Searching for IRES

Abstract

The cell has many ways to regulate the production of proteins. One mechanism is through the changes to the machinery of translation initiation. These alterations favor the translation of one subset of mRNAs over another. It was first shown that internal ribosome entry sites (IRESes) within viral RNA genomes allowed the production of viral proteins more efficiently than most of the host proteins. The RNA secondary structure of viral IRESes has sometimes been conserved between viral species even though the primary sequences differ. These structures are important for IRES function, but no similar structure conservation has yet to be shown in cellular IRES. With the advances in mathematical modeling and computational approaches to complex biological problems, is there a way to predict an IRES in a data set of unknown sequences? This review examines what is known about cellular IRES structures, as well as the data sets and tools available to examine this question. We find that the lengths, number of upstream AUGs, and %GC content of 59-UTRs of the human transcriptome have a similar distribution to those of published IRES-containing UTRs. Although the UTRs containing IRESes are on the average longer, almost half of all 59-UTRs are long enough to contain an IRES. Examination of the available RNA structure prediction software and RNA motif searching programs indicates that while these programs are useful tools to fine tune the empirically determined RNA secondary structure, the accuracy of de novo secondary structure prediction of large RNA molecules and subsequent identification of new IRES elements by computational approaches, is still not possible.

Alternative translation start sites and hidden coding potential of eukaryotic mRNAs

“…(1)(2)(3) According to the scanning model, 40S ribosomal subunits are recruited to the 5 0 -terminal cap structure, scan mRNA in a 5 0 to 3 0 direction, and can initiate translation at the first AUG that they encounter (Fig. 1A).…”

“…AUG 2 is located in the optimal context (agcAUGu) and most ribosomes can recognize it as a TIS. In turn, AUG 3 and AUG 4 can be recognized by ribosomes either missing AUG 2 as a result of low-level leaky scanning or reinitiating translation after translation of a small ORF. (48) Designations: filled arrow, linear scanning; dotted arrow, translation; R, purine; Y, pyrimidine; H, not G; n, any nucleotide; 40S, small ribosomal subunit; 40S*, small ribosomal subunits in the process of recovering of initiation capacity (i.e.…”

“…(18) Translation of some eukaryotic mRNAs can be initiated in a cap-independent way through the usage of internal ribosome entry sites (IRES; reviewed elsewhere). (3,21) However, it seems likely that conventional cap-dependent linear scanning is a general translation initiation mechanism in eukaryotic cells used by default if no special signals (similar to IRES) occur in an mRNA. It should also be noted that an IRES provides only a binding site and, after the loading, 40S ribosomal subunits can move in 3 0 direction along mRNA according to the scanning model rules.…”

The Interrelating Dynamics of Hypoxic Tumor Microenvironments and Cancer Cell Phenotypes in Cancer Metastasis

“…The global protein translation switches from the normal cap-dependent translation to cap-independent translation allowing only the translation of those mRNAs that are most essential for survival [33]. Messenger RNAs that allow the translation via specific 5′ UTR sequences belong to proteins that are essential for cell survival and apoptosis like HIF-1 alpha, VEGF, Grp78, protein disulfide isomerase (PDI), p53, Bcl-2, c-Myc and others [31,34]. One program that is activated in response to cell stress is the unfolded protein response (UPR) [35,36].…”

Analysis of the 5′ untranslated region (5′UTR) of the alcohol oxidase 1 (AOX1) gene in recombinant protein expression in Pichia pastoris

“…The 5′UTR can exert an effect on translation efficiency either by adopting a secondary structure which can influence the rate of ribosome movement or by binding trans -acting factors that affect the function of the translation machinery (Chatterjee and Pal, 2009; Mignone et al, 2002; Mittelmeier and Dieckmann, 1995). Some eukaryotic 5′UTRs even contain sequences called internal ribosome entry sites (IRES), which allow the translation initiation complex with the 40S to skip over the cap and bind nearer to the first AUG in a cap-independent manner (Baird et al, 2006; Mokrejs et al, 2009). However, at the present time, IRES are defined by functional criteria only.…”