The 5'-untranslated regions of picornavirus RNAs contain independent functional domains essential for RNA replication and translation

Rohll, Jonathan B.; Percy, N; Ley, Ruth E.; Evans, David J.; Almond, Jeffrey W.; Barclay, Wendy S.

doi:10.1128/jvi.68.7.4384-4391.1994

Cited by 142 publications

(81 citation statements)

References 31 publications

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“…Notably, replacements of the functional genomic parts by functionally analogous parts of the genomes of not closely related viruses may sometimes also be relatively well tolerated, as exemplified by engineered poliovirus genomes with the IRES of encephalomyocarditis virus (EMCV; a cardiovirus) (117,268) or human hepatitis C virus (HCV) (285) in place of their own structurally different IRES.…”

Section: (Relative) Neutrality Of Various Mutationsmentioning

confidence: 99%

“…An explanation may consist of the assumption that even these "incorrect" tetraloops (or, rather, their minute proportions) may acquire an acceptable conformation (52,305,306). A strong, though not fatal, debilitation of poliovirus caused by inversion of the sequence of stem-loop b of oriL could be partially ameliorated by spontaneous acquisition of nucleotide substitutions in the loop (117).…”

Section: Rehabilitation After Adverse Changes In the Untranslated Regmentioning

confidence: 99%

“…In many enteroviruses, it is represented by a multidomain quasi-globular RNA structure maintained by a tertiary kissing interaction. Polioviruses and other representatives of enterovirus C species have two stem-loops, X and Y, while enteroviruses of species B have an additional stem-loop, Z, and human rhinoviruses have a single stem-loop (115)(116)(117)(118)(119)(120)(121). Picornavirus oriRs are polyfunctional (122), being involved in negative RNA strand initiation (116,119,123), polyadenylation of the genomic RNA (124), and control of translation through (primarily but not only protein-mediated) interaction with the 5= UTR, which results in noncovalent circularization of the genome (96,(125)(126)(127)(128)(129)(130).…”

Section: Introductionmentioning

confidence: 99%

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Emergency Services of Viral RNAs: Repair and Remodeling

Agol

Gmyl

2018

Microbiol Mol Biol Rev

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Reproduction of RNA viruses is typically error-prone due to the infidelity of their replicative machinery and the usual lack of proofreading mechanisms. The error rates may be close to those that kill the virus. Consequently, populations of RNA viruses are represented by heterogeneous sets of genomes with various levels of fitness. This is especially consequential when viruses encounter various bottlenecks and new infections are initiated by a single or few deviating genomes. Nevertheless, RNA viruses are able to maintain their identity by conservation of major functional elements. This conservatism stems from genetic robustness or mutational tolerance, which is largely due to the functional degeneracy of many protein and RNA elements as well as to negative selection. Another relevant mechanism is the capacity to restore fitness after genetic damages, also based on replicative infidelity. Conversely, error-prone replication is a major tool that ensures viral evolvability. The potential for changes in debilitated genomes is much higher in small populations, because in the absence of stronger competitors low-fit genomes have a choice of various trajectories to wander along fitness landscapes. Thus, low-fit populations are inherently unstable, and it may be said that to run ahead it is useful to stumble. In this report, focusing on picornaviruses and also considering data from other RNA viruses, we review the biological relevance and mechanisms of various alterations of viral RNA genomes as well as pathways and mechanisms of rehabilitation after loss of fitness. The relationships among mutational robustness, resilience, and evolvability of viral RNA genomes are discussed.

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Section: (Relative) Neutrality Of Various Mutationsmentioning

confidence: 99%

Section: Rehabilitation After Adverse Changes In the Untranslated Regmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Emergency Services of Viral RNAs: Repair and Remodeling

Agol

Gmyl

2018

Microbiol Mol Biol Rev

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“…The genome can essentially be considered modular, consisting of structural (P1) and replication (P2 and P3) components, together with the flanking translation and replication determinants occupying the 5 and 3 NCRs (3,4). This modularity is emphasized in in vitro studies in which viable recombinants have been engineered or selected (5,6). More compellingly, studies of paralysis induced by vaccine derived recombinant polioviruses (VDRP)--in which the live attenuated Sabin vaccine strain has recombined with a co-circulating species C enterovirus--have demonstrated the importance of recombination in vivo (7).…”

Section: Introductionmentioning

confidence: 99%

Biochemical and genetic analysis of the role of the viral polymerase in enterovirus recombination

Woodman

Arnold

Cameron

et al. 2016

Nucleic Acids Research

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Genetic recombination in single-strand, positive-sense RNA viruses is a poorly understand mechanism responsible for generating extensive genetic change and novel phenotypes. By moving a critical cis-acting replication element (CRE) from the polyprotein coding region to the 3′ non-coding region we have further developed a cell-based assay (the 3′CRE-REP assay) to yield recombinants throughout the non-structural coding region of poliovirus from dually transfected cells. We have additionally developed a defined biochemical assay in which the only protein present is the poliovirus RNA dependent RNA polymerase (RdRp), which recapitulates the strand transfer events of the recombination process. We have used both assays to investigate the role of the polymerase fidelity and nucleotide turnover rates in recombination. Our results, of both poliovirus intertypic and intratypic recombination in the CRE-REP assay and using a range of polymerase variants in the biochemical assay, demonstrate that RdRp fidelity is a fundamental determinant of recombination frequency. High fidelity polymerases exhibit reduced recombination and low fidelity polymerases exhibit increased recombination in both assays. These studies provide the basis for the analysis of poliovirus recombination throughout the non-structural region of the virus genome and provide a defined biochemical assay to further dissect this important evolutionary process.

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“…Similar results were obtained when Gitlin et al 77 targeted the well conserved and highly structured 5′ noncoding region of the poliovirus RNA genome 77 . As we have noted, RNA-protein interactions may also negatively influence RNAi sensitivity [106][107][108] .…”

Section: Rnai Insensitivity Due To Viral Rna Structurementioning

confidence: 78%

RNA interference against viruses: strike and counterstrike

2007

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RNA interference (RNAi) is a conserved sequence-specific, gene-silencing mechanism that is induced by double-stranded RNA. RNAi holds great promise as a novel nucleic acid-based therapeutic against a wide variety of diseases, including cancer, infectious diseases and genetic disorders. Antiviral RNAi strategies have received much attention and several compounds are currently being tested in clinical trials. Although induced RNAi is able to trigger profound and specific inhibition of virus replication, it is becoming clear that RNAi therapeutics are not as straightforward as we had initially hoped. Difficulties concerning toxicity and delivery to the right cells that earlier hampered the development of antisense-based therapeutics may also apply to RNAi. In addition, there are indications that viruses have evolved ways to escape from RNAi. Proper consideration of all of these issues will be necessary in the design of RNAi-based therapeutics for successful clinical intervention of human pathogenic viruses.

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The 5'-untranslated regions of picornavirus RNAs contain independent functional domains essential for RNA replication and translation

Cited by 142 publications

References 31 publications

Emergency Services of Viral RNAs: Repair and Remodeling

Emergency Services of Viral RNAs: Repair and Remodeling

Biochemical and genetic analysis of the role of the viral polymerase in enterovirus recombination

RNA interference against viruses: strike and counterstrike

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