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AU-rich element

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Adenylate-uridylate-rich elements (AU-rich elements; AREs) are found in the 3' untranslated region (UTR) of many messenger RNAs (mRNAs) that code for proto-oncogenes, nuclear transcription factors, and cytokines. AREs are one of the most common determinants of RNA stability in mammalian cells.[1] The function of AREs was originally discovered by Shaw and Kamen in 1986.[2]

AREs are defined as a region with frequent adenine and uridine bases in a mRNA. They usually target the mRNA for rapid degradation.[3][2] ARE-directed mRNA degradation is influenced by many exogenous factors, including phorbol esters, calcium ionophores, cytokines, and transcription inhibitors. These observations suggest that AREs play a critical role in the regulation of gene transcription during cell growth and differentiation, and the immune response.[1] As evidence of its critical role, deletion of the AREs from the 3'UTR in either the TNF gene or GM-CSF gene in mice leads to over expression of each respective gene product, causing dramatic disease phenotypes.[4][5]

AREs have been divided into three classes with different sequences. The best characterised adenylate uridylate (AU)-rich Elements have a core sequence of AUUUA within U-rich sequences (for example WWWU(AUUUA)UUUW where W is A or U). This lies within a 50–150 base sequence, repeats of the core AUUUA element are often required for function.

A number of different proteins (e.g. HuA, HuB, HuC, HuD, HuR) bind to these elements and stabilise the mRNA while others (AUF1, TTP, BRF1, TIA-1, TIAR, and KSRP) destabilise the mRNA, miRNAs may also bind to some of them.[6] For example, the human microRNA, miR16, contains an UAAAUAUU sequence that is complementary to the ARE sequence and appears to be required for ARE-mRNA turnover.[7] HuD (also called ELAVL4) binds to AREs and increases the half-life of ARE-bearing mRNAs in neurons during brain development and plasticity.[8]

AREsite—a database for ARE containing genes—has recently been developed with the aim to provide detailed bioinformatic characterization of AU-rich elements.[9]

Classifications

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  • Class I ARE elements, like the c-fos gene, have dispersed AUUUA motifs within or near U-rich regions.
  • Class II elements, like the GM-CSF gene, have overlapping AUUUA motifs within or near U-rich regions.
  • Class III elements, like the c-jun gene, are a much less well-defined class—they have a U-rich region but no AUUUA repeats.

No real ARE consensus sequence has been determined yet, and these categories are based neither on the same biological functions, nor on the homologous proteins.[3]

Mechanism of ARE-mediated decay

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AREs are recognized by RNA binding proteins such as tristetraprolin (TTP), AUF1, and Hu Antigen R (HuR).[10] Although the exact mechanism is not very well understood, recent publications have attempted to propose the action of some of these proteins. AUF1, also known as hnRNP D, binds AREs through RNA recognition motifs (RRMs). AUF1 is also known to interact with the translation initiation factor eIF4G and with poly(A)-binding protein, indicating that AUF1 senses the translational status of mRNA and decays accordingly through the excision of the poly(A) tail.[10]

Proposed ARE Element Mechanism.
The proposed mechanism for which ARE elements function & control sequencing.

TTP's (ZFP36's) expression is rapidly induced by insulin.[11] Immunoprecipitation experiments have shown that TTP co-precipitates with an exosome, suggesting that it helps recruit exosomes to the mRNA containing AREs.[12] Alternatively, HuR proteins have a stabilizing effect—their binding to AREs increases the half-life of mRNAs. Similar to other RNA-binding proteins, this class of proteins contain three RRMs, two of which are specific to ARE elements.[13] A likely mechanism for HuR action relies on the idea that these proteins compete with other proteins that normally have a destabilizing effect on mRNAs.[14] HuRs are involved in genotoxic response—they accumulate in the cytoplasm in response to UV exposure and stabilize mRNAs that encode proteins involved in DNA repair.

Disease

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Problems with mRNA stability have been identified in viral genomes, cancer cells, and various diseases. Research shows that many of these problems arise because of faulty ARE function. Deficiency of the ZFP36 family show that ZFP36 ARE binding proteins are critical regulators of T cell homeostasis and autoimmunity.[15] Some of these problems have been listed below:[10]

  • The c-fos gene produces a transcription factor that is activated in several cancers, the ARE present in c-fos plays a role in its post-transcriptional regulation.
  • c-myc gene, also responsible for producing transcription factors found in several cancers, the ARE present in c-myc plays a role in its post-transcriptional regulation.
  • The Cox-2 gene catalyses the production of prostaglandins—it overexpresses in several cancers, and is stabilized by the binding of CUGBP2 RNA-binding protein to ARE

References

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  1. ^ a b Chen, Chyi-Ying A.; Shyu, Ann-Bin (November 1995). "AU-rich elements: characterization and importance in mRNA degradation". Trends in Biochemical Sciences. 20 (11): 465–470. doi:10.1016/S0968-0004(00)89102-1. PMID 8578590.
  2. ^ a b Shaw G, Kamen R (August 1986). "A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation". Cell. 46 (5): 659–667. doi:10.1016/0092-8674(86)90341-7. PMID 3488815. S2CID 40332253.
  3. ^ a b C Barreau, L Paillard & H B Osborne (2006). "AU-rich elements and associated factors: are there unifying principles?". Nucleic Acids Res. 33 (22): 7138–7150. doi:10.1093/nar/gki1012. PMC 1325018. PMID 16391004.
  4. ^ Kontoyiannis, D.; Pasparakis, M.; Pizarro, T. T.; Cominelli, F.; Kollias, G. (March 1999). "Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies". Immunity. 10 (3): 387–398. doi:10.1016/s1074-7613(00)80038-2. ISSN 1074-7613. PMID 10204494.
  5. ^ Arao, Yukitomo; Stumpo, Deborah J.; Hoenerhoff, Mark J.; Tighe, Robert M.; Yu, Yen-Rei; Sutton, Deloris; Kashyap, Amogh; Beerman, Isabel; Blackshear, Perry J. (August 2023). "Lethal eosinophilic crystalline pneumonia in mice expressing a stabilized Csf2 mRNA". FASEB Journal. 37 (8): e23100. doi:10.1096/fj.202300757R. ISSN 1530-6860. PMC 11078221. PMID 37462673.
  6. ^ Federico Bolognani & Nora Perrone-Bizzozero (2008). "RNA-protein interactions and control of mRNA stability in neurons". J Neurosci Res. 86 (3): 481–489. doi:10.1002/jnr.21473. PMID 17853436. S2CID 27076039.
  7. ^ Q, Jing; S, Huang; S, Guth; T, Zarubin; A, Motoyama; J, Chen; F, Di Padova; Sc, Lin; H, Gram; J, Han (2005-03-11). "Involvement of microRNA in AU-rich element-mediated mRNA instability". Cell. 120 (5): 623–634. doi:10.1016/j.cell.2004.12.038. ISSN 0092-8674. PMID 15766526.
  8. ^ Nora Perrone-Bizzozero & Federico Bolognani (2002). "Role of HuD and other RNA-binding proteins in neural development and plasticity". J Neurosci Res. 68 (2): 121–126. doi:10.1002/jnr.10175. PMID 11948657.
  9. ^ Gruber AR, Fallmann J, Kratochvill F, Kovarik P, Hofacker IL (2011). "AREsite: a database for the comprehensive investigation of AU-rich elements". Nucleic Acids Res. 39 (Database issue): D66–9. doi:10.1093/nar/gkq990. PMC 3013810. PMID 21071424.
  10. ^ a b c Elliott, David; Ladomery, Michael (2011). Stability and Degradation of mRNA. Oxford: Oxford UP. p. 312.
  11. ^ Cao, H; JF Jr, Urban; RA, Anderson (Apr 2008). "Insulin Increases Tristetraprolin and Decreases VEGF Gene Expression in Mouse 3T3-L1 Adipocytes". Obesity. 16 (6): 1208–1218. doi:10.1038/oby.2008.65. PMID 18388887. S2CID 19149343.
  12. ^ Tiedje, Christopher; Kotlyarov, Alexey; Gaestel, Matthias (2010). "Molecular Mechanisms of Phosphorylation-regulated TTP (tristetraprolin) Action and Screening for Further TTP-interacting Proteins" (PDF). Biochemical Society Transactions. 38 (6): 1632–1637. doi:10.1042/bst0381632. PMID 21118139.
  13. ^ Dai, Weijun; Zhang, Gen; Makeyev, Eugene V. (24 Sep 2011). "RNA-binding Protein HuR Autoregulates Its Expression by Promoting Alternative Polyadenylation Site Usage". Nucleic Acids Research. 40 (2): 787–800. doi:10.1093/nar/gkr783. PMC 3258158. PMID 21948791.
  14. ^ Brennan, C. M.; Steinz, J. A. (Feb 2001). "HuR and MRNA Stability". Cellular and Molecular Life Sciences. 58 (2): 266–277. doi:10.1007/pl00000854. PMC 11146503. PMID 11289308. S2CID 35201269.
  15. ^ Cook, Melissa E.; Bradstreet, Tara R.; Webber, Ashlee M.; Kim, Jongshin; Santeford, Andrea; Harris, Kevin M.; Murphy, Maegan K.; Tran, Jennifer; Abdalla, Nada M.; Schwarzkopf, Elizabeth A.; Greco, Suellen C.; Halabi, Carmen M.; Apte, Rajendra S.; Blackshear, Perry J.; Edelson, Brian T. (2022-10-28). "The ZFP36 family of RNA binding proteins regulates homeostatic and autoreactive T cell responses". Science Immunology. 7 (76): eabo0981. doi:10.1126/sciimmunol.abo0981. ISSN 2470-9468. PMC 9832469. PMID 36269839.
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