Translational Regulation by Upstream Open Reading Frames and Human Diseases

Silva, Joana; Fernandes, Rafael; Romão, Luı́sa

doi:10.1007/978-3-030-19966-1_5

Cited by 39 publications

(32 citation statements)

References 104 publications

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“…The earliest known evidence for uORF involvement in translational control was shown for Saccharomyces cerevisiae General Control Non-depressible 4 (ScGCN4), a transcription factor that controls amino acid biosynthesis under conditions of starvation (reviewed in Hinnebusch, 1988 ). After these early reports, translation regulation by uORFs during stress conditions was shown in numerous organisms including Homo sapiens , Mus musculus , Drosophila melanogaster , Neurospora crassa , Danio rerio , Arabidopsis thaliana , Zea mays and higher plants (Iacono et al ., 2005 ; Barbosa et al ., 2013 ; Chew et al ., 2013 ; von Arnim et al ., 2014 ; Lei et al ., 2015 ; Young and Wek, 2016 ; Zhang et al ., 2018 , 2019 ; Chen and Tarn, 2019 ; Silva et al ., 2019 ; Wu et al ., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…Other indirect indicators that point towards uORF-mediated gene regulation are the proteins/factors that the translation machinery uses to overcome the challenge posed by the uORF. To cope with uORF-mediated translation repression, and allow protein synthesis to occur from the CDS, a cell adopts unconventional mechanisms of translation: reinitiation, leaky scanning, ribosome shunting, and the use of internal ribosome entry sites (IRES) (reviewed in Morris and Geballe, 2000 ; Skabkin et al ., 2013 ; Silva et al ., 2019 ). In brief, reinitiation is a phenomenon where the ribosome, rather than dissociating after termination at the stop codon of a uORF, successfully re-initiates translation at the start codon of the main CDS.…”

Section: Introductionmentioning

confidence: 99%

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The role of upstream open reading frames in translation regulation in the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii

Kaur

Patankar

2021

Parasitology

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The role of upstream open reading frames in translation regulation in the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii

Kaur

Patankar

2021

Parasitology

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“…The role of uORFs in the stress response in yeast and mammals is well studied (Hinnebusch, 2005;Silva et al, 2019;Houston et al, 2020). However, this area of research requires more focus in P. falciparum, more so because of the widespread occurrence of uORFs.…”

Section: Upstream Orfs In Stress Conditionsmentioning

confidence: 99%

Upstream Open Reading Frames (uORFs) in the Apicomplexan Parasites <em>Plasmodium falciparum</em> and <em>Toxoplasma gondii</em>: Small yet Powerful Regulators of Translation

Kaur¹,

Patankar²

2021

Preprint

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During their complex life cycles, the Apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii employ several genetic switches to regulate their gene expression. One such switch is mediated at the level of translation through upstream Open Reading Frames (uORFs). As uORFs are found in the upstream regions of a majority of genes in both the parasites, it is essential that their roles in translational regulation be appreciated to a greater extent. This review provides a comprehensive summary of studies that show uORF-mediated gene regulation in these parasites and highlights examples of clinically and physiologically relevant proteins that exhibit uORF-mediated regulation. In addition to these examples, several studies that use bioinformatics, transcriptomics, proteomics, and ribosome profiling also indicate the possibility of widespread translational regulation by uORFs. Further analysis of genome-wide datasets will reveal novel genes involved in key biological pathways such as cell-cycle progression, stress-response, and pathogenicity. The cumulative evidence from studies presented in this review suggests that uORFs will play crucial roles in regulating gene expression during clinical disease caused by these important human pathogens.

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“…Accumulating evidence suggests a (patho-)physiological important role of uORFmediated translational control in health and disease [2,[18][19][20][21]. Upstream ORFs have been implicated in directing protein expression during cellular integrated stress responses, as translational regulation allows for immediate response to changing environmental conditions, bypassing the need for time consuming transcription of new mRNA [5,[22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer

et al. 2021

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Upstream open reading frame (uORF)-mediated translational control has emerged as an important regulatory mechanism in human health and disease. However, a systematic search for cancer-associated somatic uORF mutations has not been performed. Here, we analyzed the genetic variability at canonical (uAUG) and alternative translational initiation sites (aTISs), as well as the associated upstream termination codons (uStops) in 3394 whole-exome-sequencing datasets from patient samples of breast, colon, lung, prostate, and skin cancer and of acute myeloid leukemia, provided by The Cancer Genome Atlas research network. We found that 66.5% of patient samples were affected by at least one of 5277 recurrent uORF-associated somatic single nucleotide variants altering 446 uAUG, 347 uStop, and 4733 aTIS codons. While twelve uORF variants were detected in all entities, 17 variants occurred in all five types of solid cancer analyzed here. Highest frequencies of individual somatic variants in the TLSs of NBPF20 and CHCHD2 reached 10.1% among LAML and 8.1% among skin cancer patients, respectively. Functional evaluation by dual luciferase reporter assays identified 19 uORF variants causing significant translational deregulation of the associated main coding sequence, ranging from 1.73-fold induction for an AUG.1 > UUG variant in SETD4 to 0.006-fold repression for a CUG.6 > GUG variant in HLA-DRB1. These data suggest that somatic uORF mutations are highly prevalent in human malignancies and that defective translational regulation of protein expression may contribute to the onset or progression of cancer.

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Translational Regulation by Upstream Open Reading Frames and Human Diseases

Cited by 39 publications

References 104 publications

The role of upstream open reading frames in translation regulation in the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii

The role of upstream open reading frames in translation regulation in the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii

Upstream Open Reading Frames (uORFs) in the Apicomplexan Parasites <em>Plasmodium falciparum</em> and <em>Toxoplasma gondii</em>: Small yet Powerful Regulators of Translation

Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer

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