Cytoplasmic polyadenylation element

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The cytoplasmic polyadenylation element (CPE) is a sequence element found in the 3' untranslated region of messenger RNA. While several sequence elements are known to regulate cytoplasmic polyadenylation, CPE is the best characterized. [1] The most common CPE sequence is UUUUAU, though there are other variations. [2] Binding of CPE binding protein (CPEB) to this region promotes the extension of the existing polyadenine tail and, in general, activation of the mRNA for protein translation. This elongation occurs after the mRNA has been exported from the nucleus to the cytoplasm. A longer poly(A) tail attracts more cytoplasmic polyadenine binding proteins (PABPs) which interact with several other cytoplasmic proteins that encourage the mRNA and the ribosome to associate. [1] The lengthening of the poly(A) tail thus has a role in increasing translational efficiency of the mRNA. The polyadenine tails are extended from approximately 40 bases to 150 bases. [2]

Cytoplasmic polyadenylation should be distinguished from nuclear polyadenylation; cytoplasmic polyadenylation occurs in the cytoplasm in specific mRNAs as opposed to occurring in the nucleus and affecting almost all eukaryotic mRNAs. [3] Among other functions, a prominent role for the CPE has been identified in oogenesis, spermatogenesis, mitosis, and the growth of new synapses [4] [5] [6] The role of the CPE was first characterized in Xenopus oocytes and embryos but recent research has identified roles for the CPE in somatic cells. [1] [7] Some proto-oncogene mRNAs have been shown to contain CPEs. One such gene is Myc . The level of production of the different CPEB proteins determines whether the expression of Myc leads to tumor formation. [8] The tumor suppressor gene TP53 has also been shown to be regulated by a CPE. Cell lines that do not produce CPEB show lower levels of the protein p53 and become immortal instead of showing senescence. [9]

The eCPE and the C-CPE are two other cytoplasmic polyadenylation elements that are found within embryos. The most common eCPE sequence is UUUUUUUUUUUU while the sequence of C-CPE is generally a very C rich region with the occasional U. All of these CPEs have in common that their effectiveness in promoting the extension of the poly(A) tail depends on their proximity to the poly(A) signal. [1] Optimally, they should be within 25 nucleotides but can be as far as 100 nucleotides from the poly(A) signal. [10] Alternately, CPEs can cause translation repression if two CPE sequences are located within 50 nucleotides of each other within the 3’ UTR. [1] The highest amounts of repression are seen when the two CPEs are 10 to 12 nucleotides apart. If the CPE has a nonconsensus sequence, a nearby Pumilio-binding element (PBE) is necessary for translational activation to result. If the CPE has a consensus sequence, the presence of the PBE can double the resulting translational activation. [10] The CPE is not the only cis-acting element to regulate 3'UTR processing as alternative polyadenylation (APA) signals, microRNA target sites, and AU rich elements (ARE) also have roles in determining the length of the poly(A) tail. [11]

Research

Research into the CPE has focused on further elucidating its role in translational regulation and its role in development. Research on Aplysia neurons has shown that the CPE has a role in regulating memory formation. When long-term memories are being formed, CPEs found in neuronal actin mRNAs allow the up-regulation of this protein. Increased concentrations of actin allow new synapses to grow, allowing memory storage. [12]

A study done on mRNA regulation during oogenesis in Drosophila has revealed that the CPE and CPE binding proteins help control the timing of protein production during development. Oocytes transcribe a large portion of their mRNA at one time and rely on other control mechanisms to determine the timing of protein production. The study showed that mRNAs that are a target of the CPEB WISP show significant polyA tail extension but not an increased number of mRNA transcripts. [13]

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">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 genetics, a transcription terminator is a section of nucleic acid sequence that marks the end of a gene or operon in genomic DNA during transcription. This sequence mediates transcriptional termination by providing signals in the newly synthesized transcript RNA that trigger processes which release the transcript RNA from the transcriptional complex. These processes include the direct interaction of the mRNA secondary structure with the complex and/or the indirect activities of recruited termination factors. Release of the transcriptional complex frees RNA polymerase and related transcriptional machinery to begin transcription of new mRNAs.

Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In eukaryotes, polyadenylation is part of the process that produces mature mRNA for translation. In many bacteria, the poly(A) tail promotes degradation of the mRNA. It, therefore, forms part of the larger process of gene expression.

The 5′ untranslated region is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of translation of a transcript by differing mechanisms in viruses, prokaryotes and eukaryotes. While called untranslated, the 5′ UTR or a portion of it is sometimes translated into a protein product. This product can then regulate the translation of the main coding sequence of the mRNA. In many organisms, however, the 5′ UTR is completely untranslated, instead forming a complex secondary structure to regulate translation.

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.

<span class="mw-page-title-main">Post-transcriptional modification</span> RNA processing within a biological cell

Transcriptional modification or co-transcriptional modification is a set of biological processes common to most eukaryotic cells by which an RNA primary transcript is chemically altered following transcription from a gene to produce a mature, functional RNA molecule that can then leave the nucleus and perform any of a variety of different functions in the cell. There are many types of post-transcriptional modifications achieved through a diverse class of molecular mechanisms.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping.

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.

<span class="mw-page-title-main">Histone 3′ UTR stem-loop</span>

The histone 3′ UTR stem-loop is an RNA element involved in nucleocytoplasmic transport of the histone mRNAs, and in the regulation of stability and of translation efficiency in the cytoplasm. The mRNAs of metazoan histone genes lack polyadenylation and a poly-A tail, instead 3′ end processing occurs at a site between this highly conserved stem-loop and a purine rich region around 20 nucleotides downstream. The stem-loop is bound by a 31 kDa stem-loop binding protein. Together with U7 snRNA binding of the HDE, SLBP binding nucleates the formation of the processing complex.

<span class="mw-page-title-main">Poly(A)-binding protein</span> RNA binding protein

Poly(A)-binding protein is an RNA-binding protein which triggers the binding of eukaryotic initiation factor 4 complex (eIF4G) directly to the poly(A) tail of mRNA which is 200-250 nucleotides long. The poly(A) tail is located on the 3' end of mRNA and was discovered by Mary Edmonds, who also characterized the poly-A polymerase enzyme that generates the poly(a) tail. The binding protein is also involved in mRNA precursors by helping polyadenylate polymerase add the poly(A) nucleotide tail to the pre-mRNA before translation. The nuclear isoform selectively binds to around 50 nucleotides and stimulates the activity of polyadenylate polymerase by increasing its affinity towards RNA. Poly(A)-binding protein is also present during stages of mRNA metabolism including nonsense-mediated decay and nucleocytoplasmic trafficking. The poly(A)-binding protein may also protect the tail from degradation and regulate mRNA production. Without these two proteins in-tandem, then the poly(A) tail would not be added and the RNA would degrade quickly.

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

CPEB, or cytoplasmic polyadenylation element binding protein, is a highly conserved RNA-binding protein that promotes the elongation of the polyadenine tail of messenger RNA. CPEB is present at postsynaptic sites and dendrites where it stimulates polyadenylation and translation in response to synaptic activity. CPEB most commonly activates the target RNA for translation, but can also act as a repressor, dependent on its phosphorylation state. As a repressor, CPEB interacts with the deadenylation complex and shortens the polyadenine tail of mRNAs. In animals, CPEB is expressed in several alternative splicing isoforms that are specific to particular tissues and functions, including the self-cleaving Mammalian CPEB3 ribozyme. CPEB was first identified in Xenopus oocytes and associated with meiosis; a role has also been identified in the spermatogenesis of Caenorhabditis elegans.

<span class="mw-page-title-main">Gurken localisation signal</span>

mRNA localization is a common mode of posttranscriptional regulation of gene expression that targets a protein to its site of function. Proteins are highly dependent on cellular environments for stability and function, therefore, mRNA localization signals are crucial for maintaining protein function. The Gurken localisation signal is an RNA regulatory element conserved across many species of Drosophila. The element consists of an RNA stem loop within the coding region of the messenger RNA that forms a signal for dynein-mediated Gurken mRNA transport to the dorsoanterior cap near the nucleus of the oocyte.

<span class="mw-page-title-main">PABPC1</span> Protein-coding gene in the species Homo sapiens

Polyadenylate-binding protein 1 is a protein that in humans is encoded by the PABPC1 gene. The protein PABP1 binds mRNA and facilitates a variety of functions such as transport into and out of the nucleus, degradation, translation, and stability. There are two separate PABP1 proteins, one which is located in the nucleus (PABPN1) and the other which is found in the cytoplasm (PABPC1). The location of PABP1 affects the role of that protein and its function with RNA.

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

In enzymology, a polynucleotide adenylyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">CPEB1</span> Protein-coding gene in humans

Cytoplasmic polyadenylation element-binding protein 1 is a protein that in humans is encoded by the CPEB1 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.

TMEM143 is a protein that in humans is encoded by TMEM143 gene. TMEM143, a dual-pass protein, is predicted to reside in the mitochondria and high expression has been found in both human skeletal muscle and the heart. Interaction with other proteins indicate that TMEM143 could potentially play a role in tumor suppression/expression and cancer regulation.

<span class="mw-page-title-main">GLD-2</span> Protein-coding gene in the species Homo sapiens

GLD-2 is a cytoplasmic poly(A) polymerase (cytoPAPs) which adds successive AMP monomers to the 3’ end of specific RNAs, forming a poly(A) tail, which is a process known as polyadenylation.

<span class="mw-page-title-main">BC200 lncRNA</span>

Brain cytoplasmic 200 long-noncoding RNA is a 200 nucleotide RNA transcript found predominantly in the brain with a primary function of regulating translation by inhibiting its initiation. As a long non-coding RNA, it belongs to a family of RNA transcripts that are not translated into protein (ncRNAs). Of these ncRNAs, lncRNAs are transcripts of 200 nucleotides or longer and are almost three times more prevalent than protein-coding genes. Nevertheless, only a few of the almost 60,000 lncRNAs have been characterized, and little is known about their diverse functions. BC200 is one lncRNA that has given insight into their specific role in translation regulation, and implications in various forms of cancer as well as Alzheimer's disease.

References

  1. 1 2 3 4 5 Charlesworth, Amanda; Meijer, Hedda A.; de Moor, Cornelia H. (2013-07-01). "Specificity factors in cytoplasmic polyadenylation". Wiley Interdisciplinary Reviews: RNA. 4 (4): 437–461. doi:10.1002/wrna.1171. ISSN   1757-7012. PMC   3736149 . PMID   23776146.
  2. 1 2 Ivshina, Maria; Lasko, Paul; Richter, Joel D. (11 October 2014). "Cytoplasmic Polyadenylation Element Binding Proteins in Development, Health, and Disease". Annual Review of Cell and Developmental Biology. 30 (1): 393–415. doi: 10.1146/annurev-cellbio-101011-155831 . PMID   25068488.
  3. ↑ Hunt, Arthur G.; Xu, Ruqiang; Addepalli, Balasubrahmanyam; Rao, Suryadevara; Forbes, Kevin P.; Meeks, Lisa R.; Xing, Denghui; Mo, Min; Zhao, Hongwei (2008-01-01). "Arabidopsis mRNA polyadenylation machinery: comprehensive analysis of protein-protein interactions and gene expression profiling". BMC Genomics. 9: 220. doi: 10.1186/1471-2164-9-220 . ISSN   1471-2164. PMC   2391170 . PMID   18479511.
  4. ↑ de Moor, C.H.; Richter, J.D. (1999). "Cytoplasmic polyadenylation mediate masking and unmasking of cyclin B1 mRNA". EMBO J. 18 (8): 2294–2303. doi:10.1093/emboj/18.8.2294. PMC   1171312 . PMID   10205182.
  5. ↑ Luitjens, C; Gallegos, M; Kraemer, B; Kimble, J; Wickens, M (2000). "CPEB proteins control two key steps in spermatogenesis in C. elegans". Genes Dev. 14 (20): 2596–609. doi:10.1101/gad.831700. PMC   316992 . PMID   11040214.
  6. ↑ Villalba, Ana; Coll, Olga; Gebauer, Fátima (2011). "Cytoplasmic polyadenylation and translational control". Current Opinion in Genetics & Development. 21 (4): 452–457. doi:10.1016/j.gde.2011.04.006. PMID   21536428.
  7. ↑ Rutledge, Charlotte E.; Lau, Ho-Tak; Mangan, Hazel; Hardy, Linda L.; Sunnotel, Olaf; Guo, Fan; MacNicol, Angus M.; Walsh, Colum P.; Lees-Murdock, Diane J. (2014-02-20). "Efficient Translation of Dnmt1 Requires Cytoplasmic Polyadenylation and Musashi Binding Elements". PLOS ONE. 9 (2): e88385. Bibcode:2014PLoSO...988385R. doi: 10.1371/journal.pone.0088385 . ISSN   1932-6203. PMC   3930535 . PMID   24586322.
  8. ↑ Chen, Yun; Tsai, Ya-Hui; Tseng, Sheng-Hong (2016-11-01). "Regulation of the Expression of Cytoplasmic Polyadenylation Element Binding Proteins for the Treatment of Cancer". Anticancer Research. 36 (11): 5673–5680. doi: 10.21873/anticanres.11150 . ISSN   0250-7005. PMID   27793888.
  9. ↑ Burns, David M.; Richter, Joel D. (2008-12-15). "CPEB regulation of human cellular senescence, energy metabolism, and p53 mRNA translation". Genes & Development. 22 (24): 3449–3460. doi:10.1101/gad.1697808. ISSN   0890-9369. PMC   2607074 . PMID   19141477.
  10. 1 2 Piqué, Maria; López, José Manuel; Foissac, Sylvain; Guigó, Roderic; Méndez, Raúl (2008). "A Combinatorial Code for CPE-Mediated Translational Control". Cell. 132 (3): 434–448. doi: 10.1016/j.cell.2007.12.038 . PMID   18267074.
  11. ↑ Zhang, Xiaokan; Virtanen, Anders; Kleiman, Frida E. (2010-11-15). "To polyadenylate or to deadenylate". Cell Cycle. 9 (22): 4437–4449. doi:10.4161/cc.9.22.13887. ISSN   1538-4101. PMC   3048043 . PMID   21084869.
  12. ↑ Liu, Jinming; Schwartz, James H. (2003-01-03). "The cytoplasmic polyadenylation element binding protein and polyadenylation of messenger RNA in Aplysia neurons". Brain Research. 959 (1): 68–76. doi:10.1016/s0006-8993(02)03729-0. ISSN   0006-8993. PMID   12480159. S2CID   558770.
  13. ↑ Cui, Jun; Sartain, Caroline V.; Pleiss, Jeffrey A.; Wolfner, Mariana F. (2013-11-01). "Cytoplasmic polyadenylation is a major mRNA regulator during oogenesis and egg activation in Drosophila". Developmental Biology. 383 (1): 121–131. doi:10.1016/j.ydbio.2013.08.013. PMC   3821703 . PMID   23978535.
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