RNase III cleavage demonstrates a long range RNA: RNA duplex element flanking the hepatitis C virus internal ribosome entry site

Beguiristain, Nerea

doi:10.1093/nar/gki822

Cited by 26 publications

(61 citation statements)

References 50 publications

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“…17 in Fig. 7, in 77 out of 77 isolates) has been described before in several studies (Honda et al 1999b;Wang et al 2000;Kim et al 2003;Beguiristain et al 2005). The interaction of 5 ′ UTR and Rep-Core is displayed in Supplemental Figure 2A.…”

Section: Long-range Interactionssupporting

confidence: 55%

Conserved RNA secondary structures and long-range interactions in hepatitis C viruses

Fricke

Dünnes

Zayas

et al. 2015

RNA

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Hepatitis C virus (HCV) is a hepatotropic virus with a plus-strand RNA genome of ∼9.600 nt. Due to error-prone replication by its RNA-dependent RNA polymerase (RdRp) residing in nonstructural protein 5B (NS5B), HCV isolates are grouped into seven genotypes with several subtypes. By using whole-genome sequences of 106 HCV isolates and secondary structure alignments of the plus-strand genome and its minus-strand replication intermediate, we established refined secondary structures of the 5 ′ untranslated region (UTR), the cis-acting replication element (CRE) in NS5B, and the 3 ′ UTR. We propose an alternative structure in the 5 ′ UTR, conserved secondary structures of 5B stem-loop (SL)1 and 5BSL2, and four possible structures of the X-tail at the very 3 ′ end of the HCV genome. We predict several previously unknown long-range interactions, most importantly a possible circularization interaction between distinct elements in the 5 ′ and 3 ′ UTR, reminiscent of the cyclization elements of the related flaviviruses. Based on analogy to these viruses, we propose that the 5 ′ -3 ′ UTR base-pairing in the HCV genome might play an important role in viral RNA replication. These results may have important implications for our understanding of the nature of the cis-acting RNA elements in the HCV genome and their possible role in regulating the mutually exclusive processes of viral RNA translation and replication.

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Section: Long-range Interactionssupporting

confidence: 55%

Conserved RNA secondary structures and long-range interactions in hepatitis C viruses

Fricke

Dünnes

Zayas

et al. 2015

RNA

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“…The RNA molecule representing the 59 end (59HCV-691) contained the first 691 nt of the HCV genome, therefore encompassing the whole 59 UTR and a significant portion of the core-coding sequence. This should resemble the functional folding of the IRES to be examined (Wang et al 2000;Kim et al 2003;Beguiristain et al 2005). For the 39 construct, the 39 UTR was extended at its 59 end with the three last hairpins of the NS5B coding sequence (39HCV-9181), thus enabling the correct interplay between these regions and favoring functional folding (You et al 2004;Friebe et al 2005).…”

Section: Resultsmentioning

confidence: 99%

“…The 59 core coding sequence shows a high sequence conservation rate, which was initially thought to be related to the existence of alternative reading frames (Walewski et al 2001;Xu et al 2001;Choi et al 2003;Branch et al 2005); however, its importance has recently been shown in the preservation of structures important for IRES activity and replication (domains V and VI) ( Fig. 1A; Wang et al 2000;Kim et al 2003;Beguiristain et al 2005;McMullan et al 2007;Vassilaki et al 2008). Within the 39 end of the NS5B coding sequence, the stem-loop 5BSL3.2 is embedded in a cruciform structure that has been identified as a cis-essential element for viral RNA synthesis (cis-acting replication element [CRE]) ( Fig.…”

Section: Introductionmentioning

confidence: 99%

A long-range RNA–RNA interaction between the 5′ and 3′ ends of the HCV genome

Romero-López¹,

Berzal‐Herranz²

2009

RNA

112

146

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The RNA genome of the hepatitis C virus (HCV) contains multiple conserved structural cis domains that direct protein synthesis, replication, and infectivity. The untranslatable regions (UTRs) play essential roles in the HCV cycle. Uncapped viral RNAs are translated via an internal ribosome entry site (IRES) located at the 59 UTR, which acts as a scaffold for recruiting multiple protein factors. Replication of the viral genome is initiated at the 39 UTR. Bioinformatics methods have identified other structural RNA elements thought to be involved in the HCV cycle. The 5BSL3.2 motif, which is embedded in a cruciform structure at the 39 end of the NS5B coding sequence, contributes to the three-dimensional folding of the entire 39 end of the genome. It is essential in the initiation of replication. This paper reports the identification of a novel, strand-specific, long-range RNA-RNA interaction between the 59 and 39 ends of the genome, which involves 5BSL3.2 and IRES motifs. Mutants harboring substitutions in the apical loop of domain IIId or in the internal loop of 5BSL3.2 disrupt the complex, indicating these regions are essential in initiating the kissing interaction. No complex was formed when the UTRs of the related foot and mouth disease virus were used in binding assays, suggesting this interaction is specific for HCV sequences. The present data firmly suggest the existence of a higher-order structure that may mediate a protein-independent circularization of the HCV genome. The 59-39 end bridge may have a role in viral translation modulation and in the switch from protein synthesis to RNA replication.

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“…These conformational changes involve the HCV IRES, which switches from a closed ‘circular’ conformation ‘C’ (5,7), formed by LRA (bases 24–38 in inter-domains I-II with bases 428–442 in the basal part of domain VI) to an open ‘O’ form (where bases 428–442 interact with bases 494–508; i.e. those forming the basal part of stem-loop VI).…”

Section: Discussionmentioning

confidence: 99%

In vitro characterization of a miR-122-sensitive double-helical switch element in the 5′ region of hepatitis C virus RNA

Díaz-Toledano

Ariza-Mateos

Birk

et al. 2009

Nucleic Acids Research

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It has been proposed that the hepatitis C virus (HCV) internal ribosome entry site (IRES) resides within a locked conformation, owing to annealing of its immediate flanking sequences. In this study, structure probing using Escherichia coli dsRNA-specific RNase III and other classical tools showed that this region switches to an open conformation triggered by the liver-specific microRNA, miR-122. This structural transition, observed in vitro, may be the mechanistic basis for the involvement of downstream IRES structural domain VI in translation, as well as providing a role of liver-specific miR-122 in HCV infection. In addition, the induced RNA switching at the 5′ untranslated region could ultimately represent a new mechanism of action of micro-RNAs.

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RNase III cleavage demonstrates a long range RNA: RNA duplex element flanking the hepatitis C virus internal ribosome entry site

Cited by 26 publications

References 50 publications

Conserved RNA secondary structures and long-range interactions in hepatitis C viruses

Conserved RNA secondary structures and long-range interactions in hepatitis C viruses

A long-range RNA–RNA interaction between the 5′ and 3′ ends of the HCV genome

In vitro characterization of a miR-122-sensitive double-helical switch element in the 5′ region of hepatitis C virus RNA

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