scholarly journals Conserved Peptide Upstream Open Reading Frames Act Via Ribosome Stalling to Regulate Translation in Response to Environmental Signals.

2021 ◽  
Author(s):  
Barry Causier ◽  
Tayah Hopes ◽  
Mary McKay ◽  
Zachary Paling ◽  
Brendan Davies
Keyword(s):  
Growth And Development ◽  
Open Reading Frames ◽  
Peptide Sequence ◽  
Dependent Manner ◽  
Environmental Signals ◽  
Ribosome Stalling ◽  
Mrna Transcripts ◽  
Upstream Open Reading Frames ◽  
Fine Tune ◽  
Reading Frames

The regulation of protein synthesis plays a key role in growth and development in all organisms. Upstream open reading frames (uORFs) are commonly found in eukaryotic mRNA transcripts and typically inhibit translation of downstream ORFs, in part by stalling ribosomes. Conserved peptide uORFs (CPuORFs) are a rare subset of uORFs, some of which conditionally regulate translation. Here we identify three Arabidopsis CPuORFs that specifically regulate translation of any downstream ORF, in response to the agriculturally significant environmental signals, heat shock and water limitation. Mechanistically, we provide evidence that CPuORF translation causes ribosome stalling, in a peptide sequence-dependent manner, attenuating translation of downstream ORFs. We propose a model in which plant CPuORFs are not simply on/off switches for translation, but rather act conditionally, along a continuum, to fine-tune translation dynamically.

scholarly journals Plants Utilise Ancient Conserved Peptide Upstream Open Reading Frames as Environmental Sensors

2021 ◽  
Author(s):  
Barry Causier ◽  
Tayah Hopes ◽  
Mary McKay ◽  
Zachary Paling ◽  
Brendan Davies
Keyword(s):  
Protein Synthesis ◽  
Growth And Development ◽  
Open Reading Frames ◽  
Environmental Sensors ◽  
Environmental Signals ◽  
Broad Application ◽  
Ribosome Stalling ◽  
Mrna Transcripts ◽  
Upstream Open Reading Frames ◽  
Reading Frames

The regulation of protein synthesis plays an important role in growth and development in all organisms. Upstream open reading frames (uORFs) are commonly found in eukaryotic mRNA transcripts and typically attenuate the translation of associated downstream main ORFs (mORFs). Conserved peptide uORFs (CPuORFs) are a rare subset of uORFs, some of which have been shown to conditionally regulate translation by ribosome stalling. Here we identify three Arabidopsis CPuORFs of ancient origin that regulate translation of any downstream ORF, in response to agriculturally significant environmental signals: heat stress and water limitation. We provide evidence that different sequence classes of CPuORF stall ribosomes during different phases of translation and show that plant CPuORFs act as environmental sensors that can be utilised as inducible regulators of translation with broad application.

scholarly journals DENR promotes translation reinitiation via ribosome recycling to drive expression of oncogenes including ATF4

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jonathan Bohlen ◽  
Liza Harbrecht ◽  
Saioa Blanco ◽  
Katharina Clemm von Hohenberg ◽  
Kai Fenzl ◽  
...  
Keyword(s):  
Stress Response ◽  
Cancer Cells ◽  
Strong Correlation ◽  
Molecular Mechanisms ◽  
Open Reading Frames ◽  
Translation Efficiency ◽  
Dependent Manner ◽  
Translation Factors ◽  
Upstream Open Reading Frames ◽  
Reading Frames

Abstract Translation efficiency varies considerably between different mRNAs, thereby impacting protein expression. Translation of the stress response master-regulator ATF4 increases upon stress, but the molecular mechanisms are not well understood. We discover here that translation factors DENR, MCTS1 and eIF2D are required to induce ATF4 translation upon stress by promoting translation reinitiation in the ATF4 5′UTR. We find DENR and MCTS1 are only needed for reinitiation after upstream Open Reading Frames (uORFs) containing certain penultimate codons, perhaps because DENR•MCTS1 are needed to evict only certain tRNAs from post-termination 40S ribosomes. This provides a model for how DENR and MCTS1 promote translation reinitiation. Cancer cells, which are exposed to many stresses, require ATF4 for survival and proliferation. We find a strong correlation between DENR•MCTS1 expression and ATF4 activity across cancers. Furthermore, additional oncogenes including a-Raf, c-Raf and Cdk4 have long uORFs and are translated in a DENR•MCTS1 dependent manner.

scholarly journals Exhaustive identification of conserved upstream open reading frames with potential translational regulatory functions from animal genomes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hiro Takahashi ◽  
Shido Miyaki ◽  
Hitoshi Onouchi ◽  
Taichiro Motomura ◽  
Nobuo Idesako ◽  
...  
Keyword(s):  
Regulatory Peptides ◽  
Open Reading Frames ◽  
Dependent Manner ◽  
Wide Range ◽  
Eukaryotic Mrnas ◽  
Taxonomic Range ◽  
Upstream Open Reading Frames ◽  
Functional Peptides ◽  
Reading Frames ◽  
Animal Genomes

Abstract Upstream open reading frames (uORFs) are present in the 5′-untranslated regions of many eukaryotic mRNAs, and some peptides encoded by these regions play important regulatory roles in controlling main ORF (mORF) translation. We previously developed a novel pipeline, ESUCA, to comprehensively identify plant uORFs encoding functional peptides, based on genome-wide identification of uORFs with conserved peptide sequences (CPuORFs). Here, we applied ESUCA to diverse animal genomes, because animal CPuORFs have been identified only by comparing uORF sequences between a limited number of species, and how many previously identified CPuORFs encode regulatory peptides is unclear. By using ESUCA, 1517 (1373 novel and 144 known) CPuORFs were extracted from four evolutionarily divergent animal genomes. We examined the effects of 17 human CPuORFs on mORF translation using transient expression assays. Through these analyses, we identified seven novel regulatory CPuORFs that repressed mORF translation in a sequence-dependent manner, including one conserved only among Eutheria. We discovered a much higher number of animal CPuORFs than previously identified. Since most human CPuORFs identified in this study are conserved across a wide range of Eutheria or a wider taxonomic range, many CPuORFs encoding regulatory peptides are expected to be found in the identified CPuORFs.

scholarly journals Exhaustive identification of conserved upstream open reading frames with potential translational regulatory functions from animal genomes

2019 ◽  
Author(s):  
Hiro Takahashi ◽  
Shido Miyaki ◽  
Hitoshi Onouchi ◽  
Taichiro Motomura ◽  
Nobuo Idesako ◽  
...  
Keyword(s):  
Regulatory Peptides ◽  
Open Reading Frames ◽  
Dependent Manner ◽  
Wide Range ◽  
Eukaryotic Mrnas ◽  
Taxonomic Range ◽  
Upstream Open Reading Frames ◽  
Functional Peptides ◽  
Reading Frames ◽  
Animal Genomes

AbstractUpstream open reading frames (uORFs) are present in the 5’-untranslated regions of many eukaryotic mRNAs, and some peptides encoded by these regions play important regulatory roles in controlling main ORF (mORF) translation. We previously developed a novel pipeline, ESUCA, to comprehensively identify plant uORFs encoding functional peptides, based on genome-wide identification of uORFs with conserved peptide sequences (CPuORFs). Here, we applied ESUCA to diverse animal genomes, because animal CPuORFs have been identified only by comparing uORF sequences between a limited number of species, and how many previously identified CPuORFs encode regulatory peptides is unclear. By using ESUCA, 1,517 (1,373 novel and 144 known) CPuORFs were extracted from four evolutionarily divergent animal genomes. We examined the effects of 17 human CPuORFs on mORF translation using transient expression assays. Through these analyses, we identified seven novel regulatory CPuORFs that repressed mORF translation in a sequence-dependent manner, including one conserved only among Eutheria. We discovered a much higher number of animal CPuORFs than previously identified. Since most human CPuORFs identified in this study are conserved across a wide range of Eutheria or a wider taxonomic range, many CPuORFs encoding regulatory peptides are expected to be found in the identified CPuORFs.

scholarly journals uORF Shuffling Fine-Tunes Gene Expression at a Deep Level of the Process

Plants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 608
Author(s):  
Yukio Kurihara
Keyword(s):  
Gene Expression ◽  
Deep Level ◽  
Ribosome Profiling ◽  
Open Reading Frames ◽  
Protein Coding ◽  
Polycistronic Mrna ◽  
Upstream Open Reading Frames ◽  
Fine Tune ◽  
Insight Into ◽  
Reading Frames

Upstream open reading frames (uORFs) are present in the 5’ leader sequences (or 5’ untranslated regions) upstream of the protein-coding main ORFs (mORFs) in eukaryotic polycistronic mRNA. It is well known that a uORF negatively affects translation of the mORF. Emerging ribosome profiling approaches have revealed that uORFs themselves, as well as downstream mORFs, can be translated. However, it has also been revealed that plants can fine-tune gene expression by modulating uORF-mediated regulation in some situations. This article reviews several proposed mechanisms that enable genes to escape from uORF-mediated negative regulation and gives insight into the application of uORF-mediated regulation for precisely controlling gene expression.

scholarly journals Translational buffering by ribosome stalling in upstream open reading frames

2022 ◽  
Author(s):  
Ty A Bottorff ◽  
Adam P Geballe ◽  
Arvind Rasi Subramaniam
Keyword(s):  
Protein Expression ◽  
Kinetic Modeling ◽  
Human Cells ◽  
Open Reading Frames ◽  
General Mechanism ◽  
Developmental Transitions ◽  
Alternative Models ◽  
Ribosome Stalling ◽  
Upstream Open Reading Frames ◽  
Reading Frames

Upstream open reading frames (uORFs) are present in over half of all human mRNAs. uORFs can potently regulate the translation of downstream open reading frames by several mechanisms: siphoning away scanning ribosomes, regulating re-initiation, and allowing interactions between scanning and elongating ribosomes. However, the consequences of these different mechanisms for the regulation of protein expression remain incompletely understood. Here, we performed systematic measurements on the uORF-containing 5′ UTR of the cytomegaloviral UL4 mRNA to test alternative models of uORF-mediated regulation in human cells. We find that a terminal diproline-dependent elongating ribosome stall in the UL4 uORF prevents decreases in main ORF translation when ribosome loading onto the mRNA is reduced. This uORF-mediated buffering is insensitive to the location of the ribosome stall along the uORF. Computational kinetic modeling based on our measurements suggests that scanning ribosomes dissociate rather than queue when they collide with stalled elongating ribosomes within the UL4 uORF. We identify several human uORFs that repress main ORF translation via a similar terminal diproline motif. We propose that ribosome stalls in uORFs provide a general mechanism for buffering against reductions in main ORF translation during stress and developmental transitions.

scholarly journals A First Step towards Learning which uORFs Regulate Gene Expression

2006 ◽  
Vol 3 (2) ◽  
pp. 109-122 ◽  
Author(s):  
◽  
Christopher H. Bryant ◽  
Graham J.L. Kemp ◽  
Marija Cvijovic
Keyword(s):  
Gene Expression ◽  
Inductive Logic ◽  
Preliminary Evidence ◽  
Open Reading Frames ◽  
Yeast Saccharomyces Cerevisiae ◽  
Regulate Gene Expression ◽  
Integrative System ◽  
Upstream Open Reading Frames ◽  
Reading Frames ◽  
Regulate Gene

Summary We have taken a first step towards learning which upstream Open Reading Frames (uORFs) regulate gene expression (i.e., which uORFs are functional) in the yeast Saccharomyces cerevisiae. We do this by integrating data from several resources and combining a bioinformatics tool, ORF Finder, with a machine learning technique, inductive logic programming (ILP). Here, we report the challenge of using ILP as part of this integrative system, in order to automatically generate a model that identifies functional uORFs. Our method makes searching for novel functional uORFs more efficient than random sampling. An attempt has been made to predict novel functional uORFs using our method. Some preliminary evidence that our model may be biologically meaningful is presented.

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