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Specificity factors in cytoplasmic polyadenylation

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Poly(A) tail elongation after export of an messenger RNA (mRNA) to the cytoplasm is called cytoplasmic polyadenylation. It was first discovered in oocytes and embryos, where it has roles in meiosis and development. In recent years, however, has been implicated in many other processes, including synaptic plasticity and mitosis. This review aims to introduce cytoplasmic polyadenylation with an emphasis on the factors and elements mediating this process for different mRNAs and in different animal species. We will discuss the RNA sequence elements mediating cytoplasmic polyadenylation in the 3′ untranslated regions of mRNAs, including the CPE, MBE, TCS, eCPE, and C‐CPE. In addition to describing the role of general polyadenylation factors, we discuss the specific RNA binding protein families associated with cytoplasmic polyadenylation elements, including CPEB (CPEB1, CPEB2, CPEB3, and CPEB4), Pumilio (PUM2), Musashi (MSI1, MSI2), zygote arrest (ZAR2), ELAV like proteins (ELAVL1, HuR), poly(C) binding proteins (PCBP2, αCP2, hnRNP‐E2), and Bicaudal C (BICC1). Some emerging themes in cytoplasmic polyadenylation will be highlighted. To facilitate understanding for those working in different organisms and fields, particularly those who are analyzing high throughput data, HUGO gene nomenclature for the human orthologs is used throughout. Where human orthologs have not been clearly identified, reference is made to protein families identified in man. WIREs RNA 2013, 4:437–461. doi: 10.1002/wrna.1171 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications Translation > Translation Regulation RNA Processing > 3' End Processing

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The nuclear cleavage and polyadenylation complex in vertebrates. The Cleavage and Polyadenylation Specificity Factor (CPSF) protein complex binds to the poly(A) signal PAS, it contains CPSF1‐4 and the associated factors FIP1L and Symplekin (SYMPK).The CPSF3 subunit is the endonuclease acting at the cleavage site. The Cleavage Factor 1 complex (CFIm) recognizes the upstream element (USE), it is composed of NUDT21, CPSF6, and CPSF7. The CSTF complex recognizes the GU‐ or U‐rich downstream element (DSE). CPSF, CSTF, SYMPK, and CFIm interact at the protein level, stabilizing the RNA binding, thus promoting correct cleavage and polyadenylation site recognition and recruitment of the poly(A) polymerase (PAPOLA or PAPOLG). The nuclear poly(A) binding protein (PABPN1) interacts with CFIm and PAPOLA and contributes to the efficiency of polyadenylation. Double arrows indicate interactions. The cleavage site is indicated by a bold single headed arrow. Some of these interactions have been inferred from work in yeast. For further details, see two recent reviews.
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Cytoplasmic polyadenylation during Xenopus oocyte maturation. The cytoplasmic polyadenylation element (CPE) recruits its binding protein CPEB1. This binding can be stabilized, especially on noncanonical CPEs, by the recruitment of Pumilio (PUM2) to the Pumilio binding element (PBE) and protein–protein interactions between CPEB1 and PUM2. CPEB1 in turn interacts with the cytoplasmic CPSF complex, consisting of CPSF1,2 and 4 and the associated factor SYMPK (the endonuclease CPSF3 is absent and FIP1L has not been tested). CPSF1 recognizes the poly(A) signal (PAS). Before oocyte maturation translation is Repressed: CPEB1 and PUM2 mediate mRNA deadenylation and translational repression by recruiting deadenylases (CPEB1 recruits PARN, PUM2 can bind the CNOT complex) and disrupting closed loop complex formation (PUM2 by direct cap interaction, CPEB1 by recruiting a choice of eIF4E binding or cap binding proteins). In addition, CPEB1 binds the embryonic poly(A) binding protein PABPCL1. The poly(A) polymerase PAPD4 is secured in the complex by interactions with CPEB1 and CPSF, but its activity is repressed and/or masked by active deadenylation. Upon the stimulation of meiotic maturation, translation is Activated: CPEB1 is phosphorylated (yellow P). Deadenylases and translational repression complexes are ejected from the complex and/or inactivated, PAPD4 mediates elongation of the poly(A) tail and PABPC1L dissociates from CPEB1 and transferred to the poly(A) tail, where it can stimulate the formation of the closed loop complex and activate translation. More details and references can be found in the text.
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The closed loop complex enhances translation by increasing eIF4A and eIF3 recruitment. Cytoplasmic poly(A) binding proteins (e.g., PABPC1 or PABPC1L) stabilize the cap binding translation initiation complex consisting of eIF4E (4E), eIF4G, and eIF4A (4A), forming the closed loop complex. In addition, PABPC proteins can bind poly(A) binding protein interacting protein 1 (PAIP1), which, like eIF4G can bind eIF4A and the ribosome recruiting complex eIF3. This leads to enhanced translation mediated by the poly(A) tail. For references, see text.
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
Translation > Translation Regulation
RNA Processing > 3′ End Processing

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