Multiple upstream AUG codons mediate translational control of GCN4

Mueller, Peter P.; Hinnebusch, Alan G.

doi:10.1016/0092-8674(86)90384-3

Cited by 611 publications

(597 citation statements)

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“…This fusion contains the wild-type GCN4 mRNA leader with the four uORFs and thus, exhibits efficient translational regulation of GCN4 expression (Mueller and Hinnebusch 1986). As expected, low-level expression of GCN4-lacZ from p180 was observed in the Dgcn2 GCD18 strain under nonstarvation (R) or histidine starvation conditions (DR), because the Dgcn2 allele present in this strain impairs derepression of GCN4 translation (Gcn À phenotype) ( Figure 2F).…”

Section: Resultsmentioning

confidence: 80%

“…Plasmids p180, p226, and p227 contain distinct GCN4-LacZ fusions (Mueller and Hinnebusch 1986). Two fragments of 890-bp containing sequences belonging to the 39-end coding regions of wild-type GUA1 and of the gua1-G388D allele were amplified by PCR using as template genomic DNA from strains H117 and H166, respectively, and primers 1 and 3 ( Table 2).…”

Section: F35mentioning

confidence: 99%

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Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae

et al. 2011

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Purine nucleotides are structural components of the genetic material, function as phosphate donors, participate in cellular signaling, are cofactors in enzymatic reactions, and constitute the main carriers of cellular energy. Thus, imbalances in A/G nucleotide biosynthesis affect nearly the whole cellular metabolism and must be tightly regulated. We have identified a substitution mutation (G388D) that reduces the activity of the GMP synthase Gua1 in budding yeast and the total G-nucleotide pool, leading to precipitous reductions in the GDP/GTP ratio and ATP level in vivo. gua1-G388D strongly reduces the rate of growth, impairs general protein synthesis, and derepresses translation of GCN4 mRNA, encoding a transcriptional activator of diverse amino acid biosynthetic enzymes. Although processing of pre-tRNA i Met and other tRNA precursors, and the aminoacylation of tRNA iMet are also strongly impaired in gua1-G388D cells, tRNA i GTP complex (TC) and the multifactor complex (MFC) required for translation initiation accumulate $10-fold in gua1-G388D cells and, to a lesser extent, in wild-type (WT) cells treated with 6-azauracil (6AU). Consistently, addition of an external supply of guanine reverts all the phenotypes of gua1-G388D cells, but not those of gua1-G388D Dhpt1 mutants unable to refill the internal GMP pool through the salvage pathway. These and other findings suggest that a defect in guanine nucleotide biosynthesis evokes a reduction in the rate of general protein synthesis by impairing multiple steps of the process, disrupts the gene-specific reinitiation mechanism for translation of GCN4 mRNA and has far-reaching effects in cell biology and metabolism.

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Section: Resultsmentioning

confidence: 80%

Section: F35mentioning

confidence: 99%

Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae

et al. 2011

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“…The upstream AUG is followed by codons for arginine, valine and a termination codon. Multiple short open reading frames have been found in the 5' -leader of yeast GCN4 mRNA where they either attenuate or stimulate expression, depending on the growth conditions [46]. Similar mechanisms may also regulate 43 kDa protein expression at the translational level in rodent muscle.…”

Section: Northern Blot Analysismentioning

confidence: 99%

Expression of RNA transcripts for the postsynaptic 43 kDa protein in innervated and denervated rat skeletal muscle

Froehner

1989

FEBS Letters

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A cDNA clone encoding the mouse muscle postsynaptic 43 kDa protein was isolated and sequenced. The amino acid sequence of this protein, which is closely associated with nicotinic acetylcholine receptors at Torpedo electrocyte and vertebrate skeletal muscle synapses, is very similar in different species. A cysteine-rich region homologous to part of the regulatory domain of protein kinase C may be important in interactions of this protein with the lipid bilayer. RNA transcripts for the 43 kDa protein increase only 2-3-fold after denervation of rat skeletal muscle, in sharp contrast to the a-subunit of the muscle nicotinic receptor which increases more than 30-fold. Thus, the expression of these two proteins is regulated by different mechanisms.

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“…This is best exemplified by the posttranscriptional regulation mechanisms of the S. cerevisiae GCN4 gene, which encodes a transcription factor involved in responses to amino acid starvation. The GCN4 mRNA 5h UTR contains four uORFs, of which only uORF1 and uORF4 are required for wild-type translational control of GCN4 expression (Mueller & Hinnebusch, 1986). The precise details of this mechanism, and its relation to amino acid starvation responses, are reviewed elsewhere (Hinnebusch, 1997).…”

Section: Alternative Post-termination Events : Resumed Scanningmentioning

confidence: 99%

Endless possibilities: translation termination and stop codon recognition

et al. 2001

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OverviewThe process of protein synthesis can be divided into three main phases : initiation, during which the ribosomal subunits join the mRNA and locate the AUG initiator codon ; elongation, during which sense codons are decoded and the bulk of the polypeptide is made ; and termination, during which a stop codon directs the release of the completed polypeptide from the ribosome. Whereas the general principles of sense codon decoding by transfer RNAs are well established, a clear picture of translation termination and stop codon recognition has hitherto been lacking. Recently however, the use of optimized, complex, reconstituted in vitro termination reactions to identify the roles of key termination factors, and the solution of tertiary structures of termination factors, has allowed a reappraisal of termination factor structure and function. This review will describe these recent advances, many of which have resulted from studies of termination in micro-organisms, and in the light of the new information, discuss models for the mechanism of termination and recognition of the stop codon. While the mechanism of peptide chain termination is normally effective, stop codons are not always recognized efficiently, and during the translation of certain viral RNAs can be suppressed or read through, resulting in the expression of additional coding information. How stop codons are reassigned to encode ' sense ' at a given frequency in some RNAs will be reviewed in the context of current understanding of termination and stop codon recognition mechanisms. The translation termination apparatus in eukaryotes and prokaryotesDuring translation termination, a stop codon located in the ribosomal A-site is recognized by a release factor or release factor complex, which binds the ribosome and triggers release of the nascent peptide. In eukaryotes, translation is terminated by a heterodimer consisting of two proteins, release factors eRF1 and eRF3, which interact in vivo (Frolova et al., 1994 ;Zhouravleva et al., 1995 ;Stansfield et al., 1995). eRF1 recognizes all three stop codons and triggers peptidyl-tRNA hydrolysis by the ribosome, releasing the nascent peptide (Frolova et al., 1994 ; Drugeon et al., 1997). Eukaryote termination efficiency is enhanced by the GTPase release factor eRF3, the second component of the heterodimer eRF complex. In response to a stop codon in the ribosomal A-site, formation of a quaternary complex comprising the ribosome, eRF1, GTP and eRF3 triggers GTP hydrolysis and enhances the rate of peptidyl release (Zhouravleva et al., 1995 ; Frolova et al., 1994 ; Fig. 1). In yeast, eRF1 and eRF3 are encoded by essential genes (SUP35 and SUP45, respectively), mutations in which produce nonsense suppression phenotypes (Stansfield & Tuite, 1994).In contrast to eukaryotes, the role of stop codon recognition during translation termination in eubacteria is divided between two so-called class 1 release factors, RF1 and RF2, which in Escherichia coli are encoded by the essential prfA and prfB genes, respectively (Scolni...

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Multiple upstream AUG codons mediate translational control of GCN4

Cited by 611 publications

References 18 publications

Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae

Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae

Expression of RNA transcripts for the postsynaptic 43 kDa protein in innervated and denervated rat skeletal muscle

Endless possibilities: translation termination and stop codon recognition

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