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]

Contents

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] HuD (also called ELAVL4) binds to AREs and increases the half-life of ARE-bearing mRNAs in neurons during brain development and plasticity. [7]

AREsite—a database for ARE containing genes—has recently been developed with the aim to provide detailed bioinformatic characterization of AU-rich elements. [8]

Classifications

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

AREs are recognized by RNA binding proteins such as tristetraprolin (TTP), AUF1, and Hu Antigen R (HuR). [9] 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. [9]

The proposed mechanism for which ARE elements function & control sequencing. Animation455.gif
The proposed mechanism for which ARE elements function & control sequencing.

TTP's (ZFP36's) expression is rapidly induced by insulin. [10] Immunoprecipitation experiments have shown that TTP co-precipitates with an exosome, suggesting that it helps recruit exosomes to the mRNA containing AREs. [11] 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. [12] 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. [13] 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

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. [14] Some of these problems have been listed below: [9]

Related Research Articles

<span class="mw-page-title-main">Messenger RNA</span> RNA that is read by the ribosome to produce a protein

In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.

<span class="mw-page-title-main">Gene expression</span> Conversion of a genes sequence into a mature gene product or products

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, and ultimately affect a phenotype. These products are often proteins, but in non-protein-coding genes such as transfer RNA (tRNA) and small nuclear RNA (snRNA), the product is a functional non-coding RNA. The process of gene expression is used by all known life—eukaryotes, prokaryotes, and utilized by viruses—to generate the macromolecular machinery for life.

A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.

<span class="mw-page-title-main">Tumor necrosis factor</span> Protein

Tumor necrosis factor (TNF), formerly known as TNF-α, is an inflammatory protein and a principal mediator of the innate immune response. TNF is produced primarily by macrophages in response to antigens, and activates inflammatory pathways through its two receptors, TNFR1 and TNFR2. It is a member of the tumor necrosis factor superfamily, a family of type II transmembrane proteins that function as cytokines. Excess production of TNF plays a critical role in the pathology of several inflammatory diseases, and anti-TNF therapies are often employed to treat these diseases.

<span class="mw-page-title-main">Three prime untranslated region</span> Sequence at the 3 end of messenger RNA that does not code for product

In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally influence gene expression.

In molecular biology, the TATA box is a sequence of DNA found in the core promoter region of genes in archaea and eukaryotes. The bacterial homolog of the TATA box is called the Pribnow box which has a shorter consensus sequence.

RNA-binding proteins are proteins that bind to the double or single stranded RNA in cells and participate in forming ribonucleoprotein complexes. RBPs contain various structural motifs, such as RNA recognition motif (RRM), dsRNA binding domain, zinc finger and others. They are cytoplasmic and nuclear proteins. However, since most mature RNA is exported from the nucleus relatively quickly, most RBPs in the nucleus exist as complexes of protein and pre-mRNA called heterogeneous ribonucleoprotein particles (hnRNPs). RBPs have crucial roles in various cellular processes such as: cellular function, transport and localization. They especially play a major role in post-transcriptional control of RNAs, such as: splicing, polyadenylation, mRNA stabilization, mRNA localization and translation. Eukaryotic cells express diverse RBPs with unique RNA-binding activity and protein–protein interaction. According to the Eukaryotic RBP Database (EuRBPDB), there are 2961 genes encoding RBPs in humans. During evolution, the diversity of RBPs greatly increased with the increase in the number of introns. Diversity enabled eukaryotic cells to utilize RNA exons in various arrangements, giving rise to a unique RNP (ribonucleoprotein) for each RNA. Although RBPs have a crucial role in post-transcriptional regulation in gene expression, relatively few RBPs have been studied systematically.It has now become clear that RNA–RBP interactions play important roles in many biological processes among organisms.

In eukaryote cells, RNA polymerase III is a protein that transcribes DNA to synthesize 5S ribosomal RNA, tRNA, and other small RNAs.

<span class="mw-page-title-main">TATA-binding protein</span> Protein-coding gene in the species Homo sapiens

The TATA-binding protein (TBP) is a general transcription factor that binds to a DNA sequence called the TATA box. This DNA sequence is found about 30 base pairs upstream of the transcription start site in some eukaryotic gene promoters.

Cleavage and polyadenylation specificity factor (CPSF) is involved in the cleavage of the 3' signaling region from a newly synthesized pre-messenger RNA (pre-mRNA) molecule in the process of gene transcription. In eukaryotes, messenger RNA precursors (pre-mRNA) are transcribed in the nucleus from DNA by the enzyme, RNA polymerase II. The pre-mRNA must undergo post-transcriptional modifications, forming mature RNA (mRNA), before they can be transported into the cytoplasm for translation into proteins. The post-transcriptional modifications are: the addition of a 5' m7G cap, splicing of intronic sequences, and 3' cleavage and polyadenylation.

An E-box is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG, with a palindromic canonical sequence of CACGTG, is recognized and bound by transcription factors to initiate gene transcription. Once the transcription factors bind to the promoters through the E-box, other enzymes can bind to the promoter and facilitate transcription from DNA to mRNA.

<span class="mw-page-title-main">G-CSF factor stem-loop destabilising element</span> RNA element

The G-CSF factor stem-loop destabilising element (SLDE) is an RNA element secreted by fibroblasts and endothelial cells in response to the inflammatory mediators interleukin-1 (IL-1) and tumour necrosis factor-alpha and by activated macrophages. The synthesis of G-CSF is regulated both transcriptionally and through control of mRNA stability. In unstimulated cells G-CSF mRNA is unstable but becomes stabilised in response to IL-1 or tumour necrosis factor alpha, and also in the case of monocytes and macrophages, in response to lipopolysaccharide. It is likely that the presence of the SLDE in the G-CSF mRNA contributes to the specificity of regulation of G-CSF mRNA and enhances the rate of shortening of the poly(A) tail.

<span class="mw-page-title-main">ELAV-like protein 1</span> Protein found in humans

ELAV-like protein 1 or HuR is a protein that in humans is encoded by the ELAVL1 gene.

<span class="mw-page-title-main">ZFP36</span> Protein-coding gene in the species Homo sapiens

Tristetraprolin (TTP), also known as zinc finger protein 36 homolog (ZFP36), is a protein that in humans, mice and rats is encoded by the ZFP36 gene. It is a member of the TIS11 family, along with butyrate response factors 1 and 2.

<span class="mw-page-title-main">HNRPD</span> Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoprotein D0 (HNRNPD) also known as AU-rich element RNA-binding protein 1 (AUF1) is a protein that in humans is encoded by the HNRNPD gene. Alternative splicing of this gene results in four transcript variants.

<span class="mw-page-title-main">TIAL1</span> Protein-coding gene in the species Homo sapiens

Nucleolysin TIAR is a protein that in humans is encoded by the TIAL1 gene.

<span class="mw-page-title-main">CUGBP1</span> Protein-coding gene in the species Homo sapiens

CUG triplet repeat, RNA binding protein 1, also known as CUGBP1, is a protein which in humans is encoded by the CUGBP1 gene.

Post-transcriptional regulation is the control of gene expression at the RNA level. It occurs once the RNA polymerase has been attached to the gene's promoter and is synthesizing the nucleotide sequence. Therefore, as the name indicates, it occurs between the transcription phase and the translation phase of gene expression. These controls are critical for the regulation of many genes across human tissues. It also plays a big role in cell physiology, being implicated in pathologies such as cancer and neurodegenerative diseases.

<span class="mw-page-title-main">HSUR</span>

HSURs are viral small regulatory RNAs. They are found in Herpesvirus saimiri which is responsible for aggressive T-cell leukemias in primates. They are nuclear RNAs which bind host proteins to form small nuclear ribonucleoproteins (snRNPs). The RNAs are 114–143 nucleotides in length and the HSUR family has been subdivided into HSURs numbered 1 to 7. The function of HSURs has not yet been identified; they do not affect transcription so are thought to act post-transcriptionally, potentially influencing the stability of host mRNAs.

In epigenetics, proline isomerization is the effect that cis-trans isomerization of the amino acid proline has on the regulation of gene expression. Similar to aspartic acid, the amino acid proline has the rare property of being able to occupy both cis and trans isomers of its prolyl peptide bonds with ease. Peptidyl-prolyl isomerase, or PPIase, is an enzyme very commonly associated with proline isomerization due to their ability to catalyze the isomerization of prolines. PPIases are present in three types: cyclophilins, FK507-binding proteins, and the parvulins. PPIase enzymes catalyze the transition of proline between cis and trans isomers and are essential to the numerous biological functions controlled and affected by prolyl isomerization Without PPIases, prolyl peptide bonds will slowly switch between cis and trans isomers, a process that can lock proteins in a nonnative structure that can affect render the protein temporarily ineffective. Although this switch can occur on its own, PPIases are responsible for most isomerization of prolyl peptide bonds. The specific amino acid that precedes the prolyl peptide bond also can have an effect on which conformation the bond assumes. For instance, when an aromatic amino acid is bonded to a proline the bond is more favorable to the cis conformation. Cyclophilin A uses an "electrostatic handle" to pull proline into cis and trans formations. Most of these biological functions are affected by the isomerization of proline when one isomer interacts differently than the other, commonly causing an activation/deactivation relationship. As an amino acid, proline is present in many proteins. This aids in the multitude of effects that isomerization of proline can have in different biological mechanisms and functions.

References

  1. 1 2 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. 1 2 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. 1 2 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: Official Publication of the Federation of American Societies for Experimental Biology. 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. ↑ 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.
  8. ↑ 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.
  9. 1 2 3 Elliott, David; Ladomery, Michael (2011). Stability and Degradation of mRNA. Oxford: Oxford UP. p. 312.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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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