Key Points
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The regulated translation of messenger RNAs is crucial for many developmental processes, including oocyte maturation, establishment of the embryonic axes, and regulation of 'synaptic memory' in the central nervous system.
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The initiation complex is a key target for both positive and negative regulators of translation. Particular features of an mRNA also affect its translational efficiency, including sequences that lie in its 3′ and 5′ untranslated regions (UTRs).
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During oocyte maturation, there is an intricate network of translational activation and repression of stored maternal mRNAs. One crucial factor for this is the serine/threonine kinase Mos, one of whose functions is to induce translational activation of cyclin B1 mRNA. Intriguingly, the translation of Mos itself must first be activated during maturation.
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Many dormant mRNAs, including Mos and cyclin B1, contain short poly(A) tails, which must be elongated for translational initiation to occur. Polyadenylation requires two elements in the 3′ UTR: the hexanucleotide AAUAAA and the cytoplasmic polyadenylation element (CPE), the latter of which varies in copy number and distance from the hexanucleotide.
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The CPE is bound by CPEB, which, through an interaction with the AAUAAA-binding factor (CPSF), recruits poly(A) polymerase to the mRNA, and thus triggers polyadenylation. CPEB is also proposed to act indirectly as a masking factor, but the main protein that mediates translational repression is maskin, an eIF4E-associated factor. An attractive model is that polyadenylation relieves repression by triggering dissociation of maskin from the eIF4E, the cap binding protein.
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After oocyte maturation, most CPEB is destroyed, apart from that associating with spindles and centrosomes. Maskin also localizes to those structures, and both proteins are proposed to regulate translation initiation during embryonic cell divisions. One crucial target is thought to be cyclin B1 mRNA.
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A possible role for CPEB-mediated translational activation in neuronal synapses is indicated by the localization of CPEB in postsynaptic densities of hippocampal neurons. At this locale, synaptic plasticity may be controlled, as least in part, by the polyadenylation and translation of CPE-containing mRNAs.
Abstract
The regulated translation of messenger RNA is essential for cell-cycle progression, establishment of the body plan during early development, and modulation of key activities in the central nervous system. Cytoplasmic polyadenylation, which is one mechanism of controlling translation, is driven by CPEB — a highly conserved, sequence-specific RNA-binding protein that binds to the cytoplasmic polyadenylation element, and modulates translational repression and mRNA localization. What are the features and functions of this multifaceted protein?
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Glossary
- POLYSOMES
-
Complex of ribosomes bound to a single messenger RNA molecule.
- GERM LAYERS
-
Embryonic cell layers (endoderm, mesoderm and ectoderm) from which the embryonic organs and structures are derived.
- eIF3
-
Eukaryotic translation initiation factor that mediates dissociation of the 40S and 60S ribosomal subunits and the recruitment of the Met–tRNA–eIF2 complex and the 40S ribosomal subunit to the messenger RNA.
- UTR
-
Non-coding portions of the messenger RNA that precede the starting codon (5′ UTR) or follow the termination codon (3′ UTR).
- 40S PRE-INITIATION COMPLEX
-
Ribonucleoprotein particle that includes the transfer RNA, the 40S ribosomal subunit and the eIF2.
- eIF2
-
Eukaryotic translation-initiation factor that mediates the recruitment of the Met–tRNAi to the 40S ribosomal subunit.
- eIF5B
-
Eukaryotic translation-initiation factor that mediates recruitment of the 60S ribosomal subunit to the mRNA-associated 40S ribosomal subunit.
- MONOSOME
-
Single ribosome bound to a mRNA.
- hnRNPs
-
Proteins that bind the heterogeneous nuclear RNA (hnRNA) and that are involved in splicing, RNA transport and translation.
- PROPHASE
-
Initial phase of the cell cycle (mitosis or meiosis), in which the chromatin is condensed. Meiosis contains two prophases not separated by a DNA-replication event.
- METAPHASE
-
Phase of the cell cycle (mitosis or meiosis) in which the nuclear membrane breaks down and the chromosomes are arranged on the equator of the spindle. Meiosis contains two metaphases not separated by a DNA-replication event.
- CDC2
-
Serine/threonine kinase that constitutes the catalytic subunit of the M-phase-promoting factor (MPF).
- CYCLIN B1
-
Regulatory subunit of the M-phase-promoting factor (MPF).
- PARTHENOGENESIS
-
Cell division of an egg without fertilization.
- ZINC FINGER
-
Nucleic-acid-binding protein structures containing cysteine or histidine residues at both extremities of the domain, which are involved in the tetrahedral coordination of a zinc atom.
- RNA-RECOGNITION MOTIF
-
(RRM). Sequence-specific RNA-recognition domain present in RNA-binding proteins. It consists of ∼90 amino acids in α-helical and β-sheet topology, arranged in an αβαββαβ structure.
- AURORA KINASES
-
Family of serine/threonine kinases required for bipolar spindle assembly and chromosome segregation.
- NUCLEAR LOCALIZATION SIGNAL
-
Small stretch of amino acids recognized by the importin protein complex that directs the translocation of the targeted protein through the nuclear pore into the nucleus.
- RNA INTERFERENCE
-
(RNAi). A technique in which double-stranded RNA targeted against a gene product is introduced into cells or an organism, resulting in null or hypomorphic phenotypes.
- PAM MATRIX
-
A matrix of weights derived from how often different amino acids replace other amino acids during evolution. PAM stands for 'per cent accepted mutations', and these were inferred from the types of change observed in these proteins. Every change was tabulated and entered in a matrix enumerating all possible amino-acid changes.
- ANIMAL POLE BLASTOMERES
-
Embryonic cells that will form the ectoderm.
- 3′-DEOXYADENOSINE
-
Analogue of ATP that acts as a chain terminator during RNA synthesis or polyadenylation.
- POSTSYNAPTIC DENSITY
-
Dense structure beneath the postsynaptic site, in which an array of synaptic proteins is anchored to a specific set of cytoskeletal and/or signalling proteins.
- αCAMKII
-
Calcium–calmodulin- dependent kinase II; activated in response to synaptic activity.
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Mendez, R., Richter, J. Translational control by CPEB: a means to the end. Nat Rev Mol Cell Biol 2, 521–529 (2001). https://doi.org/10.1038/35080081
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DOI: https://doi.org/10.1038/35080081
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