Suppression of ribosomal reinitiation at upstream open reading frames in amino acid-starved cells forms the basis for GCN4 translational control.

Abastado, Jean-Pierre; Miller, Paul; Jackson, Belinda M.; Hinnebusch, Alan G.

doi:10.1128/mcb.11.1.486

Cited by 231 publications

(235 citation statements)

References 47 publications

(72 reference statements)

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“…The presence of upstream start codons has been observed in many cellular mRNAs for transcription factor genes from yeast (GCN4), animals (jun) and plants (OPAQUE2, SN, LC, CPRF-1, MYBST1, OBF1, LIP19, MLIP15, Arabidopsis TGA1), and in some cases it has been shown that such a feature can inhibit translation of downstream coding sequences. In the case of GCN4, amino acid availability regulates GCN4 expression at the level of translational initiation (Abastado et al, 1991). Thus, the upstream ORFs (uORFs) of GCN4 constitute a translational control element that allows ribosomes to reach the start codon of the major ORF only when cells are deprived of an amino acid.…”

Section: The 5ј Leader Sequences Of the Bzip Transcriptsmentioning

confidence: 99%

Two bZIP proteins from Antirrhinum flowers preferentially bind a hybrid C‐box/G‐box motif and help to define a new sub‐family of bZIP transcription factors

et al. 1998

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SummaryTwo genes encoding bZIP proteins are expressed in flowers of Antirrhinum majus, predominantly in vascular tissues, carpels and anthers. The sequences of cDNA clones encoding these proteins show them to belong to a distinct subfamily of bZIP proteins which also includes LIP19 from rice and MLIPI5 and OBF1 from maize. The sub-family is characterized by the inclusion of very small proteins consisting of essentially a basic domain and a long leucine zipper. Members also have a conserved upstream open reading frame (uORF) in their 5Ј leader sequences, implying a common mode of post-transcriptional control. In vitro, the Antirrhinum bZIP proteins preferentially bind to a novel hybrid C-box/G-box motif which is found in the promoters of some plant histone genes and of some nuclear-encoded genes with plastidial protein products. Expression of the bZIP proteins in transgenic tobacco under control of the CaMV 35S promoter supports the view that they can regulate expression of genes which contain the preferred target motif within their regulatory sequences, although both enhancement and repression of transcript levels of target genes were observed, indicating that the bZIP proteins probably interact with other factors to modulate transcription in different ways, as has been observed for the small MAF family of bZIP proteins in vertebrates.

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Section: The 5ј Leader Sequences Of the Bzip Transcriptsmentioning

confidence: 99%

Two bZIP proteins from Antirrhinum flowers preferentially bind a hybrid C‐box/G‐box motif and help to define a new sub‐family of bZIP transcription factors

et al. 1998

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“…uORF stop codon and CDS initiation codon allows more time for the scanning 40S to reacquire a new eIF2⅐GTP⅐Met-tRNA i Met complex, a significant feature of the delayed translation reinitiation model that was originally identified in the yeast Saccharomyces cerevisiae for the transcriptional activator GCN4 (19,21,43) and subsequently suggested for the related mammalian ATF4 (24,33,34).…”

Section: Ribosome Reinitiation In the Isrmentioning

confidence: 99%

“…3A) (24,34). The GCN4 5Ј-leader contains four uORFs, each encoding polypeptides two to three residues in length (19,21). In the delayed translation reinitiation model, the 5Ј-proximal uORF1 in the ATF4 and GCN4 5Ј-leaders acts as a positive element that promotes downstream translation reinitiation (19,20,24).…”

Section: Delayed Translation Reinitiationmentioning

confidence: 99%

Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response

Young

Wek

2016

Journal of Biological Chemistry

331

313

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Translation regulation largely occurs during initiation, which features ribosome assembly onto mRNAs and selection of the translation start site. Short, upstream ORFs (uORFs) located in the 5-leader of the mRNA can be selected for translation. Multiple transcripts associated with stress amelioration are preferentially translated through uORF-mediated mechanisms during activation of the integrated stress response (ISR) in which phosphorylation of the ␣ subunit of eIF2 results in a coincident global reduction in translation initiation. This review presents key features of uORFs that serve to optimize translational control that is essential for regulation of cell fate in response to environmental stresses.Multiple genome-wide analyses, including those utilizing ribosome and polysome profiling and mass spectrometry approaches, have provided evidence demonstrating that translation is a major regulator of gene expression (1-5). In addition to protein coding sequences (CDSs), 2 another class of ORFs suggested to be translated at high frequency consists of short, upstream ORFs (uORFs) that are located within the 5Ј-leader of mRNAs (3-6). Over 40% of mammalian mRNAs contain uORFs, illustrating that uORFs are prevalent genome-wide and can serve as major regulators of translation (5,7,8). Approximation of uORF prevalence has relied upon the use of an AUG to denote the uORF start codon; however, recent ribosome profiling studies indicate that non-canonical initiation codons (e.g. CUG, UUG, and GUG) can also serve as competent sites of translation initiation (3, 4, 6). These findings suggest that the magnitude of uORF prevalence and the contribution of uORF translation in the regulation of gene expression have likely been underestimated.Typically, uORFs are considered to be inhibitors of downstream translation initiation at CDSs. The inhibitory effect of uORFs is attributed to the fact that in eukaryotes the 43S preinitiation complex binds to the 5Ј-cap structure of the mRNA, then scans processively 5Ј to 3Ј and initiates translation at the first encountered initiation codon that is in an optimal context (9). The 43S preinitiation complex is composed of multiple factors including eIF3, eIF1, eIF1A, the eIF2⅐GTP⅐Met-tRNA i Met ternary complex, and the small 40S ribosomal subunit (10). Disassociation of the eIF2 ternary complex and other critical initiation factors during translation of constitutively repressing uORFs is suggested to be the cause of the low levels of subsequent translation reinitiation at downstream coding sequences.Although uORFs can serve as repressors of CDS translation in a constitutive manner, there are also examples of uORFs that serve as dampeners in a controlled fashion or even promote translation initiation at the CDS in response to environmental stresses (4, 5, 11). Based on these studies, uORFs can have the following core properties that are critical for translational control (Fig. 1). 1) They enhance reinitiation after uORF translation, allowing for degrees of translation initiation at the downstre...

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“…Of importance to this discussion of regulation of (post-) termination events are the findings that ribosomes can resume scanning after terminating translation at uORF1, and that they can subsequently acquire competence to reinitiate at downstream AUG codons (Hinnebusch, 1997). In contrast, ribosomes terminating translation at the uORF4 termination codon are released from the mRNA (Abastado et al, 1991 ;Dever et al, 1992). This key difference between the behaviour of post-termination ribosomes at uORFs 1 and 4 results from the character of the nucleotide context immediately preceding (3 nt) and following (10 nt) the respective uORF stop codons (Grant & Hinnebusch, 1994).…”

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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Suppression of ribosomal reinitiation at upstream open reading frames in amino acid-starved cells forms the basis for GCN4 translational control.

Cited by 231 publications

References 47 publications

Two bZIP proteins from Antirrhinum flowers preferentially bind a hybrid C‐box/G‐box motif and help to define a new sub‐family of bZIP transcription factors

Two bZIP proteins from Antirrhinum flowers preferentially bind a hybrid C‐box/G‐box motif and help to define a new sub‐family of bZIP transcription factors

Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response

Endless possibilities: translation termination and stop codon recognition

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