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Cheng-Yu Hou, Wen-Chi Lee, Hsiao-Chun Chou, Ai-Ping Chen, Shu-Jen Chou, Ho-Ming Chen
High-throughput approaches for profiling the 5' ends of RNA degradation intermediates on a genome-wide scale are frequently applied to analyze and validate cleavage sites guided by microRNAs (miRNAs). However, the complexity of the RNA degradome other than miRNA targets is currently largely uncharacterized, and this limits the application of RNA degradome studies. We conducted a global analysis of 5'-truncated mRNA ends that mapped to coding sequences (CDSs) of Arabidopsis (Arabidopsis thaliana), rice (Oryza sativa) and soybean (Glycine max)...
October 14, 2016: Plant Cell
María de la Luz Guerrero-González, María Azucena Ortega-Amaro, Margarita Juárez-Montiel, Juan Francisco Jiménez-Bremont
In eukaryotic mRNAs, small upstream open reading frames (uORFs) located in the 5'-untranslated region control the translation of the downstream main ORF. Polyamine oxidase (PAO) enzymes catalyze the oxidation of higher polyamines such as spermidine and spermine, and therefore contribute to the maintenance of intracellular polyamine content and to the regulation of physiological processes through their catabolic products. Recently, we reported that the Arabidopsis thaliana Polyamine Oxidase 2 (AtPAO2) is post-transcriptionally regulated by its 5'-UTR region through an uORF...
August 5, 2016: Plant Physiology and Biochemistry: PPB
Heather J Beck, Ian M C Fleming, Gary R Janssen
Analysis of the Escherichia coli transcriptome identified a unique subset of messenger RNAs (mRNAs) that contain a conventional untranslated leader and Shine-Dalgarno (SD) sequence upstream of the gene's start codon while also containing an AUG triplet at the mRNA's 5'- terminus (5'-uAUG). Fusion of the coding sequence specified by the 5'-terminal putative AUG start codon to a lacZ reporter gene, as well as primer extension inhibition assays, reveal that the majority of the 5'-terminal upstream open reading frames (5'-uORFs) tested support some level of lacZ translation, indicating that these mRNAs can function both as leaderless and canonical SD-leadered mRNAs...
2016: PloS One
Xue-Hai Liang, Wen Shen, Hong Sun, Michael T Migawa, Timothy A Vickers, Stanley T Crooke
Increasing the levels of therapeutic proteins in vivo remains challenging. Antisense oligonucleotides (ASOs) are often used to downregulate gene expression or to modify RNA splicing, but antisense technology has not previously been used to directly increase the production of selected proteins. Here we used a class of modified ASOs that bind to mRNA sequences in upstream open reading frames (uORFs) to specifically increase the amounts of protein translated from a downstream primary ORF (pORF). Using ASO treatment, we increased the amount of proteins expressed from four genes by 30-150% in a dose-dependent manner in both human and mouse cells...
August 2016: Nature Biotechnology
Qingqing Cai, Hiroko Fukushima, Mai Yamamoto, Nami Ishii, Tomoaki Sakamoto, Tetsuya Kurata, Hiroyasu Motose, Taku Takahashi
The acaulis5 (acl5) mutant of Arabidopsis thaliana is defective in the biosynthesis of thermospermine and shows a dwarf phenotype associated with excess xylem differentiation. SAC51 was identified from a dominant suppressor of acl5, sac51-d, and encodes a basic helix-loop-helix protein. The sac51-d mutant has a premature termination codon in an upstream open reading frame (uORF) that is conserved among all four members of the SAC51 family, SAC51 and SACL1-SACL3 This suggests that thermospermine cancels the inhibitory effect of the uORF in main ORF translation...
August 2016: Plant & Cell Physiology
Sara K Young, Ronald C Wek
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 α subunit of eIF2 results in a coincident global reduction in translation initiation...
August 12, 2016: Journal of Biological Chemistry
Caitlin Kozel, Brytteny Thompson, Samantha Hustak, Chelsea Moore, Akio Nakashima, Chingakham Ranjit Singh, Megan Reid, Christian Cox, Evangelos Papadopoulos, Rafael E Luna, Abbey Anderson, Hideaki Tagami, Hiroyuki Hiraishi, Emily Archer Slone, Ken-Ichi Yoshino, Masayo Asano, Sarah Gillaspie, Jerome Nietfeld, Jean-Pierre Perchellet, Stefan Rothenburg, Hisao Masai, Gerhard Wagner, Alexander Beeser, Ushio Kikkawa, Sherry D Fleming, Katsura Asano
ATF4 is a pro-oncogenic transcription factor whose translation is activated by eIF2 phosphorylation through delayed re-initiation involving two uORFs in the mRNA leader. However, in yeast, the effect of eIF2 phosphorylation can be mimicked by eIF5 overexpression, which turns eIF5 into translational inhibitor, thereby promoting translation of GCN4, the yeast ATF4 equivalent. Furthermore, regulatory protein termed eIF5-mimic protein (5MP) can bind eIF2 and inhibit general translation. Here, we show that 5MP1 overexpression in human cells leads to strong formation of 5MP1:eIF2 complex, nearly comparable to that of eIF5:eIF2 complex produced by eIF5 overexpression...
June 20, 2016: Nucleic Acids Research
Aquillah Mumo Kanzi, Brenda Diana Wingfield, Emma Theodora Steenkamp, Sanushka Naidoo, Nicolaas Albertus van der Merwe
In this study, the complete mitochondrial (mt) genomes of Chrysoporthe austroafricana (190,834 bp), C. cubensis (89,084 bp) and C. deuterocubensis (124,412 bp) were determined. Additionally, the mitochondrial genome of another member of the Cryphonectriaceae, namely Cryphonectria parasitica (158,902 bp), was retrieved and annotated for comparative purposes. These genomes showed high levels of synteny, especially in regions including genes involved in oxidative phosphorylation and electron transfer, unique open reading frames (uORFs), ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs), as well as intron positions...
2016: PloS One
Guo-Liang Chew, Andrea Pauli, Alexander F Schier
Upstream open reading frames (uORFs) are ubiquitous repressive genetic elements in vertebrate mRNAs. While much is known about the regulation of individual genes by their uORFs, the range of uORF-mediated translational repression in vertebrate genomes is largely unexplored. Moreover, it is unclear whether the repressive effects of uORFs are conserved across species. To address these questions, we analyse transcript sequences and ribosome profiling data from human, mouse and zebrafish. We find that uORFs are depleted near coding sequences (CDSes) and have initiation contexts that diminish their translation...
2016: Nature Communications
Nadine C Hornig, Carine de Beaufort, Friederike Denzer, Martine Cools, Martin Wabitsch, Martin Ukat, Alexandra E Kulle, Hans-Udo Schweikert, Ralf Werner, Olaf Hiort, Laura Audi, Reiner Siebert, Ole Ammerpohl, Paul-Martin Holterhus
A subset of patients with monogenic disorders lacks disease causing mutations in the protein coding region of the corresponding gene. Here we describe a recurrent germline mutation found in two unrelated patients with complete androgen insensitivity syndrome (CAIS) generating an upstream open reading frame (uORF) in the 5' untranslated region (5'-UTR) of the androgen receptor (AR) gene. We show in patient derived primary genital skin fibroblasts as well as in cell-based reporter assays that this mutation severely impacts AR function by reducing AR protein levels without affecting AR mRNA levels...
2016: PloS One
Nya D Nelson, Andrea Marcogliese, Katie Bergstrom, Michael Scheurer, Donald Mahoney, Alison A Bertuch
JAK2, MPL, and CALR mutations, which underlie essential thrombocythemia (ET) in most adults, are infrequent in children. Consequently, additional tests are needed to confirm pediatric ET diagnoses. We report a child with suspected ET and normal JAK2, MPL, and CALR analyses. Serum thrombopoietin (TPO) was markedly elevated, leading to analysis of the TPO gene, TPHO, which contains an upstream open reading frame (uORF) known to repress THPO translation. Sequencing revealed a de novo, germline stopgain mutation in the uORF, explaining the elevated TPO and thrombocytosis...
August 2016: Pediatric Blood & Cancer
Sara K Young, Thomas D Baird, Ronald C Wek
In the integrated stress response, phosphorylation of eIF2α (eIF2α-P) reduces protein synthesis while concomitantly promoting preferential translation of specific transcripts associated with stress adaptation. Translation of the glutamyl-prolyl-tRNA synthetase gene EPRS is enhanced in response to eIF2α-P. To identify the underlying mechanism of translation control, we employed biochemical approaches to determine the regulatory features by which upstream ORFs (uORFs) direct downstream translation control and expression of the EPRS coding region...
May 13, 2016: Journal of Biological Chemistry
Jiří Černý, Martin Selinger, Martin Palus, Zuzana Vavrušková, Hana Tykalová, Lesley Bell-Sakyi, Ján Štěrba, Libor Grubhoffer, Daniel Růžek
A short upstream open reading frame (uORF) was recently identified in the 5' untranslated region of some tick-borne encephalitis virus (TBEV) strains. However, it is not known if the peptide encoded by TBEV uORF (TuORF) is expressed in infected cells. Here we show that TuORF forms three phylogenetically separated clades which are typical of European, Siberian, and Far-Eastern TBEV subtypes. Analysis of selection pressure acting on the TuORF area showed that it is under positive selection pressure. Theoretically, TuORF may code for a short hydrophobic peptide embedded in a biological membrane...
June 2016: Virus Genes
Timothy G Johnstone, Ariel A Bazzini, Antonio J Giraldez
Regulation of gene expression is fundamental in establishing cellular diversity and a target of natural selection. Untranslated mRNA regions (UTRs) are key mediators of post-transcriptional regulation. Previous studies have predicted thousands of ORFs in 5'UTRs, the vast majority of which have unknown function. Here, we present a systematic analysis of the translation and function of upstream open reading frames (uORFs) across vertebrates. Using high-resolution ribosome footprinting, we find that (i)uORFs are prevalent within vertebrate transcriptomes, (ii) the majority show signatures of active translation, and (iii)uORFs act as potent regulators of translation and RNA levels, with a similar magnitude to miRNAs...
April 1, 2016: EMBO Journal
Qiwen Hu, Catharina Merchante, Anna N Stepanova, Jose M Alonso, Steffen Heber
Upstream open reading frames (uORFs) are open reading frames that occur within the 5' UTR of an mRNA. uORFs have been found in many organisms. They play an important role in gene regulation, cell development, and in various metabolic processes. It is believed that translated uORFs reduce the translational efficiency of the main coding region. However, only few uORFs are experimentally characterized. In this paper, we use ribosome footprinting together with a semi-supervised approach based on stacking classification models to identify translated uORFs in Arabidopsis thaliana...
March 2016: IEEE Transactions on Nanobioscience
Erin E Heyer, Melissa J Moore
Fully assembled ribosomes exist in two populations: polysomes and monosomes. While the former has been studied extensively, to what extent translation occurs on monosomes and its importance for overall translational output remain controversial. Here, we used ribosome profiling to examine the translational status of 80S monosomes in Saccharomyces cerevisiae. We found that the vast majority of 80S monosomes are elongating, not initiating. Further, most mRNAs exhibit some degree of monosome occupancy, with monosomes predominating on nonsense-mediated decay (NMD) targets, upstream open reading frames (uORFs), canonical ORFs shorter than ∼ 590 nt, and ORFs for which the total time required to complete elongation is substantially shorter than that required for initiation...
February 11, 2016: Cell
Shelley R Starck, Jordan C Tsai, Keling Chen, Michael Shodiya, Lei Wang, Kinnosuke Yahiro, Manuela Martins-Green, Nilabh Shastri, Peter Walter
Translated regions distinct from annotated coding sequences have emerged as essential elements of the proteome. This includes upstream open reading frames (uORFs) present in mRNAs controlled by the integrated stress response (ISR) that show "privileged" translation despite inhibited eukaryotic initiation factor 2-guanosine triphosphate-initiator methionyl transfer RNA (eIF2·GTP·Met-tRNA(i )(Met)). We developed tracing translation by T cells to directly measure the translation products of uORFs during the ISR...
January 29, 2016: Science
Stanislava Gunišová, Petra Beznosková, Mahabub Pasha Mohammad, Vladislava Vlčková, Leoš Shivaya Valášek
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...
April 2016: RNA
Sara K Young, Lakshmi Reddy Palam, Cheng Wu, Matthew S Sachs, Ronald C Wek
Upon exposure to environmental stress, phosphorylation of the α subunit of eIF2 (eIF2α-P) represses global protein synthesis, coincident with preferential translation of gene transcripts that mitigate stress damage or alternatively trigger apoptosis. Because there are multiple mammalian eIF2 kinases, each responding to different stress arrangements, this translational control scheme is referred to as the integrated stress response (ISR). Included among the preferentially translated mRNAs induced by eIF2α-P is that encoding the transcription factor CHOP (DDIT3/GADD153)...
March 18, 2016: Journal of Biological Chemistry
Alexandra Popa, Kevin Lebrigand, Pascal Barbry, Rainer Waldmann
BACKGROUND: Open reading frames are common in long noncoding RNAs (lncRNAs) and 5'UTRs of protein coding transcripts (uORFs). The question of whether those ORFs are translated was recently addressed by several groups using ribosome profiling. Most of those studies concluded that certain lncRNAs and uORFs are translated, essentially based on computational analysis of ribosome footprints. However, major discrepancies remain on the scope of translation and the translational status of individual ORFs...
2016: BMC Genomics
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