Several suppressible stop codons are associated with downstream structural elements, which in the case of the Drosophila hdc stop codon, is a hairpin that can function in heterologous mRNAs Steneberg and Samakovlis ; Jungreis et al. Components of the translation apparatus, including eRF1, eRF3, and the ribosome, are post-translationally modified, but the functional consequences of these modifications remain largely uncharacterized.
OGFOD1 catalyzes hydroxylation of a conserved prolyl residue in rps23 at a site that projects into the decoding center. This modification has varying effects on termination in yeast and human cells, and at stop codons with different contexts e. It could potentially regulate read-through on specific mRNAs in specific circumstances. The Gln of the GGQ motif of yeast eRF1 is methylated by a methyltransferase that consists of the catalytic Mtq2 subunit and the zinc finger protein Trm Graille et al.
The human cytomegalovirus uORF2-encoded peptide impairs translation of the gp48 gene Janzen et al. These regulatory nascent peptides bind to the ribosomal tunnel and perturb the PTC so that although the eRF1 GGQ-loop is appropriately positioned, it cannot promote peptide release Bhushan et al. Systematic analysis of uORFs in Arabidopsis thaliana suggests that this mechanism is prevalent in all eukaryotes Ebina et al. Stalling in A. The small molecule drug ataluren PTC , which is being developed to ameliorate diseases caused by nonsense mutations, has similarly been reported to enhance insertion of near-cognate aminoacyl-tRNAs Roy et al.
Reinitiation after translation of a uORF, first reported more than 30 years ago Kozak , , is now recognized as a key regulatory process in post-transcriptional control of eukaryotic gene expression. Reinitiation of translation can occur by different mechanisms depending on how far the recycling process has progressed.
Efficient reinitiation usually occurs only after translation of short ORFs, and the level of reinitiation drops with uORF length Luukkonen et al. The realization that reinitiation efficiency is determined by the time taken to translate a uORF rather than by its length led to the hypothesis that reinitiation depends on ribosomal retention of a critical factor during elongation and termination Kozak This factor would dissociate stochastically, and only those ribosomes that retained it would be reinitiation-competent.
Consistently, eIF3 binds primarily on the solvent surface of the 40S subunit des Georges et al. In vitro reconstitution experiments Skabkin et al. They encode proteins involved in establishing circadian rhythms and, consistently, silencing of DENR led to shortened circadian periods Janich et al. Post-termination ribosomes are usually weakly anchored to mRNA, and if they are not split by ABCE1 in in vitro reconstituted mammalian translation reactions Skabkin et al.
They then stop at triplets that are cognate to the P-site deacylated tRNA and reinitiate translation. In a model Skabkin et al. There are circumstances in which post-TCs become tethered to mRNA in a manner that promotes reinitiation near the stop codon. For example, the bicistronic subgenomic mRNAs of caliciviruses encode major and minor capsid proteins, and translation of ORF2 occurs by reinitiation. In conclusion, recycling can be interrupted at distinct steps to allow post-termination ribosomes to reinitiate translation by diverse mechanisms.
This allows access of ribosomes to the principal ORF in an mRNA to be regulated, but also enables the coding capacity of viral mRNAs to be maximized and, as suggested previously Skabkin et al. We thank M. Weisser and N. Ban for the figures. Additional Perspectives on Translation Mechanisms and Control available at www. Previous Section Next Section. Figure 1. Figure 2. Figure 3. Figure 4. Regulation of Termination by Post-Translational Modification Components of the translation apparatus, including eRF1, eRF3, and the ribosome, are post-translationally modified, but the functional consequences of these modifications remain largely uncharacterized.
Previous Section. In vitro reconstitution of eukaryotic translation reveals cooperativity between release factors eRF1 and eRF3. Cell : — Evolution of nonstop, no-go and nonsense-mediated mRNA decay and their termination factor-derived components. BMC Evol Biol 8 : CrossRef Medline Google Scholar. J Biol Chem : — Proc Natl Acad Sci : — Structural basis of highly conserved ribosome recycling in eukaryotes and archaea.
Nature : — Beier H , Grimm M. Misreading of termination codons in eukaryotes by natural nonsense suppressor tRNAs. Nucleic Acids Res 29 : — Terminating eukaryote translation: Domain 1 of release factor eRF1 functions in stop codon recognition.
RNA 6 : — RNA 22 : — Structural basis for translational stalling by human cytomegalovirus and fungal arginine attenuator peptide. Mol Cell 40 : — New insights into the incorporation of natural suppressor tRNAs at stop codons in Saccharomyces cerevisiae. Nucleic Acids Res 42 : — New insights into stop codon recognition by eRF1. Nucleic Acids Res 43 : — Structural basis for stop codon recognition in eukaryotes.
Three distinct peptides from the N domain of translation termination factor eRF1 surround stop codon in the ribosome.
RNA 16 : — Chemical footprinting reveals conformational changes of 18S and 28S rRNAs at different steps of translation termination on the human ribosome. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans.
Proto-genes and de novo gene birth. Involvement of human release factors eRF3a and eRF3b in translation termination and regulation of the termination complex formation.
Mol Cell Biol 25 : — EMBO J 21 : — Structural insights into eRF3 and stop codon recognition by eRF1. Genes Dev 23 : — Identification of eRF1 residues that play critical and complementary roles in stop codon recognition. RNA 18 : — Structure of mammalian eIF3 in the context of the 43S preinitiation complex. Dever TE , Green R. The elongation, termination, and recycling phases of translation in eukaryotes.
Cold Spring Harb Perspect Biol 4 : a Ribosome profiling reveals pervasive and regulated stop codon readthrough in Drosophila melanogaster.
Identification of novel Arabidopsis thaliana upstream open reading frames that control expression of the main coding sequences in a peptide sequence-dependent manner. Eukaryotic release factor 3 is required for multiple turnovers of peptide release catalysis by eukaryotic release factor 1. Distinct eRF3 requirements suggest alternate eRF1 conformations mediate peptide release during eukaryotic translation termination.
Mol Cell 30 : — Optimal translational termination requires C4 lysyl hydroxylation of eRF1. Mol Cell 53 : — Firth AE , Brierley I. Non-canonical translation in RNA viruses. J Gen Virol 93 : — Nucleic Acids Res 39 : — Structural view on recycling of archaeal and eukaryotic ribosomes after canonical termination and ribosome rescue.
Curr Opin Struct Biol 22 : — Eukaryotic polypeptide chain release factor eRF3 is an eRF1- and ribosome-dependent guanosine triphosphatase. RNA 2 : — RNA 5 : — Methylation of class I translation termination factors: Structural and functional aspects. Biochimie 94 : — Biochimie 88 : — He F , Jacobson A. Nonsense-mediated mRNA decay: Degradation of defective transcripts is only part of the story. Annu Rev Genet 49 : — Novel ciliate genetic code variants including the reassignment of all three stop codons to sense codons in Condylostoma magnum.
Mol Biol Evol 33 : — Nat Struct Mol Biol 24 : — Structural insights into ribosomal rescue by Dom34 and Hbs1 at near-atomic resolution. Nat Commun 7 : Google Scholar. Hinnebusch AG. Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 59 : — The new protein is then released, and the translation complex comes apart. Further Exploration Concept Links for further exploration gene expression frameshift mutation nonsense mutation RNA intron exon codon amino acid chromosome mutation protein genetic code gene tRNA proteome ribosome peptide cytoplasm splicing transcription.
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Change LearnCast Settings. Peptide bonds form between the amino group of the amino acid attached to the A-site tRNA and the carboxyl group of the amino acid attached to the P-site tRNA.
The formation of each peptide bond is catalyzed by peptidyl transferase , an RNA-based enzyme that is integrated into the 50S ribosomal subunit. The energy for each peptide bond formation is derived from GTP hydrolysis, which is catalyzed by a separate elongation factor. The amino acid bound to the P-site tRNA is also linked to the growing polypeptide chain. Amazingly, the E. Figure 2.
The large ribosomal subunit joins the small subunit, and a second tRNA is recruited. As the mRNA moves relative to the ribosome, the polypeptide chain is formed. Entry of a release factor into the A site terminates translation and the components dissociate.
Many antibiotics inhibit bacterial protein synthesis. For example, tetracycline blocks the A site on the bacterial ribosome, and chloramphenicol blocks peptidyl transfer. What specific effect would you expect each of these antibiotics to have on protein synthesis? Upon aligning with the A site, these stop codons are recognized by release factors in prokaryotes and eukaryotes that instruct peptidyl transferase to add a water molecule to the carboxyl end of the P-site amino acid.
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