Internal ribosome entry site

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An internal ribosome entry site, abbreviated IRES, is a nucleotide sequence that allows for translation initiation in the middle of a messenger RNA (mRNA) sequence as part of the greater process of protein synthesis. Usually, in eukaryotes, translation can only be initiated at the 5' end of the mRNA molecule, since 5' cap recognition is required for the assembly of the initiation complex. IRES mimics the 5' cap structure, and is recognized by the 40S pre-initiation complex.

These sequences were first discovered in poliovirus RNA in 1986 in the labs of Sonenberg and Wimmer. They are described as distinct regions of RNA molecules being able to attract the eukaryotic ribosome to close vicinity of the mRNA molecule and make it to initiate translation. The process got known as the internal initiation of translation. The regions having the IRES activity possibly have a distinct secondary or even tertiary structure, but nobody found at the levels of either primary or secondary structure a general feature common to all IRES segments reported to date. However, when an IRES segment is located in between two reporter genes in eukaryotic mRNA molecules as bi-cistronic mRNA, it can drive translation of the downstream protein coding region independently of the 5'-cap structure bound to the 5' end of the mRNA molecule. In such a setup both proteins are produced in the cell. The first reporter protein located in the first cistron is synthesized by the cap-dependent initiation approach while translation initiation of the second protein is directed by the IRES segment located in the intercistronic spacer region between the two reporter protein coding regions. However, this so-called “method of bicistronic constructs” has several bottlenecks when used in vivo and is often deceitful [1].

IRES are located in the 5'UTR of RNA viruses and allow translation of the RNAs in a cap-independent manner. It was later discovered that also some mammalian mRNAs also have IRES, although there are considerable objections whether their existence has been proved sufficiently. There are known several cases of mis-reported IRES segments which were later recognized as promoter-containing regions (original authors disregarded their own results and published additional results showing that the 'IRES' activity observer originally was indeed a promoter activity or aberrantly spliced mRNA biased the results). There is a possible explanation that the IRES function in eukaryotic mRNAs are the house-keeping genes involved in stress survival, and other processes critical to survival, but it is questionable whether such a general statement is really true. As of November 2005, there are about 50 viruses reported to contain IRES segments and about 73 mRNA sequences containing them as well. A definitive approach to present the supporting experimental data and to re-evaluate the former findings in current context of the knowledge started at http://www.iresite.org.

Contrary to cellular IRESs, existence of IRESs in viral mRNA have been shown unambiguously. One should not forget that many RNA-viruses possess proteins covalently linked to the 5’-end of their mRNAs, which certainly don’t functionally substitute for cap-structure of cellular mRNAs, leaving no other way but to initiate translation internally. Moreover, mechanisms of functioning of some of them have been studied. For example Hepatitis C Virus-related IRESs directly bind 40S ribosomal subunit in such a way that their initiator codons are located in ribosomal P-site without mRNA scanning. These IRESs don’t require eukaryotic initiation factors eIF1, 1A, 4A, 4B, and 4F. Other group of IRESs represents picornavirus mRNA. They don't attract 40S directly, but rather through high-affinity eIF4G-binding site [2].