Form confers function: Case of the 3'X region of the hepatitis C virus genome

Abstract

At the 3' end of genomic hepatitis C virus (HCV) RNA there is a highly conserved untranslated region, the 3'X-tail, which forms part of the 3'UTR. This region plays key functions in regulation of critical processes of the viral life cycle. The 3'X region is essential for viral replication and infectivity. It is also responsible for regulation of switching between translation and transcription of the viral RNA. There is some evidence indicating the contribution of the 3'X region to the translation efficiency of the viral polyprotein and to the encapsidation process. Several different secondary structure models of the 3'X region, based on computer predictions and experimental structure probing, have been proposed. It is likely that the 3'X region adopts more than one structural form in infected cells and that a specific equilibrium between the various forms regulates several aspects of the viral life cycle. The most intriguing explanations of the structural heterogeneity problem of the 3'X region came with the discovery of its involvement in long-range RNA-RNA interactions and the potential for homodimer formation. This article summarizes current knowledge on the structure and function of the 3'X region of hepatitis C genomic RNA, reviews previous opinions, presents new hypotheses and summarizes the questions that still remain unanswered.

Keywords: 3’UTR; 3’X RNA; 3’X region; 3’X-tail; Hepatitis C virus; RNA structure.

Figure 1

Secondary structure model of the 3'UTR of hepatitis C virus genome with adjacent 3' terminal sequence of the coding region. The stop codon is indicated by a gray ellipse. The regions involved in the kissing-interactions are marked with blue lines; the region involved in dimerization is indicated by a red line; the seed region for miR122 is highlighted in bold.

Figure 2

Diverse secondary structure models proposed for the 3'X region of hepatitis C virus genome. A: The 3xSL model[17,18]; B: The 4xSL model[20]; C: The 2xSL model[21]. The region involved in the kissing-interactions is indicated with blue line, the region involved in dimerization is marked with red line; possible alternative folding of separate fragments are displayed as gray rectangles.

Figure 3

Long-range RNA-RNA interactions proposed for the 3'X region of hepatitis C virus genome. A: The homodimeric interactions between two 3'X regions embedded into two RNA molecules, model according to Cantero-Camacho et al[24]; B: The kissing-interactions with SL5B3.2[22,28,31,33]. Nucleotide sequence involved in dimerization is additionally indicated with red line, while those involved in the kissing-interactions are marked with blue lines.