Journal articles: 'Translation initiation sites'

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Paek, Ki Young, Ka Young Hong, Incheol Ryu, Sung Mi Park, Sun Ju Keum, Oh Sung Kwon, and Sung Key Jang. "Translation initiation mediated by RNA looping." Proceedings of the National Academy of Sciences 112, no. 4 (January 12, 2015): 1041–46. http://dx.doi.org/10.1073/pnas.1416883112.

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Eukaryotic translation initiation commences at the initiation codon near the 5′ end of mRNA by a 40S ribosomal subunit, and the recruitment of a 40S ribosome to an mRNA is facilitated by translation initiation factors interacting with the m7G cap and/or poly(A) tail. The 40S ribosome recruited to an mRNA is then transferred to the AUG initiation codon with the help of translation initiation factors. To understand the mechanism by which the ribosome finds an initiation codon, we investigated the role of eIF4G in finding the translational initiation codon. An artificial polypeptide eIF4G fused with MS2 was localized downstream of the reporter gene through MS2-binding sites inserted in the 3′ UTR of the mRNA. Translation of the reporter was greatly enhanced by the eIF4G-MS2 fusion protein regardless of the presence of a cap structure. Moreover, eIF4G-MS2 tethered at the 3′ UTR enhanced translation of the second cistron of a dicistronic mRNA. The encephalomyocarditis virus internal ribosome entry site, a natural translational-enhancing element facilitating translation through an interaction with eIF4G, positioned downstream of a reporter gene, also enhanced translation of the upstream gene in a cap-independent manner. Finally, we mathematically modeled the effect of distance between the cap structure and initiation codon on the translation efficiency of mRNAs. The most plausible explanation for translational enhancement by the translational-enhancing sites is recognition of the initiation codon by the ribosome bound to the ribosome-recruiting sites through “RNA looping.” The RNA looping hypothesis provides a logical explanation for augmentation of translation by enhancing elements located upstream and/or downstream of a protein-coding region.

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Gelsinger, Diego Rivera, Emma Dallon, Rahul Reddy, Fuad Mohammad, Allen R. Buskirk, and Jocelyne DiRuggiero. "Ribosome profiling in archaea reveals leaderless translation, novel translational initiation sites, and ribosome pausing at single codon resolution." Nucleic Acids Research 48, no. 10 (May 8, 2020): 5201–16. http://dx.doi.org/10.1093/nar/gkaa304.

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Abstract High-throughput methods, such as ribosome profiling, have revealed the complexity of translation regulation in Bacteria and Eukarya with large-scale effects on cellular functions. In contrast, the translational landscape in Archaea remains mostly unexplored. Here, we developed ribosome profiling in a model archaeon, Haloferax volcanii, elucidating, for the first time, the translational landscape of a representative of the third domain of life. We determined the ribosome footprint of H. volcanii to be comparable in size to that of the Eukarya. We linked footprint lengths to initiating and elongating states of the ribosome on leadered transcripts, operons, and on leaderless transcripts, the latter representing 70% of H. volcanii transcriptome. We manipulated ribosome activity with translation inhibitors to reveal ribosome pausing at specific codons. Lastly, we found that the drug harringtonine arrested ribosomes at initiation sites in this archaeon. This drug treatment allowed us to confirm known translation initiation sites and also reveal putative novel initiation sites in intergenic regions and within genes. Ribosome profiling revealed an uncharacterized complexity of translation in this archaeon with bacteria-like, eukarya-like, and potentially novel translation mechanisms. These mechanisms are likely to be functionally essential and to contribute to an expanded proteome with regulatory roles in gene expression.

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Ganoza, M. C., E. C. Kofoid, P. Marlière, and B. G. Louis. "Potential secondary structure at translation-initiation sites." Nucleic Acids Research 16, no. 9 (1988): 4196. http://dx.doi.org/10.1093/nar/16.9.4196-a.

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Ganoza, M. C., E. C. Kofoid, P. Marlière, and B. G. Louis. "Potential secondary structure at translation-initiation sites." Nucleic Acids Research 15, no. 1 (1987): 345–60. http://dx.doi.org/10.1093/nar/15.1.345.

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Robbins-Pianka, A., M. D. Rice, and M. P. Weir. "The mRNA landscape at yeast translation initiation sites." Bioinformatics 26, no. 21 (September 6, 2010): 2651–55. http://dx.doi.org/10.1093/bioinformatics/btq509.

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Zhang, Sai, Hailin Hu, Tao Jiang, Lei Zhang, and Jianyang Zeng. "TITER: predicting translation initiation sites by deep learning." Bioinformatics 33, no. 14 (July 12, 2017): i234—i242. http://dx.doi.org/10.1093/bioinformatics/btx247.

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Choi, Myoung-Kwon, Sung-Dong Park, In-Sick Park, and Il-Soo Moon. "Localization of Translation Initiation Factors to the Postsynaptic Sites." Journal of Life Science 21, no. 11 (November 30, 2011): 1526–31. http://dx.doi.org/10.5352/jls.2011.21.11.1526.

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Li, Guo-Liang, and Tze-Yun Leong. "Feature Selection for the Prediction of Translation Initiation Sites." Genomics, Proteomics & Bioinformatics 3, no. 2 (2005): 73–83. http://dx.doi.org/10.1016/s1672-0229(05)03012-3.

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Sendoel, Ataman, Joshua G. Dunn, Edwin H. Rodriguez, Shruti Naik, Nicholas C. Gomez, Brian Hurwitz, John Levorse, et al. "Translation from unconventional 5′ start sites drives tumour initiation." Nature 541, no. 7638 (January 2017): 494–99. http://dx.doi.org/10.1038/nature21036.

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Shah, O. Jameel, Joshua C. Anthony, Scot R. Kimball, and Leonard S. Jefferson. "4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle." American Journal of Physiology-Endocrinology and Metabolism 279, no. 4 (October 1, 2000): E715—E729. http://dx.doi.org/10.1152/ajpendo.2000.279.4.e715.

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Maintenance of cellular protein stores in skeletal muscle depends on a tightly regulated synthesis-degradation equilibrium that is conditionally modulated under an extensive range of physiological and pathophysiological circumstances. Recent studies have established the initiation phase of mRNA translation as a pivotal site of regulation for global rates of protein synthesis, as well as a site through which the synthesis of specific proteins is controlled. The protein synthetic pathway is exquisitely sensitive to the availability of hormones and nutrients and employs a comprehensive integrative strategy to interpret the information provided by hormonal and nutritional cues. The translational repressor, eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and the 70-kDa ribosomal protein S6 kinase (S6K1) have emerged as important components of this strategy, and together they coordinate the behavior of both eukaryotic initiation factors and the ribosome. This review discusses the role of 4E-BP1 and S6K1 in translational control and outlines the mechanisms through which hormones and nutrients effect changes in mRNA translation through the influence of these translational effectors.

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Prats, Anne-Catherine, Florian David, Leila H. Diallo, Emilie Roussel, Florence Tatin, Barbara Garmy-Susini, and Eric Lacazette. "Circular RNA, the Key for Translation." International Journal of Molecular Sciences 21, no. 22 (November 14, 2020): 8591. http://dx.doi.org/10.3390/ijms21228591.

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It was thought until the 1990s that the eukaryotic translation machinery was unable to translate a circular RNA. However internal ribosome entry sites (IRESs) and m6A-induced ribosome engagement sites (MIRESs) were discovered, promoting 5′ end-independent translation initiation. Today a new family of so-called “noncoding” circular RNAs (circRNAs) has emerged, revealing the pivotal role of 5′ end-independent translation. CircRNAs have a strong impact on translational control via their sponge function, and form a new mRNA family as they are translated into proteins with pathophysiological roles. While there is no more doubt about translation of covalently closed circRNA, the linearity of canonical mRNA is only theoretical: it has been shown for more than thirty years that polysomes exhibit a circular form and mRNA functional circularization has been demonstrated in the 1990s by the interaction of initiation factor eIF4G with poly(A) binding protein. More recently, additional mechanisms of 3′–5′ interaction have been reported, including m6A modification. Functional circularization enhances translation via ribosome recycling and acceleration of the translation initiation rate. This update of covalently and noncovalently closed circular mRNA translation landscape shows that RNA with circular shape might be the rule for translation with an important impact on disease development and biotechnological applications.

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Ryabova, L., H. S. Park, and T. Hohn. "Control of translation reinitiation on the cauliflower mosaic virus (CaMV) polycistronic RNA." Biochemical Society Transactions 32, no. 4 (August 1, 2004): 592–96. http://dx.doi.org/10.1042/bst0320592.

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Translation of the polycistronic 35S RNA of CaMV (cauliflower mosaic virus) occurs via a reinitiation mechanism, which requires TAV (transactivator/viroplasmin). To allow translation reinitiation of the major open reading frames on the polycistronic RNA, TAV interacts with the host translational machinery via eIF3 (eukaryotic initiation factor 3) and the 60S ribosome. Accumulation of TAV and eIF3 in the polysomal fraction isolated from CaMV-infected cells suggested that TAV prevents loss of eIF3 from the translating ribosomes during the first initiation event. The TAV–eIF3–80S complex could be detected in vitro by sucrose-gradient-sedimentation analysis. The question is whether TAV interacts directly with the 48S preinitiation complex or enters polysomes after the first initiation event. eIF4B, a component of the 48S initiation complex, can preclude formation of the TAV–eIF3 complex via competition with TAV for eIF3 binding; the eIF4B- and TAV-binding sites on eIF3g overlap. eIF4B out-competes TAV for binding to eIF3 and to the eIF3–40S complex. Transient overexpression of eIF4B in plant protoplasts specifically inhibits TAV-mediated transactivation of polycistronic translation. Our results thus indicate that eIF4B precludes TAV–eIF3–40S complex formation during the first initiation event. Consequently, overexpression of TAV in plant protoplasts affects only the second and subsequent initiation events. We propose a model in which TAV enters the host translational machinery at the eIF4B-removal step to stabilize eIF3 within polysomes.

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Nakamoto, Jose A., Wilfredo Evangelista, Daria S. Vinogradova, Andrey L. Konevega, Roberto Spurio, Attilio Fabbretti, and Pohl Milón. "The dynamic cycle of bacterial translation initiation factor IF3." Nucleic Acids Research 49, no. 12 (June 23, 2021): 6958–70. http://dx.doi.org/10.1093/nar/gkab522.

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Abstract Initiation factor IF3 is an essential protein that enhances the fidelity and speed of bacterial mRNA translation initiation. Here, we describe the dynamic interplay between IF3 domains and their alternative binding sites using pre-steady state kinetics combined with molecular modelling of available structures of initiation complexes. Our results show that IF3 accommodates its domains at velocities ranging over two orders of magnitude, responding to the binding of each 30S ligand. IF1 and IF2 promote IF3 compaction and the movement of the C-terminal domain (IF3C) towards the P site. Concomitantly, the N-terminal domain (IF3N) creates a pocket ready to accept the initiator tRNA. Selection of the initiator tRNA is accompanied by a transient accommodation of IF3N towards the 30S platform. Decoding of the mRNA start codon displaces IF3C away from the P site and rate limits translation initiation. 70S initiation complex formation brings IF3 domains in close proximity to each other prior to dissociation and recycling of the factor for a new round of translation initiation. Altogether, our results describe the kinetic spectrum of IF3 movements and highlight functional transitions of the factor that ensure accurate mRNA translation initiation.

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Hoyle, Nathaniel P., and Mark P. Ashe. "Subcellular localization of mRNA and factors involved in translation initiation." Biochemical Society Transactions 36, no. 4 (July 22, 2008): 648–52. http://dx.doi.org/10.1042/bst0360648.

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Both the process and synthesis of factors required for protein synthesis (or translation) account for a large proportion of cellular activity. In eukaryotes, the most complex and highly regulated phase of protein synthesis is that of initiation. For instance, across eukaryotes, at least 12 factors containing 22 or more proteins are involved, and there are several regulated steps. Recently, the localization of mRNA and factors involved in translation has received increased attention. The present review provides a general background to the subcellular localization of mRNA and translation initiation factors, and focuses on the potential functions of localized translation initiation factors. That is, as genuine sites for translation initiation, as repositories for factors and mRNA, and as sites of regulation.

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An, Sihyeon, Oh Sung Kwon, Jinbae Yu, and Sung Key Jang. "A cyclin-dependent kinase, CDK11/p58, represses cap-dependent translation during mitosis." Cellular and Molecular Life Sciences 77, no. 22 (February 6, 2020): 4693–708. http://dx.doi.org/10.1007/s00018-019-03436-3.

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Abstract During mitosis, translation of most mRNAs is strongly repressed; none of the several explanatory hypotheses suggested can fully explain the molecular basis of this phenomenon. Here we report that cyclin-dependent CDK11/p58—a serine/threonine kinase abundantly expressed during M phase—represses overall translation by phosphorylating a subunit (eIF3F) of the translation factor eIF3 complex that is essential for translation initiation of most mRNAs. Ectopic expression of CDK11/p58 strongly repressed cap-dependent translation, and knockdown of CDK11/p58 nullified the translational repression during M phase. We identified the phosphorylation sites in eIF3F responsible for M phase-specific translational repression by CDK11/p58. Alanine substitutions of CDK11/p58 target sites in eIF3F nullified its effects on cell cycle-dependent translational regulation. The mechanism of translational regulation by the M phase-specific kinase, CDK11/p58, has deep evolutionary roots considering the conservation of CDK11 and its target sites on eIF3F from C. elegans to humans.

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Cate, Jamie H. D. "Human eIF3: from ‘blobology’ to biological insight." Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1716 (March 19, 2017): 20160176. http://dx.doi.org/10.1098/rstb.2016.0176.

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Translation in eukaryotes is highly regulated during initiation, a process impacted by numerous readouts of a cell's state. There are many cases in which cellular messenger RNAs likely do not follow the canonical ‘scanning’ mechanism of translation initiation, but the molecular mechanisms underlying these pathways are still being uncovered. Some RNA viruses such as the hepatitis C virus use highly structured RNA elements termed internal ribosome entry sites (IRESs) that commandeer eukaryotic translation initiation, by using specific interactions with the general eukaryotic translation initiation factor eIF3. Here, I present evidence that, in addition to its general role in translation, eIF3 in humans and likely in all multicellular eukaryotes also acts as a translational activator or repressor by binding RNA structures in the 5′-untranslated regions of specific mRNAs, analogous to the role of the mediator complex in transcription. Furthermore, eIF3 in multicellular eukaryotes also harbours a 5′ 7-methylguanosine cap-binding subunit—eIF3d—which replaces the general cap-binding initiation factor eIF4E in the translation of select mRNAs. Based on results from cell biological, biochemical and structural studies of eIF3, it is likely that human translation initiation proceeds through dozens of different molecular pathways, the vast majority of which remain to be explored. This article is part of the themed issue ‘Perspectives on the ribosome’.

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Petrelli, Dezemona, Cristiana Garofalo, Matilde Lammi, Roberto Spurio, Cynthia L. Pon, Claudio O. Gualerzi, and Anna La Teana. "Mapping the Active Sites of Bacterial Translation Initiation Factor IF3." Journal of Molecular Biology 331, no. 3 (August 2003): 541–56. http://dx.doi.org/10.1016/s0022-2836(03)00731-9.

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Gao, Tingting, Zhixia Yang, Yong Wang, and Ling Jing. "Identifying translation initiation sites in prokaryotes using support vector machine." Journal of Theoretical Biology 262, no. 4 (February 2010): 644–49. http://dx.doi.org/10.1016/j.jtbi.2009.10.023.

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Weir, Michael P., and Michael D. Rice. "TRII: A Probabilistic Scoring of Drosophila melanogaster Translation Initiation Sites." EURASIP Journal on Bioinformatics and Systems Biology 2010 (2010): 1–14. http://dx.doi.org/10.1155/2010/814127.

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Noderer, William L., Ross J. Flockhart, Aparna Bhaduri, Alexander J. Diaz de Arce, Jiajing Zhang, Paul A. Khavari, and Clifford L. Wang. "Quantitative analysis of mammalian translation initiation sites by FACS ‐seq." Molecular Systems Biology 10, no. 8 (August 2014): 748. http://dx.doi.org/10.15252/msb.20145136.

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Zhu, H. Q., G. Q. Hu, Z. Q. Ouyang, J. Wang, and Z. S. She. "Accuracy improvement for identifying translation initiation sites in microbial genomes." Bioinformatics 20, no. 18 (July 9, 2004): 3308–17. http://dx.doi.org/10.1093/bioinformatics/bth390.

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Zien, A., G. Ratsch, S. Mika, B. Scholkopf, T. Lengauer, and K. R. Muller. "Engineering support vector machine kernels that recognize translation initiation sites." Bioinformatics 16, no. 9 (September 1, 2000): 799–807. http://dx.doi.org/10.1093/bioinformatics/16.9.799.

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Patakottu, Balakota Reddy, Prashant Kumar Singh, Pawan Malhotra, V. S. Chauhan, and Swati Patankar. "In vivo analysis of translation initiation sites in Plasmodium falciparum." Molecular Biology Reports 39, no. 3 (June 4, 2011): 2225–32. http://dx.doi.org/10.1007/s11033-011-0971-3.

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Sen, Nandini, Feng Cao, and John E. Tavis. "Translation of Duck Hepatitis B Virus Reverse Transcriptase by Ribosomal Shunting." Journal of Virology 78, no. 21 (November 1, 2004): 11751–57. http://dx.doi.org/10.1128/jvi.78.21.11751-11757.2004.

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ABSTRACT The duck hepatitis B virus (DHBV) polymerase (P) is translated by de novo initiation from a downstream open reading frame (ORF) that partially overlaps the core (C) ORF on the bicistronic pregenomic RNA (pgRNA). The DHBV P AUG is in a poor context for translational initiation and is preceded by 14 AUGs that could intercept scanning ribosomes, yet P translation is unanticipatedly rapid. Therefore, we assessed C and P translation in the context of the pgRNA. Mutating the upstream C ORF revealed that P translation was inversely related to C translation, primarily due to occlusion of P translation by ribosomes translating C. Translation of the pgRNA was found to be cap dependent, because inserting a stem-loop (BamHI-SL) that blocked >90% of scanning ribosomes at the 5′ end of the pgRNA greatly inhibited C and P synthesis. Neither mutating AUGs between the C and P start sites in contexts similar to that of the P AUG nor blocking ribosomal scanning by inserting the BamHI-SL between the C and P start codons greatly altered P translation, indicating that most ribosomes that translate P do not scan through these sequences. Finally, optimizing the P AUG context did not increase P translation. Therefore, the majority of the ribosomes that translate P are shunted from a donor region near the 5′ end of the pgRNA to an acceptor site at or near the P AUG, and the shunt acceptor sequences may augment initiation at the P AUG.

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Kimball, Scot R., Rick L. Horetsky, David Ron, Leonard S. Jefferson, and Heather P. Harding. "Mammalian stress granules represent sites of accumulation of stalled translation initiation complexes." American Journal of Physiology-Cell Physiology 284, no. 2 (February 1, 2003): C273—C284. http://dx.doi.org/10.1152/ajpcell.00314.2002.

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In eukaryotic cells subjected to environmental stress, untranslated mRNA accumulates in discrete cytoplasmic foci that have been termed stress granules. Recent studies have shown that in addition to mRNA, stress granules also contain 40S ribosomal subunits and various translation initiation factors, including the mRNA binding proteins eIF4E and eIF4G. However, eIF2, the protein that transfers initiator methionyl-tRNAi(Met-tRNAi) to the 40S ribosomal subunit, has not been detected in stress granules. This result is surprising because the eIF2 · GTP · Met-tRNAi complex is thought to bind to the 40S ribosomal subunit before the eIF4G · eIF4E · mRNA complex. In the present study, we show in both NIH-3T3 cells and mouse embryo fibroblasts that stress granules contain not only eIF2 but also the guanine nucleotide exchange factor for eIF2, eIF2B. Moreover, we show that phosphorylation of the α-subunit of eIF2 is necessary and sufficient for stress granule formation during the unfolded protein response. Finally, we also show that stress granules contain many, if not all, of the components of the 48S preinitiation complex, but not 60S ribosomal subunits, suggesting that they represent stalled translation initiation complexes.

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Ichihara, Kazuya, Akinobu Matsumoto, Hiroshi Nishida, Yuki Kito, Hideyuki Shimizu, Yuichi Shichino, Shintaro Iwasaki, Koshi Imami, Yasushi Ishihama, and Keiichi I. Nakayama. "Combinatorial analysis of translation dynamics reveals eIF2 dependence of translation initiation at near-cognate codons." Nucleic Acids Research 49, no. 13 (July 6, 2021): 7298–317. http://dx.doi.org/10.1093/nar/gkab549.

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Abstract Although ribosome-profiling and translation initiation sequencing (TI-seq) analyses have identified many noncanonical initiation codons, the precise detection of translation initiation sites (TISs) remains a challenge, mainly because of experimental artifacts of such analyses. Here, we describe a new method, TISCA (TIS detection by translation Complex Analysis), for the accurate identification of TISs. TISCA proved to be more reliable for TIS detection compared with existing tools, and it identified a substantial number of near-cognate codons in Kozak-like sequence contexts. Analysis of proteomics data revealed the presence of methionine at the NH2-terminus of most proteins derived from near-cognate initiation codons. Although eukaryotic initiation factor 2 (eIF2), eIF2A and eIF2D have previously been shown to contribute to translation initiation at near-cognate codons, we found that most noncanonical initiation events are most probably dependent on eIF2, consistent with the initial amino acid being methionine. Comprehensive identification of TISs by TISCA should facilitate characterization of the mechanism of noncanonical initiation.

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MEIJER, Hedda A., and Adri A. M. THOMAS. "Control of eukaryotic protein synthesis by upstream open reading frames in the 5′-untranslated region of an mRNA." Biochemical Journal 367, no. 1 (October 1, 2002): 1–11. http://dx.doi.org/10.1042/bj20011706.

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Control of gene expression is achieved at various levels. Translational control becomes crucial in the absence of transcription, such as occurs in early developmental stages. One of the initiating events in translation is that the 40S subunit of the ribosome binds the mRNA at the 5′-cap structure and scans the 5′-untranslated region (5′-UTR) for AUG initiation codons. AUG codons upstream of the main open reading frame can induce formation of a translation-competent ribosome that may translate and (i) terminate and re-initiate, (ii) terminate and leave the mRNA, resulting in down-regulation of translation of the main open reading frame, or (iii) synthesize an N-terminally extended protein. In the present review we discuss how upstream AUGs can control the expression of the main open reading frame, and a comparison is made with other elements in the 5′-UTR that control mRNA translation, such as hairpins and internal ribosome entry sites. Recent data indicate the flexibility of controlling translation initiation, and how the mode of ribosome entry on the mRNA as well as the elements in the 5′-UTR can accurately regulate the amount of protein synthesized from a specific mRNA.

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de Breyne, Sylvain, and Théophile Ohlmann. "Focus on Translation Initiation of the HIV-1 mRNAs." International Journal of Molecular Sciences 20, no. 1 (December 28, 2018): 101. http://dx.doi.org/10.3390/ijms20010101.

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To replicate and disseminate, viruses need to manipulate and modify the cellular machinery for their own benefit. We are interested in translation, which is one of the key steps of gene expression and viruses that have developed several strategies to hijack the ribosomal complex. The type 1 human immunodeficiency virus is a good paradigm to understand the great diversity of translational control. Indeed, scanning, leaky scanning, internal ribosome entry sites, and adenosine methylation are used by ribosomes to translate spliced and unspliced HIV-1 mRNAs, and some require specific cellular factors, such as the DDX3 helicase, that mediate mRNA export and translation. In addition, some viral and cellular proteins, including the HIV-1 Tat protein, also regulate protein synthesis through targeting the protein kinase PKR, which once activated, is able to phosphorylate the eukaryotic translation initiation factor eIF2α, which results in the inhibition of cellular mRNAs translation. Finally, the infection alters the integrity of several cellular proteins, including initiation factors, that directly or indirectly regulates translation events. In this review, we will provide a global overview of the current situation of how the HIV-1 mRNAs interact with the host cellular environment to produce viral proteins.

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Tech, M., N. Pfeifer, B. Morgenstern, and P. Meinicke. "TICO: a tool for improving predictions of prokaryotic translation initiation sites." Bioinformatics 21, no. 17 (June 30, 2005): 3568–69. http://dx.doi.org/10.1093/bioinformatics/bti563.

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McKENNEY, KEITH, JINGXIANG TIAN, SIMONE NUNES-DUBY, JOEL HOSKINS, and PRASAD REDDY. "A Whole Genome Shotgun Gene Fusion Method for Isolation of Translation Initiation Sites in Escherichia coli: Identification of Haemophilus influenzae Translation Initiation Sites in E. coli." Microbial & Comparative Genomics 2, no. 2 (January 1997): 113–21. http://dx.doi.org/10.1089/omi.1.1997.2.113.

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Czibener, Cecilia, Diego Alvarez, Eduardo Scodeller, and Andrea V. Gamarnik. "Characterization of internal ribosomal entry sites of Triatoma virus." Journal of General Virology 86, no. 8 (August 1, 2005): 2275–80. http://dx.doi.org/10.1099/vir.0.80842-0.

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Triatoma virus (TrV) belongs to a new family of RNA viruses known as Dicistroviridae. Nucleotide sequence comparisons between different dicistroviruses allowed two putative internal ribosomal entry sites (IRESs) in the TrV RNA to be defined: the 5′UTR IRES of 548 nt and the intergenic region (IGR) IRES of 172 nt. Using monocistronic and bicistronic RNAs, it was shown that the TrV genome contains two functional IRESs that mediate translation initiation in a cap-independent manner. In addition, it was found that the two TrV IRESs were able to direct efficient translation of reporter genes in microinjected Xenopus oocytes, suggesting minimum requirements for host factors. The IGR IRES begins with a non-canonical CUC; however, mutations of this triplet to AUG or CCU did not impair IRES function, indicating that the CUC is not essential for the initiation process. Furthermore, translation efficiency from two TrV IRESs was differentially modulated by IFN-α and viral infection.

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Xu, Chuan, and Jianzhi Zhang. "Mammalian Alternative Translation Initiation Is Mostly Nonadaptive." Molecular Biology and Evolution 37, no. 7 (March 7, 2020): 2015–28. http://dx.doi.org/10.1093/molbev/msaa063.

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Abstract Alternative translation initiation (ATLI) refers to the existence of multiple translation initiation sites per gene and is a widespread phenomenon in eukaryotes. ATLI is commonly assumed to be advantageous through creating proteome diversity or regulating protein synthesis. We here propose an alternative hypothesis that ATLI arises primarily from nonadaptive initiation errors presumably due to the limited ability of ribosomes to distinguish sequence motifs truly signaling translation initiation from similar sequences. Our hypothesis, but not the adaptive hypothesis, predicts a series of global patterns of ATLI, all of which are confirmed at the genomic scale by quantitative translation initiation sequencing in multiple human and mouse cell lines and tissues. Similarly, although many codons differing from AUG by one nucleotide can serve as start codons, our analysis suggests that using non-AUG start codons is mostly disadvantageous. These and other findings strongly suggest that ATLI predominantly results from molecular error, requiring a major revision of our understanding of the precision and regulation of translation initiation.

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Xi, Qiaoran, Rafael Cuesta, and Robert J. Schneider. "Regulation of Translation by Ribosome Shunting through Phosphotyrosine-Dependent Coupling of Adenovirus Protein 100k to Viral mRNAs." Journal of Virology 79, no. 9 (May 1, 2005): 5676–83. http://dx.doi.org/10.1128/jvi.79.9.5676-5683.2005.

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ABSTRACT Adenovirus simultaneously inhibits cap-dependent host cell mRNA translation while promoting the translation of its late viral mRNAs during infection. Studies previously demonstrated that tyrosine kinase activity plays a central role in the control of late adenovirus protein synthesis. The tyrosine kinase inhibitor genistein decreases late viral mRNA translation and prevents viral inhibition of cellular protein synthesis. Adenovirus protein 100k blocks cellular mRNA translation by disrupting the cap-initiation complex and promotes viral mRNA translation through an alternate mechanism known as ribosome shunting. 100k protein interaction with initiation factor eIF4G and the viral 5′ noncoding region on viral late mRNAs, known as the tripartite leader, are both essential for ribosome shunting. We show that adenovirus protein 100k promotes ribosome shunting in a tyrosine phosphorylation-dependent manner. The primary sites of phosphorylated tyrosine on protein 100k were mapped and mutated, and two key sites are shown to be essential for protein 100k to promote ribosome shunting. Mutation of the two tyrosine phosphorylation sites in 100k protein does not impair interaction with initiation factor 4G, but it severely reduces association of 100k with tripartite leader mRNAs. 100k protein therefore promotes ribosome shunting and selective translation of viral mRNAs by binding specifically to the adenovirus tripartite leader in a phosphotyrosine-dependent manner.

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Willett, Mark, Michele Brocard, Alexandre Davide, and Simon J. Morley. "Translation initiation factors and active sites of protein synthesis co-localize at the leading edge of migrating fibroblasts." Biochemical Journal 438, no. 1 (July 27, 2011): 217–27. http://dx.doi.org/10.1042/bj20110435.

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Cell migration is a highly controlled essential cellular process, often dysregulated in tumour cells, dynamically controlled by the architecture of the cell. Studies involving cellular fractionation and microarray profiling have previously identified functionally distinct mRNA populations specific to cellular organelles and architectural compartments. However, the interaction between the translational machinery itself and cellular structures is relatively unexplored. To help understand the role for the compartmentalization and localized protein synthesis in cell migration, we have used scanning confocal microscopy, immunofluorescence and a novel ribopuromycylation method to visualize translating ribosomes. In the present study we show that eIFs (eukaryotic initiation factors) localize to the leading edge of migrating MRC5 fibroblasts in a process dependent on TGN (trans-Golgi network) to plasma membrane vesicle transport. We show that eIF4E and eIF4GI are associated with the Golgi apparatus and membrane microdomains, and that a proportion of these proteins co-localize to sites of active translation at the leading edge of migrating cells.

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LIU, HUIQING, and LIMSOON WONG. "DATA MINING TOOLS FOR BIOLOGICAL SEQUENCES." Journal of Bioinformatics and Computational Biology 01, no. 01 (April 2003): 139–67. http://dx.doi.org/10.1142/s0219720003000216.

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We describe a methodology, as well as some related data mining tools, for analyzing sequence data. The methodology comprises three steps: (a) generating candidate features from the sequences, (b) selecting relevant features from the candidates, and (c) integrating the selected features to build a system to recognize specific properties in sequence data. We also give relevant techniques for each of these three steps. For generating candidate features, we present various types of features based on the idea of k-grams. For selecting relevant features, we discuss signal-to-noise, t-statistics, and entropy measures, as well as a correlation-based feature selection method. For integrating selected features, we use machine learning methods, including C4.5, SVM, and Naive Bayes. We illustrate this methodology on the problem of recognizing translation initiation sites. We discuss how to generate and select features that are useful for understanding the distinction between ATG sites that are translation initiation sites and those that are not. We also discuss how to use such features to build reliable systems for recognizing translation initiation sites in DNA sequences.

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Mittelmeier, T. M., and C. L. Dieckmann. "In vivo analysis of sequences required for translation of cytochrome b transcripts in yeast mitochondria." Molecular and Cellular Biology 15, no. 2 (February 1995): 780–89. http://dx.doi.org/10.1128/mcb.15.2.780.

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Respiratory chain proteins encoded by the yeast mitochondrial genome are synthesized within the organelle. Mitochondrial mRNAs lack a 5' cap structure and contain long AU-rich 5' untranslated regions (UTRs) with many potential translational start sites and no apparent Shine-Dalgarno-like complementarity to the 15S mitochondrial rRNA. However, translation initiation requires specific interactions between the 5' UTRs of the mRNAs, mRNA-specific activators, and the ribosomes. In an initial step toward identifying potential binding sites for the mRNA-specific translational activators and the ribosomes, we have analyzed the effects of deletions in the 5' UTR of the mitochondrial COB gene on translation of COB transcripts in vivo. The deletions define two regions of the COB 5' UTR that are important for translation and indicate that sequence just 5' of the AUG is involved in selection of the correct start codon. Taken together, the data implicate specific regions of the 5' UTR of COB mRNA as possible targets for the mitochondrial translational machinery.

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Stewart, Joanna D., Joanne L. Cowan, Lisa S. Perry, Mark J. Coldwell, and Christopher G. Proud. "ABC50 mutants modify translation start codon selection." Biochemical Journal 467, no. 2 (April 2, 2015): 217–29. http://dx.doi.org/10.1042/bj20141453.

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ATP-binding cassette 50 (ABC50; also known as ABCF1) binds to eukaryotic initiation factor 2 (eIF2) and is required for efficient translation initiation. An essential step of this process is accurate recognition and selection of the initiation codon. It is widely accepted that the presence and movement of eIF1, eIF1A and eIF5 are key factors in modulating the stringency of start-site selection, which normally requires an AUG codon in an appropriate sequence context. In the present study, we show that expression of ABC50 mutants, which cannot hydrolyse ATP, decreases general translation and relaxes the discrimination against the use of non-AUG codons at translation start sites. These mutants do not appear to alter the association of key initiation factors to 40S subunits. The stringency of start-site selection can be restored through overexpression of eIF1, consistent with the role of that factor in enhancing stringency. The present study indicates that interfering with the function of ABC50 influences the accuracy of initiation codon selection.

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Yakhnin, Helen, Carol S. Baker, Igor Berezin, Michael A. Evangelista, Alisa Rassin, Tony Romeo, and Paul Babitzke. "CsrA Represses Translation of sdiA , Which Encodes the N -Acylhomoserine-l-Lactone Receptor of Escherichia coli, by Binding Exclusively within the Coding Region of sdiA mRNA." Journal of Bacteriology 193, no. 22 (September 9, 2011): 6162–70. http://dx.doi.org/10.1128/jb.05975-11.

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The RNA binding protein CsrA is the central component of a conserved global regulatory system that activates or represses gene expression posttranscriptionally. In every known example of CsrA-mediated translational control, CsrA binds to the 5′ untranslated region of target transcripts, thereby repressing translation initiation and/or altering the stability of the RNA. Furthermore, with few exceptions, repression by CsrA involves binding directly to the Shine-Dalgarno sequence and blocking ribosome binding. sdiA encodes the quorum-sensing receptor for N -acyl- l -homoserine lactone in Escherichia coli . Because sdiA indirectly stimulates transcription of csrB , which encodes a small RNA (sRNA) antagonist of CsrA, we further explored the relationship between sdiA and the Csr system. Primer extension analysis revealed four putative transcription start sites within 85 nucleotides of the sdiA initiation codon. Potential σ 70 -dependent promoters were identified for each of these primer extension products. In addition, two CsrA binding sites were predicted in the initially translated region of sdiA . Expression of chromosomally integrated sdiA ′-′ lacZ translational fusions containing the entire promoter and CsrA binding site regions indicates that CsrA represses sdiA expression. The results from gel shift and footprint studies demonstrate that tight binding of CsrA requires both of these sites. Furthermore, the results from toeprint and in vitro translation experiments indicate that CsrA represses translation of sdiA by directly competing with 30S ribosomal subunit binding. Thus, this represents the first example of CsrA preventing translation by interacting solely within the coding region of an mRNA target.

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Coldwell, Mark J., Ulrike Sack, Joanne L. Cowan, Rachel M. Barrett, Markete Vlasak, Keiley Sivakumaran, and Simon J. Morley. "Multiple isoforms of the translation initiation factor eIF4GII are generated via use of alternative promoters, splice sites and a non-canonical initiation codon." Biochemical Journal 448, no. 1 (October 18, 2012): 1–11. http://dx.doi.org/10.1042/bj20111765.

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During the initiation stage of eukaryotic mRNA translation, the eIF4G (eukaryotic initiation factor 4G) proteins act as an aggregation point for recruiting the small ribosomal subunit to an mRNA. We previously used RNAi (RNA interference) to reduce expression of endogenous eIF4GI proteins, resulting in reduced protein synthesis rates and alterations in the morphology of cells. Expression of EIF4G1 cDNAs, encoding different isoforms (f–a) which arise through selection of alternative initiation codons, rescued translation to different extents. Furthermore, overexpression of the eIF4GII paralogue in the eIF4GI-knockdown background was unable to restore translation to the same extent as eIF4GIf/e isoforms, suggesting that translation events governed by this protein are different. In the present study we show that multiple isoforms of eIF4GII exist in mammalian cells, arising from multiple promoters and alternative splicing events, and have identified a non-canonical CUG initiation codon which extends the eIF4GII N-terminus. We further show that the rescue of translation in eIF4GI/eIF4GII double-knockdown cells by our novel isoforms of eIF4GII is as robust as that observed with either eIF4GIf or eIF4GIe, and more than that observed with the original eIF4GII. As the novel eIF4GII sequence diverges from eIF4GI, these data suggest that the eIF4GII N-terminus plays an alternative role in initiation factor assembly.

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Hollerer, Ina, Emily N. Powers, and Gloria A. Brar. "Global mapping of translation initiation sites by TIS profiling in budding yeast." STAR Protocols 2, no. 1 (March 2021): 100250. http://dx.doi.org/10.1016/j.xpro.2020.100250.

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41

Walker, M. "A comparative genomic method for computational identification of prokaryotic translation initiation sites." Nucleic Acids Research 30, no. 14 (July 15, 2002): 3181–91. http://dx.doi.org/10.1093/nar/gkf423.

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42

Li, G., T. Y. Leong, and L. Zhang. "Translation initiation sites prediction with mixture Gaussian models in human cDNA sequences." IEEE Transactions on Knowledge and Data Engineering 17, no. 8 (August 2005): 1152–60. http://dx.doi.org/10.1109/tkde.2005.133.

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Tech, M., B. Morgenstern, and P. Meinicke. "TICO: a tool for postprocessing the predictions of prokaryotic translation initiation sites." Nucleic Acids Research 34, Web Server (July 1, 2006): W588—W590. http://dx.doi.org/10.1093/nar/gkl313.

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44

Tzanis, George, Christos Berberidis, and Ioannis Vlahavas. "StackTIS: A stacked generalization approach for effective prediction of translation initiation sites." Computers in Biology and Medicine 42, no. 1 (January 2012): 61–69. http://dx.doi.org/10.1016/j.compbiomed.2011.10.009.

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Mokas, Sophie, John R. Mills, Cristina Garreau, Marie-Josée Fournier, Francis Robert, Prabhat Arya, Randal J. Kaufman, Jerry Pelletier, and Rachid Mazroui. "Uncoupling Stress Granule Assembly and Translation Initiation Inhibition." Molecular Biology of the Cell 20, no. 11 (June 2009): 2673–83. http://dx.doi.org/10.1091/mbc.e08-10-1061.

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Cytoplasmic stress granules (SGs) are specialized regulatory sites of mRNA translation that form under different stress conditions known to inhibit translation initiation. The formation of SG occurs via two pathways; the eukaryotic initiation factor (eIF) 2α phosphorylation-dependent pathway mediated by stress and the eIF2α phosphorylation-independent pathway mediated by inactivation of the translation initiation factors eIF4A and eIF4G. In this study, we investigated the effects of targeting different translation initiation factors and steps in SG formation in HeLa cells. By depleting eIF2α, we demonstrate that reduced levels of the eIF2.GTP.Met-tRNAiMet ternary translation initiation complexes is sufficient to induce SGs. Likewise, reduced levels of eIF4B, eIF4H, or polyA-binding protein, also trigger SG formation. In contrast, depletion of the cap-binding protein eIF4E or preventing its assembly into eIF4F results in modest SG formation. Intriguingly, interfering with the last step of translation initiation by blocking the recruitment of 60S ribosome either with 2-(4-methyl-2,6-dinitroanilino)-N-methylpropionamideis or through depletion of the large ribosomal subunits protein L28 does not induce SG assembly. Our study identifies translation initiation steps and factors involved in SG formation as well as those that can be targeted without induction of SGs.

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Johnson, Alex G., Rosslyn Grosely, Alexey N. Petrov, and Joseph D. Puglisi. "Dynamics of IRES-mediated translation." Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1716 (March 19, 2017): 20160177. http://dx.doi.org/10.1098/rstb.2016.0177.

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Viral internal ribosome entry sites (IRESs) are unique RNA elements, which use stable and dynamic RNA structures to recruit ribosomes and drive protein synthesis. IRESs overcome the high complexity of the canonical eukaryotic translation initiation pathway, often functioning with a limited set of eukaryotic initiation factors. The simplest types of IRESs are typified by the cricket paralysis virus intergenic region (CrPV IGR) and hepatitis C virus (HCV) IRESs, both of which independently form high-affinity complexes with the small (40S) ribosomal subunit and bypass the molecular processes of cap-binding and scanning. Owing to their simplicity and ribosomal affinity, the CrPV and HCV IRES have been important models for structural and functional studies of the eukaryotic ribosome during initiation, serving as excellent targets for recent technological breakthroughs in cryogenic electron microscopy (cryo-EM) and single-molecule analysis. High-resolution structural models of ribosome : IRES complexes, coupled with dynamics studies, have clarified decades of biochemical research and provided an outline of the conformational and compositional trajectory of the ribosome during initiation. Here we review recent progress in the study of HCV- and CrPV-type IRESs, highlighting important structural and dynamics insights and the synergy between cryo-EM and single-molecule studies. This article is part of the themed issue ‘Perspectives on the ribosome’.

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47

Tarun, S. Z., and A. B. Sachs. "Binding of eukaryotic translation initiation factor 4E (eIF4E) to eIF4G represses translation of uncapped mRNA." Molecular and Cellular Biology 17, no. 12 (December 1997): 6876–86. http://dx.doi.org/10.1128/mcb.17.12.6876.

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mRNA translation in crude extracts from the yeast Saccharomyces cerevisiae is stimulated by the cap structure and the poly(A) tail through the binding of the cap-binding protein eukaryotic translation initiation factor 4E (eIF4E) and the poly(A) tail-binding protein Pab1p. These proteins also bind to the translation initiation factor eIF4G and thereby link the mRNA to the general translational apparatus. In contrast, uncapped, poly(A)-deficient mRNA is translated poorly in yeast extracts, in part because of the absence of eIF4E and Pab1p binding sites on the mRNA. Here, we report that uncapped-mRNA translation is also repressed in yeast extracts due to the binding of eIF4E to eIF4G. Specifically, we find that mutations which weaken the eIF4E binding site on the yeast eIF4G proteins Tif4631p and Tif4632p lead to temperature-sensitive growth in vivo and the stimulation of uncapped-mRNA translation in vitro. A mutation in eIF4E which disturbs its ability to interact with eIF4G also leads to a stimulation of uncapped-mRNA translation in vitro. Finally, overexpression of eIF4E in vivo or the addition of excess eIF4E in vitro reverses these effects of the mutations. These data support the hypothesis that the eIF4G protein can efficiently stimulate translation of exogenous uncapped mRNA in extracts but is prevented from doing so as a result of its association with eIF4E. They also suggest that some mRNAs may be translationally regulated in vivo in response to the amount of free eIF4G in the cell.

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Cargnello, Marie, and Ivan Topisirovic. "c-Myc steers translation in lymphoma." Journal of Experimental Medicine 216, no. 7 (June 17, 2019): 1471–73. http://dx.doi.org/10.1084/jem.20190721.

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Members of the MYC family of oncogenes are master regulators of mRNA translation. In this issue of JEM, Singh et al. (https://doi.org/10.1084/jem.20181726) demonstrate that c-Myc governs protein synthesis in lymphoma cells by interfering with SRSF1- and RBM42-mediated suppression of mRNA translation and by altering selection of translation initiation sites.

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Thiadens, Klaske A. M. H., and Marieke von Lindern. "Selective mRNA translation in erythropoiesis." Biochemical Society Transactions 43, no. 3 (June 1, 2015): 343–47. http://dx.doi.org/10.1042/bst20150009.

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The daily production of up to 1011 erythrocytes is tightly controlled to maintain the number of erythrocytes in peripheral blood between narrow boundaries. Availability of growth factors and nutrients, particularly iron, control the proliferation and survival of precursor cells partly through control of mRNA translation. General translation initiation mechanisms can selectively control translation of transcripts that carry specific structures in the UTRs. This selective mRNA translation is an important layer of gene expression regulation in erythropoiesis. Ribosome profiling is a recently developed high throughput sequencing technique for global mapping of translation initiation sites across the transcriptome. Here we describe what is known about control of mRNA translation in erythropoiesis and how ribosome profiling will help to further our knowledge. Ribosome footprinting will give insight in transcript-specific translation at codon resolution, which is of great value to understand many cellular processes during erythropoiesis. It will be of particular interest to understand responses to iron availability and reactive oxygen species (ROS), which affects translation initiation of transcripts harbouring upstream ORFs (uORF) and potential alternative downstream ORFs (aORF).

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Espah Borujeni, Amin, Anirudh S. Channarasappa, and Howard M. Salis. "Translation rate is controlled by coupled trade-offs between site accessibility, selective RNA unfolding and sliding at upstream standby sites." Nucleic Acids Research 42, no. 4 (November 14, 2013): 2646–59. http://dx.doi.org/10.1093/nar/gkt1139.

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Abstract The ribosome’s interactions with mRNA govern its translation rate and the effects of post-transcriptional regulation. Long, structured 5′ untranslated regions (5′ UTRs) are commonly found in bacterial mRNAs, though the physical mechanisms that determine how the ribosome binds these upstream regions remain poorly defined. Here, we systematically investigate the ribosome’s interactions with structured standby sites, upstream of Shine–Dalgarno sequences, and show that these interactions can modulate translation initiation rates by over 100-fold. We find that an mRNA’s translation initiation rate is controlled by the amount of single-stranded surface area, the partial unfolding of RNA structures to minimize the ribosome’s binding free energy penalty, the absence of cooperative binding and the potential for ribosomal sliding. We develop a biophysical model employing thermodynamic first principles and a four-parameter free energy model to accurately predict the ribosome’s translation initiation rates for 136 synthetic 5′ UTRs with large structures, diverse shapes and multiple standby site modules. The model predicts and experiments confirm that the ribosome can readily bind distant standby site modules that support high translation rates, providing a physical mechanism for observed context effects and long-range post-transcriptional regulation.

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Journal articles on the topic 'Translation initiation sites'

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