Mechanisms of internal ribosome entry in translation initiation.

Content Provider	Semantic Scholar
Author	Kieft, Jeffrey S. Grech, Angie Adams, Philip D. Doudna, Jennifer A.
Copyright Year	2001
Abstract	eukaryotic translation initiation, the 40S ribo-somal subunit must be recruited to a messenger RNA (mRNA) and positioned at the correct initiation codon. In most mRNAs, this is achieved via a series of intermolec-ular events involving a group of protein factors that assemble on the capped 5énd of the mRNA. This assembly recruits the 40S ribosomal subunit and enables it to scan to the translational start site (Merrick and Hershey 1996). The mRNA is thought to play a passive role in this process and typically lacks significant secondary structure in the 5´-untranslated region that might interfere with scanning (Fig. 1). In contrast, an alternative mechanism of translation initiation involves active roles of the 5´-and in some cases the 3´-untranslated regions of an mRNA (Jackson 1996; Sachs et al. 1997). In these cases, the untranslated regions are often highly conserved, may extend for several hundred nucleotides, and appear to contain extensive secondary and tertiary structures. Here we describe structural features of the 5´-untranslated region of hepatitis C virus (HCV) that enable its function as an internal ribosome entry site (IRES). We also discuss evidence for IRES-mediated translation in certain cellular genes, and the possible roles of conserved 3´-untrans-lated regions of HCV mRNA in translational control. IRESs occur in the 5´-untranslated regions of numerous viral genomic RNAs as well as some eukaryotic cellular RNAs. In contrast to the 7-methyl-guanosine cap-dependent mechanism used by most eukaryotic messenger RNAs, these RNA structures recruit and activate the translation machinery independent of the 5énd of the mRNA (Fig. 1) (Sachs et al. 1997). IRES RNAs have varied sequences, proposed secondary structures, and cofactor requirements, but all IRES RNAs induce translation initiation in the absence of the 5´cap structure and in the absence of a 5´terminus (they are cap-and end-independent). IRESs were first identified in the picornaviruses, and these provided the initial paradigm for understanding internal translation initiation (Jackson and Kaminski 1995). Within this family of viruses, several different IRES classes were identified based first on secondary structure and later on cofactor requirements. Site-directed mutagenesis of these IRESs, which are between 300 and 500 nucleotides in length, led to the proposal that IRESs form complex three-dimensional tertiary structures that interact with the translation machinery using contacts located throughout the IRES RNA sequence. Recently, intense interest has focused on the IRES of HCV, a viral pathogen of worldwide health concern. This IRES was first identified by Wang et al. …
Starting Page	683
Ending Page	688
Page Count	6
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://doudna.berkeley.edu/Publications/cshsqb-66-277.pdf
Alternate Webpage(s)	http://rna.berkeley.edu/Publications/cshsqb-66-277.pdf
PubMed reference number	12762029v1
Volume Number	66
Journal	Cold Spring Harbor symposia on quantitative biology
Language	English
Access Restriction	Open
Subject Keyword	Activation action Antiviral Agents Class Codon, Initiator Family Picornaviridae Genetic Translation Process Guanosine Hepatitis B Hepatitis C virus Internal Ribosome Entry Sites Nucleotides Pathogenic organism RNA RNA, Messenger Ribosome Subunits Ribosomes Transcription Initiation Translation Initiation chemical cofactor tertiary
Content Type	Text
Resource Type	Article