Five prime untranslated region

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5' untranslated region
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5′ untranslated region
transcript in eukaryotic organism (specifically humans)
Identifiers
MeSHD020121
Anatomical terminology]

The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a

coding sequence of the mRNA. In many organisms, however, the 5′ UTR is completely untranslated, instead forming a complex secondary structure
to regulate translation.

The 5′ UTR has been found to interact with proteins relating to metabolism, and proteins translate sequences[clarification needed] within the 5′ UTR. In addition, this region has been involved in transcription regulation, such as the sex-lethal gene in Drosophila.[1] Regulatory elements within 5′ UTRs have also been linked to mRNA export.[2]

General structure

Length

The 5′ UTR begins at the

pre-initiation complex
that must form to begin translation.

The 5′ UTR can also be completely missing, in the case of leaderless mRNAs.

Ribosomes of all three domains of life accept and translate such mRNAs.[6] Such sequences are naturally found in all three domains of life. Humans have many pressure-related genes under a 2–3 nucleotide leader. Mammals also have other types of ultra-short leaders like the TISU sequence.[7]

Elements

The binding of an IRP (iron regulatory protein) to and IRE (iron response element), which are hairpin loops, regulate translation.

The elements of a eukaryotic and prokaryotic 5′ UTR differ greatly. The prokaryotic 5′ UTR contains a

introns in eukaryotes. In humans, ~35% of all genes harbor introns within the 5′ UTR.[8]

Secondary structure

As the 5′ UTR has high

Hairpin loops are one such secondary structure that can be located within the 5′ UTR. These secondary structures also impact the regulation of translation.[9]

Role in translational regulation

The process of translation in bacteria
eukaryotes

Prokaryotes

In

50S ribosomal subunit
, which allows for translation to begin. Each of these steps regulates the initiation of translation.

Initiation in Archaea is less understood. SD sequences are much rarer, and the initiation factors have more in common with eukaryotic ones. There is no homolog of bacterial IF3.[10] Some mRNAs are leaderless.[11]

In both domains, genes without Shine–Dalgarno sequences are also translated in a less understood manner. A requirement seems to be a lack of secondary structure near the initiation codon.[12]

Eukaryotes

Pre-initiation complex regulation

The regulation of translation in eukaryotes is more complex than in prokaryotes. Initially, the

5′ cap, which in turn recruits the ribosomal complex to the 5′ UTR. Both eIF4E and eIF4G bind the 5′ UTR, which limits the rate at which translational initiation can occur. However, this is not the only regulatory step of translation
that involves the 5′ UTR.

poly(A) tail
, or more generally, 3′ UTR.

The various forms of mRNA and how each affects translational regulation

Closed-loop regulation

Another important regulator of translation is the interaction between 3′ UTR and the 5′ UTR.

3′ UTR and 5′ UTR causing a circularization that regulates translation
.

The closed-loop structure inhibits translation. This has been observed in

phosphorylated, displacing the Maskin binding site, allowing for the polymerization of the PolyA tail, which can recruit the translational machinery by means of PABP.[14] However, it is important to note that this mechanism has been under great scrutiny.[15]

Ferritin regulation

Main article: Iron response element

Iron levels in cells are maintained by translation regulation of many proteins involved in iron storage and metabolism. The 5′ UTR has the ability to form a hairpin loop secondary structure (known as the

mRNA, leading to a spontaneous increased risk of Alzheimer's disease.[16]

uORFs and reinitiation

Main article: Upstream open reading frame

Another form of translational regulation in eukaryotes comes from unique elements on the 5′ UTR called upstream

codon can be scanned for by ribosomes and then translated to create a product,[18]
which can regulate the translation of the main protein coding sequence or other uORFs that may exist on the same transcript.

The translation of the protein within the main ORF after a uORF sequence has been translated is known as reinitiation.

40S ribosome will bypass uORF2 because of a decrease in concentration of eIF2-TC, which means the ribosome does not acquire one in time to translate uORF2. Instead, ATF4 is translated.[19]

Other mechanisms

In addition to reinitiation, uORFs contribute to translation initiation based on:

An example IRES in the 5′ UTR of the Poliovirus genome

Internal ribosome entry sites and viruses

Main article: Internal ribosome entry site

Viral (as well as some eukaryotic) 5′ UTRs contain internal ribosome entry sites, which is a cap-independent method of translational activation. Instead of building up a complex at the 5′ cap, the IRES allows for direct binding of the ribosomal complexes to the transcript to begin translation.[20] The IRES enables the viral transcript to translate more efficiently due to the lack of needing a preinitation complex, allowing the virus to replicate quickly.[5]

Role in transcriptional regulation

msl-2 transcript

Transcription of the msl-2 transcript is regulated by multiple binding sites for fly Sxl at the 5′ UTR.[1] In particular, these poly-uracil sites are located close to a small intron that is spliced in males, but kept in females through splicing inhibition. This splicing inhibition is maintained by Sxl.[1] When present, Sxl will repress the translation of msl2 by increasing translation of a start codon located in a uORF in the 5′ UTR (see above for more information on uORFs). Also, Sxl outcompetes TIA-1 to a poly(U) region and prevents snRNP (a step in alternative splicing) recruitment to the 5′ splice site.[1]

See also

References

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