this study was to confirm its expression in human placenta characterized by the highest ALDH3B2 mRNA abundance. ALDH3B2 DNA and mRNA were sequenced. The expression was investigated using western blot. The identity of the protein was confirmed using mass spectrometry (MS). The predicted tertiary and quaternary structures, subcellular localization, and phosphorylation sites were assessed using bioinformatic analyses. All DNA and mRNA isolates contained the premature stop codon. In western blot analyses, bands corresponding to the mass of full-length protein were detected. MS analysis led to the identification of two unique peptides, one of which is encoded by the nucleotide sequence located upstream the second start codon. Bioinformatic analyses suggest cytoplasmic localization and several phosphorylation sites. Despite premature stop codon in DNA and mRNA sequences, full-length ALDH3B2 was found. It can be formed as a result of premature stop codon readthrough, complex phenomenon enabling stop codon circumvention.

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Baradaran-Heravi, Alireza, Aruna D. Balgi, Sara Hosseini-Farahabadi, Kunho Choi, Cristina Has, and Michel Roberge. "Effect of small molecule eRF3 degraders on premature termination codon readthrough." Nucleic Acids Research 49, no. 7 (March 25, 2021): 3692–708. http://dx.doi.org/10.1093/nar/gkab194.

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Abstract Premature termination codon (PTC) readthrough is considered a potential treatment for genetic diseases caused by nonsense mutations. High concentrations of aminoglycosides induce low levels of PTC readthrough but also elicit severe toxicity. Identifying compounds that enhance PTC readthrough by aminoglycosides or reduce their toxicity is a continuing challenge. In humans, a binary complex of eukaryotic release factors 1 (eRF1) and 3 (eRF3a or eRF3b) mediates translation termination. They also participate in the SURF (SMG1-UPF1-eRF1-eRF3) complex assembly involved in nonsense-mediated mRNA decay (NMD). We show that PTC readthrough by aminoglycoside G418 is considerably enhanced by eRF3a and eRF3b siRNAs and cereblon E3 ligase modulators CC-885 and CC-90009, which induce proteasomal degradation of eRF3a and eRF3b. eRF3 degradation also reduces eRF1 levels and upregulates UPF1 and selectively stabilizes TP53 transcripts bearing a nonsense mutation over WT, indicating NMD suppression. CC-90009 is considerably less toxic than CC-885 and it enhances PTC readthrough in combination with aminoglycosides in mucopolysaccharidosis type I-Hurler, late infantile neuronal ceroid lipofuscinosis, Duchenne muscular dystrophy and junctional epidermolysis bullosa patient-derived cells with nonsense mutations in the IDUA, TPP1, DMD and COL17A1 genes, respectively. Combination of CC-90009 with aminoglycosides such as gentamicin or ELX-02 may have potential for PTC readthrough therapy.

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28

Lin, Ting-Yu, and Sebastian Glatt. "ACEing premature codon termination using anticodon-engineered sup-tRNA-based therapy." Molecular Therapy - Nucleic Acids 29 (September 2022): 368–69. http://dx.doi.org/10.1016/j.omtn.2022.07.019.

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29

Zhao, W., E. Guerrero, R. H. Kerman, P. Cano, and M. A. Fernández-Viña. "DRB1*1613N: a novel DRB1 allele with a premature termination codon." Tissue Antigens 71, no. 2 (December 13, 2007): 180–82. http://dx.doi.org/10.1111/j.1399-0039.2007.00990.x.

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30

Dundar, Halil, Basak Udgu, Gürsel Biberoğlu, Aslı İnci, Fatih Ezgü, İpek Işık Gönül, İlyas Okur, and Leyla Tümer. "Triamterene-induced suppression of R227X premature termination codon in Fabry disease." Molecular Genetics and Metabolism 129, no. 2 (February 2020): S51. http://dx.doi.org/10.1016/j.ymgme.2019.11.113.

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31

Hoehn, Kenneth B., Suzanne E. McGaugh, and Mohamed A. F. Noor. "Effects of Premature Termination Codon Polymorphisms in the Drosophila pseudoobscura Subclade." Journal of Molecular Evolution 75, no. 3-4 (October 2012): 141–50. http://dx.doi.org/10.1007/s00239-012-9528-x.

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32

Papagerakis, P., H. K. Lin, K. Y. Lee, Y. Hu, J. P. Simmer, J. D. Bartlett, and J. C. C. Hu. "Premature Stop Codon in MMP20 Causing Amelogenesis Imperfecta." Journal of Dental Research 87, no. 1 (January 2008): 56–59. http://dx.doi.org/10.1177/154405910808700109.

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Proteolytic enzymes are necessary for the mineralization of dental enamel during development, and mutations in the kallikrein 4 ( KLK4) and enamelysin ( MMP20) genes cause autosomal-recessive amelogenesis imperfecta (ARAI). So far, only one KLK4 and two MMP20 mutations have been reported. We have identified an ARAI-causing point mutation (c.102G>A, g.102G>A, and p.W34X) in exon 1 of MMP20 in a proband with autosomal-recessive hypoplastic-hypomaturation amelogenesis imperfecta. The G to A transition changes the tryptophan (W) codon (TGG) at amino acid position 34 into a translation termination (X) codon (TGA). No disease-causing sequence variations were detected in KLK4. The affected enamel is thin, with mild spacing in the anterior dentition. The enamel layer is hypomineralized, does not contrast with dentin on radiographs, and tends to chip away from the underlying dentin. An intrinsic yellowish pigmentation is evident, even during eruption. The phenotype supports current ideas concerning the function of enamelysin.

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Sudo, K., M. Maekawa, T. Kanno, S. S. Li, S. Akizuki, and T. Magara. "Premature termination mutations in two patients with deficiency of lactate dehydrogenase H(B) subunit." Clinical Chemistry 40, no. 8 (August 1, 1994): 1567–70. http://dx.doi.org/10.1093/clinchem/40.8.1567.

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Abstract Two patients with low lactate dehydrogenase (LD) activity were discovered during healthcare examinations and were found to be homozygous for LD-H (heart) subunit deficiency by electrophoretic isoenzyme analysis of serum and erythrocyte hemolysate. The molecular nature of the genetic mutations was characterized by amplification by the polymerase chain reaction and DNA sequencing. In one case, a single-base substitution (T-->G transversion) at codon 147 of the LD-H(B) gene resulted in a nonsense mutation; in the other case, a deletion of 2 base pairs had occurred at codon 139, resulting in a frameshift translation and premature termination.

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34

Hall, GW, and S. Thein. "Nonsense codon mutations in the terminal exon of the beta-globin gene are not associated with a reduction in beta-mRNA accumulation: a mechanism for the phenotype of dominant beta-thalassemia." Blood 83, no. 8 (April 15, 1994): 2031–37. http://dx.doi.org/10.1182/blood.v83.8.2031.2031.

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Abstract We present in vivo evidence that there is no reduction in beta-mRNA accumulation in patients with nonsense codons in the terminal exon of the beta-globin gene. Using reverse transcriptase/polymerase chain reaction (RT-PCR), beta-globin cDNA was isolated from the reticulocytes of individuals heterozygous for nonsense codon mutations in exons II and III of the beta-globin gene. Clinically asymptomatic individuals heterozygous for mutations causing premature termination of translation in exon II [beta(0)39(C-T) and F/S71/72(+A)] were found to have almost no mutant beta-cDNA, whereas patients with nonsense codon mutations in exon III [beta 121(G-T) and beta 127(C-T)] with the clinical phenotype of thalassemia intermedia had comparable levels of mutant and normal beta-cDNA. Translation of the mutant beta-mRNA from patients with nonsense codon mutations in exon III would give rise to truncated beta- globin chains, which could explain the more severe phenotype seen in these individuals.

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35

Hall, GW, and S. Thein. "Nonsense codon mutations in the terminal exon of the beta-globin gene are not associated with a reduction in beta-mRNA accumulation: a mechanism for the phenotype of dominant beta-thalassemia." Blood 83, no. 8 (April 15, 1994): 2031–37. http://dx.doi.org/10.1182/blood.v83.8.2031.bloodjournal8382031.

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We present in vivo evidence that there is no reduction in beta-mRNA accumulation in patients with nonsense codons in the terminal exon of the beta-globin gene. Using reverse transcriptase/polymerase chain reaction (RT-PCR), beta-globin cDNA was isolated from the reticulocytes of individuals heterozygous for nonsense codon mutations in exons II and III of the beta-globin gene. Clinically asymptomatic individuals heterozygous for mutations causing premature termination of translation in exon II [beta(0)39(C-T) and F/S71/72(+A)] were found to have almost no mutant beta-cDNA, whereas patients with nonsense codon mutations in exon III [beta 121(G-T) and beta 127(C-T)] with the clinical phenotype of thalassemia intermedia had comparable levels of mutant and normal beta-cDNA. Translation of the mutant beta-mRNA from patients with nonsense codon mutations in exon III would give rise to truncated beta- globin chains, which could explain the more severe phenotype seen in these individuals.

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36

de Turris, V., P. Nicholson, R. Z. Orozco, R. H. Singer, and O. Muhlemann. "Cotranscriptional effect of a premature termination codon revealed by live-cell imaging." RNA 17, no. 12 (October 25, 2011): 2094–107. http://dx.doi.org/10.1261/rna.02918111.

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37

Wong, E., K. Hino, M. Armstrong, J. Yoon, N. Allaire, J. Conte, A. Sivachenko, C. Cotton, M. Mense, and J. Mahiou. "635 Genome-wide screen to uncover genes promoting premature termination codon readthrough." Journal of Cystic Fibrosis 21 (October 2022): S349—S350. http://dx.doi.org/10.1016/s1569-1993(22)01325-x.

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38

Borgatti, Monica, Emiliano Altamura, Francesca Salvatori, Elisabetta D’Aversa, and Nicola Altamura. "Screening Readthrough Compounds to Suppress Nonsense Mutations: Possible Application to β-Thalassemia." Journal of Clinical Medicine 9, no. 2 (January 21, 2020): 289. http://dx.doi.org/10.3390/jcm9020289.

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Several types of thalassemia (including β039-thalassemia) are caused by nonsense mutations in genes controlling globin production, leading to premature translation termination and mRNA destabilization mediated by the nonsense mediated mRNA decay. Drugs (for instance, aminoglycosides) can be designed to suppress premature translation termination by inducing readthrough (or nonsense suppression) at the premature termination codon. These findings have introduced new hopes for the development of a pharmacologic approach to cure this genetic disease. In the present review, we first summarize the principle and current status of the chemical relief for the expression of functional proteins from genes otherwise unfruitful for the presence of nonsense mutations. Second, we compare data available on readthrough molecules for β0-thalassemia. The examples reported in the review strongly suggest that ribosomal readthrough should be considered as a therapeutic approach for the treatment of β0-thalassemia caused by nonsense mutations. Concluding, the discovery of molecules, exhibiting the property of inducing β-globin, such as readthrough compounds, is of great interest and represents a hope for several patients, whose survival will depend on the possible use of drugs rendering blood transfusion and chelation therapy unnecessary.

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39

Belgrader, P., and L. E. Maquat. "Nonsense but not missense mutations can decrease the abundance of nuclear mRNA for the mouse major urinary protein, while both types of mutations can facilitate exon skipping." Molecular and Cellular Biology 14, no. 9 (September 1994): 6326–36. http://dx.doi.org/10.1128/mcb.14.9.6326-6336.1994.

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In an effort to understand the mechanisms by which nonsense codons affect RNA metabolism in mammalian cells, nonsense mutations were generated within the gene for the secretory major urinary protein (MUP) of mice. The translation of MUP mRNA normally begins within exon 1 and terminates within exon 6, the penultimate exon. Through the use of Northern (RNA) blot hybridization and assays that couple reverse transcription and PCR, a nonsense mutation within codon 50 of exon 2 or codon 143 of exon 5 was found to reduce the abundance of fully spliced, nuclear MUP mRNA to 10 to 20% of normal without an additional reduction in the abundance of cytoplasmic mRNA. In contrast, a nonsense mutation within codon 172 of exon 5 was found to have no effects on the abundance of MUP mRNA. These findings suggest that a boundary between nonsense mutations that do and do not reduce the abundance of nuclear mRNA exists within the exon preceding the exon that harbors the normal site of translation termination. In this way, the boundary is analogous to the boundary that exists within the penultimate exon of the human gene for the cytosolic enzyme triosephosphate isomerase. Assays for exon skipping, i.e., the removal of an exon as a part of the flanking introns during the process of splicing, reveal that 0.1, 2.0, and 0.1% of MUP mRNA normally lack exon 5, exon 6, and exons 5 plus 6, respectively. Relative to normal, the two nonsense mutations within exon 5 increase the abundance of RNA lacking exon 5 on average 20-fold and increase the abundance of RNA lacking exons 5 plus 6 on average 5-fold. Since only one of these nonsense mutations also reduces the abundance of fully spliced nuclear mRNA to 10 to 20% of normal, the two mechanisms by which a nonsense mutation can alter nuclear RNA metabolism must be distinct. The analysis of missense mutations within codons 143 and 172, some of which retain the nonsense mutation, indicates that the reduction in the abundance of fully spliced nuclear mRNA is dependent upon the premature termination of MUP mRNA translation, whereas skipping is attributable to nonsense mutation-mediated changes in exon 5 structure rather than to the premature termination of translation. The increase in exon 5 skipping by either the nonsense or missense mutations within codon 172 correlates with a decrease in the complementarity of exon 5 to U1 snRNA. This suggests that a 5' splice site may extend as far as 12 nucleotides into the upstream exon, which is, to our knowledge, the largest extension.

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40

Belgrader, P., and L. E. Maquat. "Nonsense but not missense mutations can decrease the abundance of nuclear mRNA for the mouse major urinary protein, while both types of mutations can facilitate exon skipping." Molecular and Cellular Biology 14, no. 9 (September 1994): 6326–36. http://dx.doi.org/10.1128/mcb.14.9.6326.

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In an effort to understand the mechanisms by which nonsense codons affect RNA metabolism in mammalian cells, nonsense mutations were generated within the gene for the secretory major urinary protein (MUP) of mice. The translation of MUP mRNA normally begins within exon 1 and terminates within exon 6, the penultimate exon. Through the use of Northern (RNA) blot hybridization and assays that couple reverse transcription and PCR, a nonsense mutation within codon 50 of exon 2 or codon 143 of exon 5 was found to reduce the abundance of fully spliced, nuclear MUP mRNA to 10 to 20% of normal without an additional reduction in the abundance of cytoplasmic mRNA. In contrast, a nonsense mutation within codon 172 of exon 5 was found to have no effects on the abundance of MUP mRNA. These findings suggest that a boundary between nonsense mutations that do and do not reduce the abundance of nuclear mRNA exists within the exon preceding the exon that harbors the normal site of translation termination. In this way, the boundary is analogous to the boundary that exists within the penultimate exon of the human gene for the cytosolic enzyme triosephosphate isomerase. Assays for exon skipping, i.e., the removal of an exon as a part of the flanking introns during the process of splicing, reveal that 0.1, 2.0, and 0.1% of MUP mRNA normally lack exon 5, exon 6, and exons 5 plus 6, respectively. Relative to normal, the two nonsense mutations within exon 5 increase the abundance of RNA lacking exon 5 on average 20-fold and increase the abundance of RNA lacking exons 5 plus 6 on average 5-fold. Since only one of these nonsense mutations also reduces the abundance of fully spliced nuclear mRNA to 10 to 20% of normal, the two mechanisms by which a nonsense mutation can alter nuclear RNA metabolism must be distinct. The analysis of missense mutations within codons 143 and 172, some of which retain the nonsense mutation, indicates that the reduction in the abundance of fully spliced nuclear mRNA is dependent upon the premature termination of MUP mRNA translation, whereas skipping is attributable to nonsense mutation-mediated changes in exon 5 structure rather than to the premature termination of translation. The increase in exon 5 skipping by either the nonsense or missense mutations within codon 172 correlates with a decrease in the complementarity of exon 5 to U1 snRNA. This suggests that a 5' splice site may extend as far as 12 nucleotides into the upstream exon, which is, to our knowledge, the largest extension.

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41

Beznosková, Petra, Zuzana Pavlíková, Jakub Zeman, Colin Echeverría Aitken, and Leoš S. Valášek. "Yeast applied readthrough inducing system (YARIS): an invivo assay for the comprehensive study of translational readthrough." Nucleic Acids Research 47, no. 12 (May 9, 2019): 6339–50. http://dx.doi.org/10.1093/nar/gkz346.

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Abstract Stop codon readthrough—the decoding of a stop codon by a near-cognate tRNA—is employed by viruses to balance levels of enzymatic and structural proteins and by eukaryotic cells to enable isoform-specific protein synthesis in response to external stimuli. Owing to the prevalence of premature termination codons in human disease, readthrough has emerged as an attractive therapeutic target. A growing list of various features, for example the +4 nucleotide immediately following the stop codon, modulate readthrough levels, underscoring the need for systematic investigation of readthrough. Here, we identified and described a complete group of yeast tRNAs that induce readthrough in the stop-codon tetranucleotide manner when overexpressed, designated readthrough-inducing tRNAs (rti-tRNAs). These rti-tRNAs are the keystones of YARIS (yeast applied readthrough inducing system), a reporter-based assay enabling simultaneous detection of readthrough levels at all twelve stop-codon tetranucleotides and as a function of the complete set of rti-tRNAs. We demonstrate the utility of YARIS for systematic study of translation readthrough by employing it to interrogate the effects of natural rti-tRNA modifications, as well as various readthrough-inducing drugs (RTIDs). This analysis identified a variety of genetic interactions demonstrating the power of YARIS to characterize existing and identify novel RTIDs.

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42

Morais, Pedro, Hironori Adachi, and Yi-Tao Yu. "Suppression of Nonsense Mutations by New Emerging Technologies." International Journal of Molecular Sciences 21, no. 12 (June 20, 2020): 4394. http://dx.doi.org/10.3390/ijms21124394.

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Nonsense mutations often result from single nucleotide substitutions that change a sense codon (coding for an amino acid) to a nonsense or premature termination codon (PTC) within the coding region of a gene. The impact of nonsense mutations is two-fold: (1) the PTC-containing mRNA is degraded by a surveillance pathway called nonsense-mediated mRNA decay (NMD) and (2) protein translation stops prematurely at the PTC codon, and thus no functional full-length protein is produced. As such, nonsense mutations result in a large number of human diseases. Nonsense suppression is a strategy that aims to correct the defects of hundreds of genetic disorders and reverse disease phenotypes and conditions. While most clinical trials have been performed with small molecules, there is an increasing need for sequence-specific repair approaches that are safer and adaptable to personalized medicine. Here, we discuss recent advances in both conventional strategies as well as new technologies. Several of these will soon be tested in clinical trials as nonsense therapies, even if they still have some limitations and challenges to overcome.

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43

Peh, J., T. Miyauchi, M. Takeda, S. Suzuki, H. Ujiie, and T. Nomura. "172 Discovery of small molecule compounds with readthrough potency at premature termination codon." Journal of Investigative Dermatology 141, no. 10 (October 2021): S177. http://dx.doi.org/10.1016/j.jid.2021.08.176.

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44

Roopnariane, Adriana, Robert J. Freed, Shawn Price, Edward J. Fox, and Timothy M. Ritty. "Osteosarcoma in a Marfan patient with a novel premature termination codon in theFBN1gene." Connective Tissue Research 52, no. 2 (July 30, 2010): 157–65. http://dx.doi.org/10.3109/03008207.2010.500430.

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45

Bidou, Laure, Olivier Bugaud, Valery Belakhov, Timor Baasov, and Olivier Namy. "Characterization of new-generation aminoglycoside promoting premature termination codon readthrough in cancer cells." RNA Biology 14, no. 3 (February 23, 2017): 378–88. http://dx.doi.org/10.1080/15476286.2017.1285480.

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46

Ferguson, Michael W., Chloe A. N. Gerak, Christalle C. T. Chow, Ettore J. Rastelli, Kyle E. Elmore, Florian Stahl, Sara Hosseini-Farahabadi, Alireza Baradaran-Heravi, Don M. Coltart, and Michel Roberge. "The antimalarial drug mefloquine enhances TP53 premature termination codon readthrough by aminoglycoside G418." PLOS ONE 14, no. 5 (May 23, 2019): e0216423. http://dx.doi.org/10.1371/journal.pone.0216423.

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47

Hoehn, Kenneth B., Suzanne E. McGaugh, and Mohamed A. F. Noor. "Erratum to: Effects of Premature Termination Codon Polymorphisms in the Drosophila pseudoobscura Subclade." Journal of Molecular Evolution 76, no. 1-2 (December 22, 2012): 81. http://dx.doi.org/10.1007/s00239-012-9537-9.

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48

Mazzoni, Cristina, and Claudio Falcone. "mRNA stability and control of cell proliferation." Biochemical Society Transactions 39, no. 5 (September 21, 2011): 1461–65. http://dx.doi.org/10.1042/bst0391461.

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Most of the studies on cell proliferation examine the control of gene expression by specific transcription factors that act on transcriptional initiation. In the last few years, it became evident that mRNA stability/turnover provides an important mechanism for post-transcriptional control of gene expression. In eukaryotes, mRNAs are mainly degraded after deadenylation by decapping and exosome pathways. Mechanisms of mRNA surveillance comprise deadenylation-independent pathways such as NMD (nonsense-mediated decay), when mRNAs harbour a PTC (premature termination codon), NSD (non-stop decay, when mRNAs lack a termination codon, and NGD (no-go decay), when mRNA translation elongation stalls. Many proteins involved in these processes are conserved from bacteria to yeast and humans. Recent papers showed the involvement of proteins deputed to decapping in controlling cell proliferation, virus replication and cell death. In this paper, we will review the newest findings in this field.

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Wang, Tong-Yun, Guo-Ju Sang, Qian Wang, Chao-Liang Leng, Zhi-Jun Tian, Jin-Mei Peng, Shu-Jie Wang, et al. "Generation of Premature Termination Codon (PTC)-Harboring Pseudorabies Virus (PRV) via Genetic Code Expansion Technology." Viruses 14, no. 3 (March 10, 2022): 572. http://dx.doi.org/10.3390/v14030572.

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Despite many efforts and diverse approaches, developing an effective herpesvirus vaccine remains a great challenge. Traditional inactivated and live-attenuated vaccines always raise efficacy or safety concerns. This study used Pseudorabies virus (PRV), a swine herpes virus, as a model. We attempted to develop a live but replication-incompetent PRV by genetic code expansion (GCE) technology. Premature termination codon (PTC) harboring PRV was successfully rescued in the presence of orthogonal system MbpylRS/tRNAPyl pair and unnatural amino acids (UAA). However, UAA incorporating efficacy seemed extremely low in our engineered PRV PTC virus. Furthermore, we failed to establish a stable transgenic cell line containing orthogonal translation machinery for PTC virus replication, and we demonstrated that orthogonal tRNAPyl is a key limiting factor. This study is the first to demonstrate that orthogonal translation system-mediated amber codon suppression strategy could precisely control PRV-PTC engineered virus replication. To our knowledge, this is the first reported PTC herpesvirus generated by GCE technology. Our work provides a proof-of-concept for generating UAAs-controlled PRV-PTC virus, which can be used as a safe and effective vaccine.

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Kangsadalampai, Sasichai, Anne Farges-Berth, S. Hande Çaglayan, and Philip G. Board. "New Mutations Causing the Premature Termination of Translation in the A Subunit Gene of Coagulation Factor XIII." Thrombosis and Haemostasis 76, no. 02 (1996): 139–42. http://dx.doi.org/10.1055/s-0038-1650542.

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SummaryThe amplification of factor XIIIA subunit gene exons and heteroduplex analysis has been used to identify two new mutations that cause severe factor XIII deficiency. One mutation in a family of French origin results from a 4 bp deletion and leads to a premature termination of translation. The other mutation occurred in a Turkish family and results from a C → T transition that inserts a premature translation stop signal at codon 400. Both mutations alter restriction enzyme sites and can be readily detected in amplified exon DNA for genetic counselling or prenatal diagnosis. The new mutations reflect the extensive molecular heterogeneity of factor XIII deficiency.

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Journal articles on the topic 'Premature termination codon'

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