A single inhibitory upstream open reading frame (uORF) is sufficient to regulate<i>Candida albicans GCN4</i>translation in response to amino acid starvation conditions

Sundaram, Arunkumar; Grant, Chris M.

doi:10.1261/rna.042267.113

Cited by 35 publications

(28 citation statements)

References 25 publications

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“…Assessment of the GCN4 mRNAs in 12 fungal species revealed that uORFs range from three to six in number and are not positionally conserved (25,89). Furthermore, the mechanism of GCN4 translation control for Candida albicans is reliant upon bypass of a single inhibitory uORF whereas GCN4 in S. cerevisiae relies on a mechanism involving delayed translation reinitiation that features multiple uORFs (Fig.…”

Section: Evolutionary Conservation Of Uorf-mediated Translation Mechamentioning

confidence: 99%

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

Young

Wek

2016

Journal of Biological Chemistry

337

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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Section: Evolutionary Conservation Of Uorf-mediated Translation Mechamentioning

confidence: 99%

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

Young

Wek

2016

Journal of Biological Chemistry

337

313

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“…The second REI-permissive uORF, uORF2 with ∼80%-90% of the uORF1 REI activity, occurs only 56-nt downstream from uORF1 and serves as a backup of uORF1 to capture all ribosomes that leaky scanned past the uORF1 AUG (Gunišová and Valášek 2014), especially during stress conditions that seem to increase the frequency of leaky scanning in general (Lee et al 2009;Raveh-Amit et al 2009;Palam et al 2011;Sundaram and Grant 2014). This ensures that the maximum capacity of this intriguing regulatory system is met.…”

Section: Introductionmentioning

confidence: 99%

In-depth analysis of cis-determinants that either promote or inhibit reinitiation on GCN4 mRNA after translation of its four short uORFs

Gunišová

Beznosková

Mohammad

et al. 2016

RNA

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Translational control in eukaryotes is exerted by many means, one of which involves a ribosome translating multiple cistrons per mRNA as in bacteria. It is called reinitiation (REI) and occurs on mRNAs where the main ORF is preceded by a short upstream uORF(s). Some uORFs support efficient REI on downstream cistrons, whereas some others do not. The mRNA of yeast transcriptional activator GCN4 contains four uORFs of both types that together compose an intriguing regulatory mechanism of its expression responding to nutrients' availability and various stresses. Here we subjected all GCN4 uORFs to a comprehensive analysis to identify all REI-promoting and inhibiting cis-determinants that contribute either autonomously or in synergy to the overall efficiency of REI on GCN4. We found that the 3 ′ sequences of uORFs 1-3 contain a conserved AU 1-2 A/ UUAU 2 motif that promotes REI in position-specific, autonomous fashion such as the REI-promoting elements occurring in 5 ′ sequences of uORF1 and uORF2. We also identified autonomous and transferable REI-inhibiting elements in the 3 ′ sequences of uORF2 and uORF3, immediately following their AU-rich motif. Furthermore, we analyzed contributions of coding triplets and terminating stop codon tetranucleotides of GCN4 uORFs showing a negative correlation between the efficiency of reinitiation and efficiency of translation termination. Together we provide a complex overview of all cis-determinants of REI with their effects set in the context of the overall GCN4 translational control.

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“…In S. cerevisiae, cap-independent translation at IRESs in the 5′ UTR of a small subset of genes is required for invasive growth (Gilbert et al, 2007). A recent study has shown that C. albicans GCN4 is translationally regulated by a uORF (Sundaram and Grant, 2014b). The length and structure of the 5′ UTR also affect microRNA-mediated translational repression (Meijer et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

The WOR1 5′ untranslated region regulates white‐opaque switching in Candida albicans by reducing translational efficiency

Guan

Liu

2015

Molecular Microbiology

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SummaryThe human fungal pathogen C andida albicans undergoes white‐opaque phenotypic switching, which enhances its adaptation to host niches. Switching is controlled by a transcriptional regulatory network of interlocking feedback loops acting on the transcription of WOR 1, the master regulator of white‐opaque switching, but regulation of the network on the translational level is not yet explored. Here, we show that the long 5′ untranslated region of WOR 1 regulates the white‐opaque phenotype. Deletion of the WOR 1 5′ UTR promotes white‐to‐opaque switching and stabilizes the opaque state. The WOR 1 5′ UTR reduces translational efficiency and the association of the transcript with polysomes. Reduced polysome association was observed for additional key regulators of cell fate and morphology with long 5′ UTR as well. Overall, we find a novel regulatory step of white‐opaque switching at the translational level. This translational regulation is implicated for many key regulators of cell fate and morphology in C . albicans.

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A single inhibitory upstream open reading frame (uORF) is sufficient to regulateCandida albicans GCN4translation in response to amino acid starvation conditions

Cited by 35 publications

References 25 publications

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

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

In-depth analysis of cis-determinants that either promote or inhibit reinitiation on GCN4 mRNA after translation of its four short uORFs

The WOR1 5′ untranslated region regulates white‐opaque switching in Candida albicans by reducing translational efficiency

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