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The five prime untranslated region (5' UTR) (also know as a Leader Sequence or Leader RNA) is the region of an mRNA that is directly upstream from the initiation codon. This region is important for the regulation of translation of a transcript by differing mechanisms dependent on organism.

The general structure of the 5' UTR of a transcript.

General Structure

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Length

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The 5' UTR begins at the transcription start site and ends one nucleotide (nt) before the initiation codon (usually AUG) of the coding region. In prokaryotes, the length of the 5' UTR tends to be 3-10 nucleotides long while in eukaryotes it tends to be anywhere from 100 to several thousands nucleotides long [1]. For example, the ste11 transcript in Schizosaccharomyces pombe has a 2273 nucleotide 5' UTR[2] while the lac operon in Escherichia coli only has 7 nucleotides in its 5' UTR[3]. The differing sizes are likely due to the complexity of the eukaryotic regulation which the 5' UTR holds, as well as the larger preinitiation complex which must form to begin translation.

Elements

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The binding of an IRP (Iron Regulatory Protein) to and IRE (Iron Response Element), which are hairpin loops, regulation translation.

The elements of a eukaryotic and prokaryotic 5' UTR differ greatly. The prokaryotic 5' UTR contains a ribosome binding site (RBS), also known as the Shine Dalgarno sequence (AGGAGGU) which is usually 3-10 base pairs upstream from the initiation codon[4]. Meanwhile the eukaryotic 5' UTR contains the Kozak consensus sequence (ACCAUGG), which contains the initiation codon[5]. The eukaryotic 5' UTR also contains cis-acting regulatory elements called upstream open reading frames (uORFs) and upstream AUGs (uAUGs), which have a great impact on the regulation of translation (see below).

Secondary Structure

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As the 5' UTR has a high GC content, secondary structures often occur within it. Hairpin loops are one such secondary structure that can be located within the 5' UTR. These secondary structures also impact the regulation of translation.[6]

Role in Translational Regulation

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The process of translation in prokaryotes.
 
The process of translation in eukaryotes.

Prokaryotes

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In prokaryotes, the initiation of translation occurs when IF-3 along with the 30S ribosomal subunit bind to the Shine-Dalgarno sequence of the 5' UTR.[7]. This then recruits many other proteins that such as the 50S ribosomal subunit that allows for translation to begin. Each of these steps regulates the initiation of translation.

Regulation of Operon Translation

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In prokaryotes, most 5' UTRs form complex secondary structure that affects how the translational machinery can bind to it. One such example of this is the autoregulation of ribosomal proteins (r-proteins). It is known that r-proteins bind directly to the 5' UTR of

Eukaryotes

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Preinitiation Complex Regulation

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The regulation of translation in eukaryotes is more complex then in prokaryotes. Initially, the eIF4F complex is recruited to the 5' cap, which in turn recruits the ribosomal complex to the 5' UTR. Both eIF4E and eIF4G bind the 5' UTR, which limit the rate at which translational initiation can occur[8]. However, this is not the only regulatory step of translation that involves the 5' UTR.

 
The various forms of mRNA and how each affects translational regulation.

Closed-loop Regulation

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

 
Interactions between proteins bound to the the 3' UTR and 5' UTR causing a circularization that regulates translation.

The closed-loop structure inhibits translation[9]. This has been observed in Xenopus laevis in which eIF4E bound to the 5' cap interacts with Maskin bound to CPEB on the 3' UTR creating translationally inactive transcripts. This translational inhibition is lifted once CPEB is phosphorylated, displacing the Masking binding site, allowing for the polymerization of the PolyA tail, which can recruit the translational machinery by means of PABP[10]. However, it is important to note that this mechanism has been under great scrutiny[11].

uORFs

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Another form of translational regulation in eukaryotes comes from unique elements on the 5' UTR called Upstream Open Reading Frames (uORF). These elements are fairly common, occuring in 35-49% of all human genes[12] . A uORF is a coding sequence located in the 5' UTR located upstream of the coding sequences initiation site. These uORFs contain their own initiation codon, know as an upstream AUG (uAUG). This codon can be scanned for by ribosomes and then translated to creates a product[13], which can regulate the translation of the main protein coding sequence or other uORFs that may exist on the same transcript.

 
An example IRES in the 5' UTR ofPoliovirus genome.

Internal Ribosome Entry Sites and Viruses

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Viruses (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[14]. 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[15].


See also

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References

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  1. ^ Lodish, Havery (2004). Molecular Cell Biology. New York, New York: W.H. Freeman and Company. p. 113. ISBN 0-7167-4366-3.
  2. ^ Rhind N, Chen Z, Yassour M, Thompson DA, Haas BJ, Habib N, Wapinski I, Roy S, Lin MF, Heiman DI, Young SK, Furuya K, Guo Y, Pidoux A, Chen HM, Robbertse B, Goldberg JM, Aoki K, Bayne EH, Berlin AM, Desjardins CA, Dobbs E, Dukaj L, Fan L, FitzGerald MG, French C, Gujja S, Hansen K, Keifenheim D, Levin JZ, Mosher RA, Müller CA, Pfiffner J, Priest M, Russ C, Smialowska A, Swoboda P, Sykes SM, Vaughn M, Vengrova S, Yoder R, Zeng Q, Allshire R, Baulcombe D, Birren BW, Brown W, Ekwall K, Kellis M, Leatherwood J, Levin H, Margalit H, Martienssen R, Nieduszynski CA, Spatafora JW, Friedman N, Dalgaard JZ, Baumann P, Niki H, Regev A, Nusbaum C. (20). "Comparative functional genomics of the fission yeasts". Science. 6032. 332 (6032): 930–936. doi:10.1126/science.1203357. PMC 3131103. PMID 21511999. {{cite journal}}: Check date values in: |date= and |year= / |date= mismatch (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Brown, T.A (2007). Genomes 3. New York, New York: Garland Science Publishing. p. 397. ISBN 978-0-8153-4138-3.
  4. ^ Brown, T.A (2007). Genomes 3. New York, New York: Garland Science Publishing. p. 397. ISBN 978-0-8153-4138-3.
  5. ^ Brown, T.A (2007). Genomes 3. New York, New York: Garland Science Publishing. p. 397. ISBN 978-0-8153-4138-3.
  6. ^ Babendure, Jeremy R.; Babendure, Jennie L.; Ding, Jian-Hua; Tsien, Roger Y. (2006). "Control of mammalian translation by mRNA structure near caps". RNA. 5. 12 (5): 851–861. doi:10.1261/rna.2309906. PMC 1440912. PMID 16540693. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  7. ^ Brown, T.A (2007). Genomes 3. New York, New York: Garland Science Publishing. p. 397. ISBN 978-0-8153-4138-3.
  8. ^ Kang, M. K.; Han, S. J. (2011). "Post-transcriptional and post-translational regulation during mouse oocyte maturation". BMB Rep. 3. 44 (3): 147–157. doi:10.5483/BMBRep.2011.44.3.147. PMID 21429291. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  9. ^ Kang, M. K.; Han, S. J. (2011). "Post-transcriptional and post-translational regulation during mouse oocyte maturation". BMB Rep. 3. 44 (3): 147–157. doi:10.5483/BMBRep.2011.44.3.147. PMID 21429291. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  10. ^ Gilbert, Scott (2010). Developmental Biology. Sunderland, MA: Sinauer Associates, Inc. p. 60. ISBN 978-0-87893-384-6.
  11. ^ Kozak, Marilyn (1). "Faulty old ideas about translational regulation paved the way for current confusion about how microRNAs function". Gene. 2. 423 (2): 108-115. doi:10.1016/j.gene.2008.07.013. PMID 18692553. {{cite journal}}: Check date values in: |date= and |year= / |date= mismatch (help); Unknown parameter |month= ignored (help)
  12. ^ Mignone, Flavio; Gissi, Carmela; Liuni, Sabino; Pesole, Graziano (2002). "Untranslated regions of mRNAs". Genome Biol. 3. 3 (3): reviews0004.1. doi:10.1186/gb-2002-3-3-reviews0004. PMID 11897027. S2CID 1087661.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: unflagged free DOI (link)
  13. ^ Wethmar, Klaus; Smink, Jeske J.; Leutz, Achim (2010). "Upstream open reading frames: molecular switches in (patho)physiology". BioEssays. 10. 32 (10): 885-893. doi:10.1002/bies.201000037. PMC 3045505. PMID 20726009. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  14. ^ Thompson, SR (November 2012). "Tricks an IRES uses to enslave ribosomes". Trends Microbiol. 11. 20 (11): 558-566. doi:10.1016/j.tim.2012.08.002. PMC 3479354. PMID 22944245.{{cite journal}}: CS1 maint: date and year (link)
  15. ^ Brown, T.A (2007). Genomes 3. New York, New York: Garland Science Publishing. p. 397. ISBN 978-0-8153-4138-3.

Category:RNA Category:Gene expression

Peer Review

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The article has a wealth of great information regarding not only the primary transcript, but other elements that it is involved with. However, much of the grammar needs to be tightened and polished. Also, some of the information presented is either misleading or bogged down in grammar. Also, there are many things which should be linked. Below are various edits which may be considered:

  • Introduction
    • Overall grammar check should be done.
    • "A primary transcript is the single-stranded RNA product synthesized by transcription of DNA, and processed in many ways to yield various functional RNAs such as mRNAs, tRNAs, and rRNAs to be used in translation" - your opening sentence is misleading. There are many primary transcripts, including rRNA and tRNA, that are never translated.
      • The sentence needs overall work. Consider breaking it into two sentences as the and is combining two unrelated thoughts.
    • You make want to consider merging precursor mRNA into your article.
    • You refer to the primary transcript being in the cell's nucleus. This is incorrect as bacteria also have primary transcript which undergo processing such as alternative splicing.
    • "Of all of these, alternative splicing is the factor that directly contributes to the diversity of mRNA found in cells" - I would consider removing this sentence. It is misleading.
  • Production of the Primary Transcript
    • Again, nucleus and translation usage must be watched.
    • There should be a link to the main transcription) page as most of this material is covered. i.e put Main Article : Transcription at the top of the section.
    • "RNA polymerase II of eukaryotes transcribes the primary transcript mRNA from the antisense DNA template in the 5' to 3' direction, and the newly synthesized mRNA is complimentary to this antisense strand of DNA (see Figure)." is extremely confusing. "primary transcript mRNA" has no meaning. I believe you are trying to say "transcribes a transcript destined to be processed into an mRNA.
  • Regulation of primary transcript production
    • "Factors that lead to histone acetylation activate transcription while factors that lead to histone deacetylation inhibit transcription" is not necessarily true. Consider H3K4AC, which can repressive.
  • Primary transcript and RNA processing
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