The stop signal controls the efficiency of release factor-mediated translational termination.

There are three important steps in protein synthesis where signals in the mRNA are critical for a successful outcome, namely the production of a functional protein. First the information in the nucleic acid which is to be translated into an amino acid sequence is signalled by successive triplet sense codons, second the frame is set by one sense codon, the initiation codon, which acts as the start of translation of the encoded information, and third the end of the information frame also has to be marked by a specific signal. The use of a range of different signals to mark each of these steps allows for differences in the efficiency with which different proteins are produced. In this review the focus is on the signal that marks the end of the frame, the translational termination signal. For a long time it was thought that termination would be the least interesting phase of protein synthesis but it has subsequently been found to have unexpected dimensions, providing a substratum of cellular regulation. The translational stop signal should now be thought of as a full stop in the large majority of cases, but as a pause in a fundamentally important minority of cases where alternative genetic events can occur.

[1]  Charles T. Caskey.  Peptide chain termination , 1980 .

[2]  R. Doolittle.  Of urfs and orfs : a primer on how to analyze devised amino acid sequences , 1986 .

[3]  Chris M. Brown,et al.  The identity of the base following the stop codon determines the efficiency of in vivo translational termination in Escherichia coli. , 1995, The EMBO journal.

[4]  R. Fleischmann,et al.  Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. , 1995, Science.

[5]  J. F. Curran,et al.  Effects of the nucleotide 3' to an amber codon on ribosomal selection rates of suppressor tRNA and release factor-1. , 1991, Journal of molecular biology.

[6]  Richard Chamberlin,et al.  Ribosome-mediated incorporation of a non-standard amino acid into a peptide through expansion of the genetic code , 1992, Nature.

[7]  Chris M. Brown,et al.  Sequence analysis suggests that tetra-nucleotides signal the termination of protein synthesis in eukaryotes. , 1990, Nucleic acids research.

[8]  Chris M. Brown,et al.  Translational termination: "stop" for protein synthesis or "pause" for regulation of gene expression. , 1992, Biochemistry.

[9]  A. Haenni,et al.  A highly conserved eukaryotic protein family possessing properties of polypeptide chain release factor , 1994, Nature.

[10]  F. Crick,et al.  UGA: A Third Nonsense Triplet in the Genetic Code , 1967, Nature.

[11]  Post-translational modifications of microtubule- and growth-associated proteins in nerve regeneration and neuropathy. , 1995, Biochemical Society transactions.

[12]  L. Gold,et al.  Posttranscriptional regulatory mechanisms in Escherichia coli. , 1988, Annual review of biochemistry.

[13]  R. Brimacombe,et al.  The ribosomal binding domain of the Escherichia coli release factors. Modification of tyrosine in the N-terminal domain of ribosomal protein L11 affects release factors 1 and 2 differentially. , 1986, The Journal of biological chemistry.

[14]  Chris M. Brown,et al.  Direct recognition of mRNA stop signals by Escherichia coli polypeptide chain release factor two. , 1994, The Journal of biological chemistry.

[15]  W. Tate,et al.  A single proteolytic cleavage in release factor 2 stabilizes ribosome binding and abolishes peptidyl-tRNA hydrolysis activity. , 1994, The Journal of biological chemistry.

[16]  Y. Nakamura,et al.  Autogenous suppression of an opal mutation in the gene encoding peptide chain release factor 2. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[17]  R. Gutell.  The Simplicity Behind the Elucidation of Complex Structure in Ribosomal RNA , 1993 .

[18]  D. W. Smith,et al.  Structure and function of suppressor tRNAs in higher eukaryotes. , 1990, Critical reviews in biochemistry and molecular biology.

[19]  Chris M. Brown,et al.  The signal for the termination of protein synthesis in procaryotes. , 1990, Nucleic acids research.

[20]  P. Sharp,et al.  The codon Adaptation Index--a measure of directional synonymous codon usage bias, and its potential applications. , 1987, Nucleic acids research.

[21]  A. Böck,et al.  Selenoprotein synthesis: an expansion of the genetic code. , 1991, Trends in biochemical sciences.

[22]  D. Jahn,et al.  Regulation of the hemA gene during 5-aminolevulinic acid formation in Pseudomonas aeruginosa , 1995, Journal of bacteriology.

[23]  Salmonella typhimurium prfA mutants defective in release factor 1 , 1991, Journal of bacteriology.

[24]  A. P. Potapov,et al.  Synergism between the GTPase activities of EF-Tu.GTP and EF-G.GTP on empty ribosomes. Elongation factors as stimulators of the ribosomal oscillation between two conformations. , 1994, Journal of molecular biology.

[25]  S. Korolev,et al.  Termination of translation in bacteria may be modulated via specific interaction between peptide chain release factor 2 and the last peptidyl-tRNA(Ser/Phe). , 1993, Nucleic acids research.

[26]  R. Brimacombe,et al.  Codon recognition in polypeptide chain termination: site directed crosslinking of termination codon to Escherichia coli release factor 2. , 1990, Nucleic acids research.

[27]  M Bjerknes,et al.  Determination of the optimal aligned spacing between the Shine-Dalgarno sequence and the translation initiation codon of Escherichia coli mRNAs. , 1994, Nucleic acids research.

[28]  P. Breining,et al.  Yeast omnipotent supressor SUP1 (SUP45): nucleotide sequence of the wildtype and a mutant gene , 1986, Nucleic Acids Res..

[29]  Y. Kohara,et al.  Rapid and precise mapping of the Escherichia coli release factor genes by two physical approaches , 1988, Journal of bacteriology.

[30]  H. Noller,et al.  Binding of tRNA to the ribosomal A and P sites protects two distinct sets of nucleotides in 16 S rRNA. , 1990, Journal of molecular biology.

[31]  L. Mora,et al.  Localization and characterization of the gene encoding release factor RF3 in Escherichia coli. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[32]  R. Goldman,et al.  Influence of codon context on UGA suppression and readthrough. , 1992, Journal of Molecular Biology.

[33]  K. Nierhaus,et al.  Solution of the ribosome riddle: how the ribosome selects the correct aminoacyl‐tRNA out of 41 similar contestants , 1993, Molecular microbiology.

[34]  R J Fletterick,et al.  Structural clues to prion replication. , 1994, Science.

[35]  M. Saier.  Differential codon usage: a safeguard against inappropriate expression of specialized genes? , 1995, FEBS letters.

[36]  L. Grivell,et al.  The yeast nuclear gene MRF1 encodes a mitochondrial peptide chain release factor and cures several mitochondrial RNA splicing defects. , 1992, Nucleic acids research.

[37]  C. Kurland,et al.  The concentration of polypeptide chain release factors 1 and 2 at different growth rates of Escherichia coli. , 1994, Journal of molecular biology.

[38]  A. Beaudet,et al.  Mammalian peptide chain termination. II. Codon specificity and GTPase activity of release factor. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[39]  J. Shine,et al.  The 3'-terminal sequence of Escherichia coli 16S ribosomal RNA: complementarity to nonsense triplets and ribosome binding sites. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[40]  E. Scolnick,et al.  Peptide chain termination, codon, protein factor, and ribosomal requirements. , 1969, Cold Spring Harbor symposia on quantitative biology.

[41]  Y. Chernoff,et al.  Deletion analysis of the SUP35 gene of the yeast Saccharomyces cerevisiae reveals two non‐overlapping functional regions in the encoded protein , 1993, Molecular microbiology.

[42]  Y. Nakamura,et al.  Identification of the prfC gene, which encodes peptide-chain-release factor 3 of Escherichia coli. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[43]  W P Tate,et al.  The translational termination signal database (TransTerm) now also includes initiation contexts. , 1994, Nucleic acids research.

[44]  M. Jacquet,et al.  In Xenopus laevis, the product of a developmentally regulated mRNA is structurally and functionally homologous to a Saccharomyces cerevisiae protein involved in translation fidelity , 1993, Molecular and cellular biology.

[45]  S. Mottagui-Tabar,et al.  The second to last amino acid in the nascent peptide as a codon context determinant. , 1994, The EMBO journal.

[46]  I. Tolstorukov,et al.  Divergence and conservation of SUP2(SUP35) gene of yeasts Pichia pinus and Saccharomyces cerevisiae , 1990, Yeast.

[47]  D. Bedwell,et al.  The efficiency of translation termination is determined by a synergistic interplay between upstream and downstream sequences in Saccharomyces cerevisiae. , 1995, Journal of molecular biology.

[48]  S. Hoshino,et al.  A human homologue of the yeast GST1 gene codes for a GTP‐binding protein and is expressed in a proliferation‐dependent manner in mammalian cells. , 1989, The EMBO journal.

[49]  R. Buckingham,et al.  Third position base changes in codons 5' and 3' adjacent UGA codons affect UGA suppression in vivo. , 1990, Biochimica et biophysica acta.

[50]  W. Tate,et al.  The NH2-terminal domain of Escherichia coli ribosomal protein L11. Its three-dimensional location and its role in the binding of release factors 1 and 2. , 1984, The Journal of biological chemistry.

[51]  M. Berry,et al.  Recognition of UGA as a selenocysteine codon in Type I deiodinase requires sequences in the 3′ untranslated region , 1991, Nature.

[52]  Isolation of a rat mitochondrial release factor. Accommodation of the changed genetic code for termination. , 1987, The Journal of biological chemistry.

[53]  R. Brimacombe,et al.  Prokaryotic translation: the interactive pathway leading to initiation. , 1994, Trends in genetics : TIG.

[54]  Ganoza Mc.  Polypeptide chain termination in cell-free extracts of E. coli. , 1966 .

[55]  M. Capecchi,et al.  Characterization of three proteins involved in polypeptide chain termination. , 1969, Cold Spring Harbor symposia on quantitative biology.

[56]  D. Nègre,et al.  G1401: a keystone nucleotide at the decoding site of Escherichia coli 30S ribosomes. , 1992, Biochemistry.

[57]  V. Smirnov,et al.  The SUP35 omnipotent suppressor gene is involved in the maintenance of the non-Mendelian determinant [psi+] in the yeast Saccharomyces cerevisiae. , 1994, Genetics.

[58]  D. Cavener,et al.  Eukaryotic start and stop translation sites. , 1991, Nucleic acids research.

[59]  Walter E. Hill,et al.  The Ribosome : structure, function, and evolution , 1990 .

[60]  S. Gangloff,et al.  A 40-kilodalton cell wall protein-coding sequence upstream of the sr gene of Streptococcus mutans OMZ175 (serotype f) , 1991, Infection and immunity.

[61]  Mark E. Dalphin,et al.  The translational termination signal database , 1993, Nucleic Acids Res..

[62]  W. Tate,et al.  Characterization of reticulocyte release factor. , 1977, The Journal of biological chemistry.

[63]  A. Surguchov,et al.  Nucleotide sequence of the SUP2 (SUP35) gene of Saccharomyces cerevisiae. , 1988, Gene.

[64]  W. Tate,et al.  The Escherichia coli ribosomal protein L11 suppresses release factor 2 but promotes the release factor 1 activities in peptide chain termination. , 1983, The Journal of biological chemistry.

[65]  T. Elliott.  Cloning, genetic characterization, and nucleotide sequence of the hemA-prfA operon of Salmonella typhimurium , 1989, Journal of bacteriology.

[66]  L. Kisselev,et al.  Termination of translation in eukaryotes is governed by two interacting polypeptide chain release factors, eRF1 and eRF3. , 1995, The EMBO journal.

[67]  Codon bias in Escherichia coli may modulate translation initiation. , 1995, Biochemical Society transactions.

[68]  S. J. Billington,et al.  A gene region in Dichelobacter nodosus encoding a lipopolysaccharide epitope. , 1995, Microbiology.

[69]  K. Nierhaus.  The translational apparatus : structure, function, regulation, evolution , 1993 .

[70]  P. Sharp,et al.  Codon usage: mutational bias, translational selection, or both? , 1993, Biochemical Society transactions.

[71]  Y. Nakamura,et al.  Sequence and functional analysis of mutations in the gene encoding peptide-chain-release factor 2 of Escherichia coli. , 1991, Biochimie.

[72]  L. Grivell,et al.  Sequence comparison of new prokaryotic and mitochondrial members of the polypeptide chain release factor family predicts a five-domain model for release factor structure. , 1992, Nucleic acids research.

[73]  S. Brenner,et al.  Genetic Code: The ‘Nonsense’ Triplets for Chain Termination and their Suppression , 1965, Nature.

[74]  M. Kozak.  Adherence to the first-AUG rule when a second AUG codon follows closely upon the first. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[75]  R. Merkl,et al.  Biased DNA repair , 1992, Nature.

[76]  H. Noller.  Ribosomal RNA and translation. , 1991, Annual review of biochemistry.

[77]  W. Craigen,et al.  Bacterial peptide chain release factors: conserved primary structure and possible frameshift regulation of release factor 2. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[78]  W P Tate,et al.  Translational termination efficiency in mammals is influenced by the base following the stop codon. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[79]  J. Ofengand,et al.  Functional effects of base changes which further define the decoding center of Escherichia coli 16S ribosomal RNA: mutation of C1404, G1405, C1496, G1497, and U1498. , 1993, Biochemistry.

[80]  I. Stansfield,et al.  The products of the SUP45 (eRF1) and SUP35 genes interact to mediate translation termination in Saccharomyces cerevisiae. , 1995, The EMBO journal.

[81]  C. Kurland.  Major codon preference: theme and variations. , 1993, Biochemical Society transactions.

[82]  R. Brimacombe,et al.  The topography of the 3'-terminal region of Escherichia coli 16S ribosomal RNA; an intra-RNA cross-linking study. , 1992, Nucleic acids research.

[83]  D. Hatfield,et al.  Transfer RNA in Protein Synthesis , 1992 .