World Library  
Flag as Inappropriate
Email this Article

Five prime untranslated region

Article Id: WHEBN0001271003
Reproduction Date:

Title: Five prime untranslated region  
Author: World Heritage Encyclopedia
Language: English
Subject: RNA, Nrf2 internal ribosome entry site (IRES), ODC internal ribosome entry site (IRES), Upstream open reading frame, Ribosome shunting
Collection: Gene Expression, Rna
Publisher: World Heritage Encyclopedia
Publication
Date:
 

Five prime untranslated region

5' untranslated region
The general structure of the 5′ UTR of a transcript.
Anatomical terminology

The 5' untranslated region (5′ UTR) (also known as a Leader Sequence or Leader RNA) is the region of an translation. The 5′ UTR has been found to interact with proteins relating to metabolism; and proteins translate sequences 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]

Contents

  • General structure 1
    • Length 1.1
    • Elements 1.2
    • Secondary structure 1.3
  • Role in translational regulation 2
    • Prokaryotes 2.1
    • Eukaryotes 2.2
      • Preinitiation complex regulation 2.2.1
      • Closed-loop regulation 2.2.2
      • Ferritin regulation 2.2.3
      • uORFs and reinitiation 2.2.4
        • Other mechanisms 2.2.4.1
      • Internal ribosome entry sites and viruses 2.2.5
  • Role in transcriptional regulation 3
    • msl-2 transcript 3.1
  • See also 4
  • References 5

General structure

Length

The 5′ UTR begins at the transcription start site and ends one nucleotide (nt) before the initiation sequence (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 thousand nucleotides long.[3] For example, the ste11 transcript in Schizosaccharomyces pombe has a 2273 nucleotide 5′ UTR[4] while the lac operon in Escherichia coli only has 7 nucleotides in its 5′ UTR.[5] 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

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.[5] 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 and termination codons (uAUGs), which have a great impact on the regulation of translation (see below). Unlike prokaryotes, 5' UTRs can harbor introns in eukaryotes. In humans, ~35% of all genes harbor introns within the 5' UTR.[6]

Secondary structure

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.[7]

Role in translational regulation

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

Prokaryotes

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.[5] This then recruits many other proteins, such as the 50S ribosomal subunit, that allows for translation to begin. Each of these steps regulates the initiation of translation.

Eukaryotes

Preinitiation complex regulation

The regulation of translation in eukaryotes is more complex than 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. However, this is not the only regulatory step of translation that involves the 5′ UTR.

RNA-binding proteins sometimes serve to prevent the pre-initiation complex from forming. An example is regulation of the msl2 gene. The protein SXL attaches to an intron segment located within the 5’UTR segment of the primary transcript, which leads to the inclusion of the intron after processing.[8] This sequence allows the recruitment of proteins that bind simultaneously to both the 5’ and 3′ UTR, not allowing translation proteins to assemble. However, it has also been noted that Sxl can also repress translation of RNAs that do not contain a 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.

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

The closed-loop structure inhibits translation. 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 Maskin binding site, allowing for the polymerization of the PolyA tail, which can recruit the translational machinery by means of PABP.[9] However, it is important to note that this mechanism has been under great scrutiny.[10]

Ferritin regulation

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 IRE, Iron response element) that is recognized by iron-regulatory proteins (IRP1 and IRP2). In low levels of iron, the ORF of the target mRNA is blocked as a result of steric hindrance from the binding of IRP1 and IRP2 to the iron-response element. When iron is high, then the two iron-regulatory proteins do not bind as strongly, and allow proteins to be expressed that have a role in iron concentration control. This function has gained some interest after it was revealed that the translation of amyloid precursor protein may be disrupted due to a single-nucleotide polymorphism to the iron response element found in the 5′ UTR of its mRNA, leading to a spontaneous increased risk of Alzheimer's Disease.[11]

uORFs and reinitiation

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, occurring 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, known as an upstream AUG (uAUG). This codon can be scanned for by ribosomes and then translated to create a product,[13] 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 reinitation.[14] The process of reinitiation is known to reduce the translation of the ORF protein. Control of protein regulation is determinant of uORF distance from the first codon in the main ORF.[14] uORFs have been found to increase reinitiation with the longer distance between its uAUG and the start codon of the main ORF, which indicate that the ribosome needs to reacquire translation factors before it can carry out translation of the main protein.[14] For example, ATF4 regulation is performed by two uORFs further upstream, named uORF1 and uORF2, which contain three amino acids and fifty-nine amino acids, respectively. The location of uORF2 overlaps with the ATF4 ORF. During normal conditions, the uORF1 is translated, and then translation of uORF2 occurs only after eIF2-TC has been reacquired. Translation of the uORF2 requires that the ribosomes pass by the ATF4 ORF, whose start codon is located within uORF2. This leads to its repression. However, during stress conditions, the 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.[14]

Other mechanisms

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

  • The nucleotides of an uORF may code for a codon that leads to a highly structured mRNA, causing the ribosome to stall.[14]
  • cis- and trans- regulation on translation of the main protein coding sequence.[14]
  • Interactions with IRES sites.[14]
An example IRES in the 5′ UTR of the Poliovirus genome.

Internal ribosome entry sites and viruses

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.[15] 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 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

  1. ^ a b c d Penalva, L. O. F.; Sanchez, L. (2003). "RNA Binding Protein Sex-Lethal (Sxl) and Control of Drosophila Sex Determination and Dosage Compensation". Microbiology and Molecular Biology Reviews 67 (3): 343–59, table of contents.  
  2. ^ Cenik, Can; Chua, Hon Nian; Zhang, Hui; Tarnawsky, Stefan P.; Akef, Abdalla; Derti, Adnan; Tasan, Murat; Moore, Melissa J.; Palazzo, Alexander F.; Roth, Frederick P. (2011). Snyder, Michael, ed. "Genome Analysis Reveals Interplay between 5′UTR Introns and Nuclear mRNA Export for Secretory and Mitochondrial Genes". PLoS Genetics 7 (4): e1001366.  
  3. ^ Lodish, Havery (2004). Molecular Cell Biology. New York, New York: W.H. Freeman and Company. p. 113.  
  4. ^ Rhind, Nicholas; Chen, Zehua; Yassour, Moran; Thompson, Dawn A.; Haas, Brian J.; Habib, Naomi; Wapinski, Ilan; Roy, Sushmita; Lin, Michael F.; Heiman, David I.; Young, Sarah K.; Furuya, Kanji; Guo, Yabin; Pidoux, Alison; Chen, Huei Mei; Robbertse, Barbara; Goldberg, Jonathan M.; Aoki, Keita; Bayne, Elizabeth H.; Berlin, Aaron M.; Desjardins, Christopher A.; Dobbs, Edward; Dukaj, Livio; Fan, Lin; Fitzgerald, Michael G.; French, Courtney; Gujja, Sharvari; Hansen, Klavs; Keifenheim, Dan; Levin, Joshua Z. (2011). "Comparative Functional Genomics of the Fission Yeasts". Science 332 (6032): 930–6.  
  5. ^ a b c d e Brown, T.A (2007). Genomes 3. New York, New York: Garland Science Publishing. p. 397.  
  6. ^ Bicknell AA, Cenik C, Chua HN, Roth FP, Moore MJ (Dec 2012). "Introns in UTRs: why we should stop ignoring them.". Bioessays 34 (12): 1025–34.  
  7. ^ Babendure, J. R.; Babendure, JL; Ding, JH; Tsien, RY (2006). "Control of mammalian translation by mRNA structure near caps". RNA 12 (5): 851–61.  
  8. ^ Araujo, Patricia R.; Yoon, Kihoon; Ko, Daijin; Smith, Andrew D.; Qiao, Mei; Suresh, Uthra; Burns, Suzanne C.; Penalva, Luiz O. F. (2012). "Before It Gets Started: Regulating Translation at the 5′ UTR". Comparative and Functional Genomics 2012: 1.  
  9. ^ Gilbert, Scott (2010). Developmental Biology. Sunderland, MA: Sinauer Associates. p. 60.  
  10. ^ Kozak, Marilyn (2008). "Faulty old ideas about translational regulation paved the way for current confusion about how microRNAs function". Gene 423 (2): 108–15.  
  11. ^ Rogers, Jack T.; Bush, Ashley I.; Cho, Hyan-Hee; Smith, Deborah H.; Thomson, Andrew M.; Friedlich, Avi L.; Lahiri, Debomoy K.; Leedman, Peter J.; Huang, Xudong; Cahill, Catherine M. (2008). "Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: Riboregulation against neural oxidative damage in Alzheimer's disease". Biochemical Society Transactions 36 (6): 1282–7.  
  12. ^ Mignone, Flavio; Gissi, Carmela; Liuni, Sabino; Pesole, Graziano (2002). Genome Biology 3 (3): reviews0004.1.  
  13. ^ Wethmar, Klaus; Smink, Jeske J.; Leutz, Achim (2010). "Upstream open reading frames: Molecular switches in (patho)physiology". BioEssays 32 (10): 885–93.  
  14. ^ a b c d e f g Somers, Joanna; Pöyry, Tuija; Willis, Anne E. (2013). "A perspective on mammalian upstream open reading frame function". The International Journal of Biochemistry & Cell Biology 45 (8): 1690–700.  
  15. ^ Thompson, Sunnie R. (2012). "Tricks an IRES uses to enslave ribosomes". Trends in Microbiology 20 (11): 558–66.  
This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and USA.gov, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for USA.gov and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
 
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
 
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.
 



Copyright © World Library Foundation. All rights reserved. eBooks from Hawaii eBook Library are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.