Mechanisms of Internal Ribosome Entry in Translation Initiation

During eukaryotic translation initiation, the 40S ribosomal subunit must be recruited to a messenger RNA(mRNA) and positioned at the correct initiation codon. Inmost mRNAs, this is achieved via a series of intermolecular events involving a group of protein factors that assemble on the capped 5′ end of the mRNA. This assembly recruits the 40S ribosomal subunit and enables it toscan to the translational start site (Merrick and Hershey1996). The mRNA is thought to play a passive role in thisprocess and typically lacks significant secondary structure in the 5′-untranslated region that might interfere withscanning (Fig. 1). In contrast, an alternative mechanismof translation initiation involves active roles of the 5′-and in some cases the 3′-untranslated regions of anmRNA (Jackson 1996; Sachs et al. 1997). In these cases,the untranslated regions are often highly conserved, mayextend for several hundred nucleotides, and appear tocontain extensive secondary and tertiary structures. Herewe describe structural features of the 5′-untranslated region of hepatitis C virus (HCV) that enable its function asan internal ribosome entry site (IRES). We also discussevidence for IRES-mediated translation in certain cellular genes, and the possible roles of conserved 3′-untranslated regions of HCV mRNA in translational control...