cis acting RNA sequences control the gag-pol translation readthrough in murine leukemia virus

Honigman, Alik; Wolf, Dana; Yaish, Shoshanit; Falk, Haya; Panet, Amos

doi:10.1016/0042-6822(91)90144-z

Cited by 40 publications

(32 citation statements)

References 35 publications

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“…On the basis of these observations, Jones et al ( 1989) suggested that a region of secondary structure near the UAG codon must be preserved; however, their study did not test the effect of destabilizing mutations upstream of the UAG codon (e.g., A2223 to C alone) nor did they measure suppression directly. In a related series of experiments carried out in uitro, Honigman et al (1991) introduced destabilizing mutations into residues in the stem of the putative stem-loop structure ( Fig. 3 ) a t positions 5' (nt 2222-2226, GACCC to AAUAU) and 3' (nt 2246-2250, GGGUC to UCAUG) of the UAG codon.…”

Section: Possible Suppression Signals In Mammalian Type C Retroviral mentioning

confidence: 99%

“…The upstream mutation had no effect on suppression in the in uitro system; in contrast, the downstream mutation prevented readthrough. These results led Honigman et al (1991) to conclude that a secondary structure involving the UAG codon and nearby nucleotides at the MuLV gug-pol junction is unlikely to be important in suppression and in addition emphasized the role of the downstream sequences. It is interesting that stem-loop structures similar to the one shown in Fig.…”

Section: Possible Suppression Signals In Mammalian Type C Retroviral mentioning

confidence: 99%

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Translational Suppression in Retroviral GENE Expression

Hatfield

Levin

Rein

et al. 1992

Advances in Virus Research

121

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Section: Possible Suppression Signals In Mammalian Type C Retroviral mentioning

confidence: 99%

Section: Possible Suppression Signals In Mammalian Type C Retroviral mentioning

confidence: 99%

Translational Suppression in Retroviral GENE Expression

Hatfield

Levin

Rein

et al. 1992

Advances in Virus Research

121

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“…MoMuLV PR(Ϫ) contains a D32L substitution (nucleotides GAT to CTT) at the active site of PR preventing protease activity. The readthrough event that produces MoMuLV Gag-Pol is dependant on a bipartite signal consisting of a purine-rich region immediately downstream from the Gag TAG codon (15,25), followed by a RNA pseudoknot structure (25). MoMuLV Gag UAA contains an additional termination codon at amino acid 18 of the PR gene (nucleotides ATA to TAA) downstream of the readthrough RNA stem-loop structure, which prevents translation of full-length PR, RT, and IN.…”

Section: Methodsmentioning

confidence: 99%

Analysis of the Contribution of Reverse Transcriptase and Integrase Proteins to Retroviral RNA Dimer Conformation

Buxton

Tachedjian

Mak

2005

J Virol

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All retroviruses contain two strands of RNA that bind together noncovalently to form dimers. The evolutionary conservation of genomic RNA dimerization illustrates its importance in the retroviral life cycle (reviewed in references 19, 51, and 57). The dimeric RNA structure is one of the conformations that human immunodeficiency virus type 1 (HIV-1) genomic RNA assumes, and different structural motifs of retroviral genomic RNA are required at distinct stages of virus production. Hence, RNA structures are thought to be important regulatory elements of HIV-1 replication (12).Dimeric RNA from several different retroviruses has been visualized by electron microscopy and was shown to interact near the 5Ј end of the genome at a region designated the dimer linkage structure (8, 9, 33, 44). In HIV-1, a region important for RNA dimerization termed the dimerization initiation site (DIS) was identified through the use of short, in vitro-transcribed RNA strands (14,34,43,47,65). The DIS is located within the 5Ј untranslated region of the genome and forms a hairpin structure (65). Mutations that prevent formation of the DIS loop self-complementary region prevent the RNA dimerization of in vitro-transcribed RNA strands (47,48,65). Dimerization of genomic RNA is critical for the strand transfer of newly synthesized viral cDNA and template switching during reverse transcription (4, 5, 10), and probably one of the most important functions of genomic RNA dimerization is that it enables the recombination of retroviral genomes during reverse transcription (4,5,71). Regions of the genome involved in RNA dimerization have also been shown to have increased recombination, such as the dimer linkage structure of murine leukemia virus (40) and the DIS in HIV-1 (4, 5). Therefore, the dimeric conformation of RNA may regulate recombination events, which are important in terms of viral fitness, enabling increased genetic variability and rescue of reverse transcription in the event of strand breakage.HIV-1 RNA structural motifs have been shown to have critical regulatory roles at multiple steps of the viral life cycle, including translation control of HIV-1 Gag and Gag-polymerase (Pol) polyproteins via an RNA stem-loop to induce ribosomal frameshifting (28) and transcriptional regulation through the trans activation response element RNA structure (11). In addition, the HIV-1 5Ј untranslated region contains multiple RNA structural motifs that are required for packaging of genomic RNA (37) and reverse transcription of viral genomic RNA (6,7,38). It has been proposed that HIV-1 genomic RNA can also assume alternative conformations that serve as a switch between a translation-competent mRNA and a dimerization and packaging-competent genomic RNA (27). It is thought that the long-distance interaction (LDI) formed by the translation-competent RNA masks the DIS, preventing dimerization. Conversely, the branched multiple hairpin (BMH) structure exposes the DIS promoting dimerization and packaging while occluding the Gag start codon (1). In vitro evidenc...

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“…In murine leukaemia virus (MLV), a 63-nucleotide read-through signal folds as a pseudoknotted 7–9 structure (MLV-PK) that can independently direct recoding of stop codons 5,6,10 , even in heterologous RNA (see Supplementary Text and Supplementary Fig. 1a).…”

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confidence: 99%

An equilibrium-dependent retroviral mRNA switch regulates translational recoding

Houck-Loomis

Durney

Salguero

et al. 2011

Nature

128

150

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Most retroviruses require translational recoding of a viral messenger RNA stop codon to maintain a precise ratio of structural (Gag) and enzymatic (Pol) proteins during virus assembly1,2. Pol is expressed exclusively as a Gag–Pol fusion either by ribosomal frameshifting or by read-through of the gag stop codon3. Both of these mechanisms occur infrequently and only affect 5–10% of translating ribosomes, allowing the virus to maintain the critical Gag to Gag–Pol ratio4–8. Although it is understood that the frequency of the recoding event is regulated by cis RNA motifs, no mechanistic explanation is currently available for how the critical protein ratio is maintained. Here we present the NMR structure of the murine leukaemia virus recoding signal and show that a protonation-dependent switch occurs to induce the active conformation. The equilibrium is such that at physiological pH the active, read-through permissive conformation is populated at approximately 6%: a level that correlates with in vivo protein quantities. The RNA functions by a highly sensitive, chemo-mechanical coupling tuned to ensure an optimal read-through frequency. Similar observations for a frameshifting signal indicate that this novel equilibrium-based mechanism may have a general role in translational recoding.

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cis acting RNA sequences control the gag-pol translation readthrough in murine leukemia virus

Cited by 40 publications

References 35 publications

Translational Suppression in Retroviral GENE Expression

Translational Suppression in Retroviral GENE Expression

Analysis of the Contribution of Reverse Transcriptase and Integrase Proteins to Retroviral RNA Dimer Conformation

An equilibrium-dependent retroviral mRNA switch regulates translational recoding

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