Functional analysis of the internal translation initiation site of foot-and-mouth disease virus

Kühn, Richard; Luz, N; Beck, Ewald

doi:10.1128/jvi.64.10.4625-4631.1990

Cited by 182 publications

(106 citation statements)

References 39 publications

(45 reference statements)

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“…Point mutations in the pyrimidine-rich tract of the FMDV IRES decreased the efficiency of internal initiation in the rabbit reticulocyte lysate system, but again these mutations involved introducing G residues (Kuhn et al, 1990). Similar qualifications apply to the finding that a linker replacement of the 5'-part of the EMCV IRES oligopyrimidine tract abrogated internal initiation in the reticulocyte lysate, for in this case the inserted linker had the potential to base-pair with a sequence in the spacer immediately downstream (Jang and Wimmer, 1990).…”

Section: Discussionmentioning

confidence: 82%

“…This prompted the construction of mutants in which the pyrimidines were substituted by purines (mainly by A residues). In view of previous claims that at least the 5 '-proximal part of the pyrimidine-rich tract is essential for IRES function in several different picornavirus species (Iizuka et al, 1989;Jang and Wimmer, 1990;Kuhn et al, 1990;Meerovitch et al, 1991;Nicholson et al, 1991;Pestova et al, 1991;Pilipenko et al, 1992), it was surprising to find that initiation efficiency was decreased by only 10-15 % when all but two of the pyrimidines were substituted by purines, and by not more than 30-35% when the whole pyrimidine-rich tract was replaced in this way.…”

Section: Introductionmentioning

confidence: 99%

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Translation of encephalomyocarditis virus RNA: parameters influencing the selection of the internal initiation site.

1994

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The initiation of encephalomyocarditis virus RNA translation is by internal ribosome entry almost exclusively at the 11th AUG codon from the 5′‐end, which is the central of the three AUG codons in the sequence..[sequence: see text].., and is located some 25 nt downstream from an oligopyrimidine tract conserved amongst related viruses. As the sequences between the oligopyrimidine tract and AUG‐10/11 are poorly conserved and thus possibly serve only as a spacer, the influence of this spacer length on initiation frequency at the three AUG codons was examined in vitro and in vivo. Deletion of 11 residues resulted in initiation almost exclusively at AUG‐12 but at significantly reduced overall efficiency. Insertion of eight residues caused a 15‐fold increase in initiation frequency at AUG‐10 and a decrease at AUG‐11. Longer insertions reduced overall efficiency without changing the initiation site preferences. With the wild‐type spacing, complete substitution of the oligopyrimidine tract by purines caused a 30‐35% decrease in initiation efficiency, and partial substitution only a 10‐15% decrease. Thus the internal initiation mechanism selects the initiation site partly on the basis of its distance from upstream elements, of which the oligopyrimidine tract is not the most critical, but for reasons not yet understood a preference for AUG‐11 is superimposed on this selection.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Translation of encephalomyocarditis virus RNA: parameters influencing the selection of the internal initiation site.

1994

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“…Results from a number of laboratories (Jang et al, 1988(Jang et al, , 1989Belsham and Brangwyn, 1990;Kuhn et a/., 1990;Pelletier and Sonenberg, 1988;Bienkowska-Szewczyk and Ehrenfeld, 1988;Jackson et a/., 1990)…”

Section: Discussionmentioning

confidence: 99%

“…Base complementarity between the pyrimidine stretch of the picornavirus mRNA and 18 S rRNA may participate in the interaction between viral mRNA and the small ribosomal subunit (Kuhn et al,, 1990;. The pyrimidine stretch UUUCC has been suggested to be an analogue of the prokaryotic Shine-Dalgarno sequence by Agol and co-workers (Pilipenko et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Conserved tertiary structure elements in the 5′ untranslated region of human enteroviruses and rhinoviruses

Chen

Sonenberg

et al. 1992

Virology

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A combination of comparative sequence analysis and thermodynamic methods reveals the conservation of tertiary structure elements in the 5' untranslated region (UTR) of human enteroviruses and rhinoviruses. The predicted common structural elements occur in the 3' end of a segment that is critical for internal ribosome binding, termed "ribosome landing pad" (RLP), of polioviruses. Base pairings between highly conserved 17-nucleotide (nt) and 21-nt sequences in the 5' UTR of human enteroviruses and rhinoviruses constitute a predicted pseudoknot that is significantly more stable than those that can be formed from a large set of randomly shuffled sequences. A conserved single-stranded polypyrimidine tract is located between two conserved tertiary elements. R. Nicholson, J. Pelletier, S.-Y. Le, and N. Sonenberg (1991, J. Virol. 65, 5886-5894) demonstrated that the point mutations of 3-nt UUU out of an essential 4-nt pyrimidine stretch sequence UUUC abolished translation. Structural analysis of the mutant sequence indicates that small point mutations within the short polypyrimidine sequence would destroy the tertiary interaction in the predicted, highly ordered structure. The proposed common tertiary structure can offer experimentalists a model upon which to extend the interpretations for currently available data. Based on these structural features possible base-pairing models between human enteroviruses and 18 S rRNA and between human rhinoviruses and 18 S rRNA are proposed. The proposed common structure implicates a biological function for these sequences in translational initiation.

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“…Instead, a viral protein (VPg) is covalently linked to the 59end of the viral RNA [4]. The 59UTR comprises a long hairpin (termed S), a poly(C) tract of variable length, a variable region folding as two to four pseudoknots, the cisreplication element (cre), and the internal ribosome entry site (IRES) element that mediates cap-independent translation of the viral RNA [5,6,7]. The 39UTR consists of a region of about 90 nt and a poly(A) tail, which stimulate IRES activity and participates in viral RNA replication [8,9].…”

Section: Introductionmentioning

confidence: 99%

Exploring IRES Region Accessibility by Interference of Foot-and-Mouth Disease Virus Infectivity

et al. 2012

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Translation initiation of picornavirus RNA is driven by an internal ribosome entry site (IRES) element located upstream of the initiator codon. RNA structure organization as well as RNA-protein interaction plays a fundamental role in internal initiation. IRES activity has been mainly analyzed in the context of reporter genes, lacking regions of the viral genome potentially affecting translation efficiency. With the aim to understand the vulnerability of the IRES and translation start region to small molecules in the context of the viral genome, we designed a set of customized RNase-resistant 2′O-methyl antisense oligoribonucleotides (2′OMe AONs) based on RNA structure data. These AONs were then used to monitor their capacity to interfere viral RNA translation, and thus, to inhibit virus yield. Foot-and-mouth disease virus (FMDV) RNA translation can be initiated at two in-frame AUG codons. We show here that a 2′OMe AON complementary to AUG2 inhibited viral multiplication more efficiently than the one that targeted AUG1. Furthermore, the response of the viral RNA to AONs targeting the IRES region denoted important differences between tissue culture cells and cell-free systems, reinforcing the need to analyze viral RNA response in living cells. Importantly, we have identified four specific motifs within the IRES element that are targets for viral inhibitors both in tissue culture cells and in cell-free systems. The identified targets define accessible regions to small molecules, which disturb either the RNA structural organization or the RNA-protein interactions needed to initiate translation in FMDV RNA.

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Functional analysis of the internal translation initiation site of foot-and-mouth disease virus

Cited by 182 publications

References 39 publications

Translation of encephalomyocarditis virus RNA: parameters influencing the selection of the internal initiation site.

Translation of encephalomyocarditis virus RNA: parameters influencing the selection of the internal initiation site.

Conserved tertiary structure elements in the 5′ untranslated region of human enteroviruses and rhinoviruses

Exploring IRES Region Accessibility by Interference of Foot-and-Mouth Disease Virus Infectivity

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