scholarly journals Quantitative Principles ofcis-translational control by general mRNA sequence features in eukaryotes

2019 ◽  
Author(s):  
Jingyi Jessica Li ◽  
Guo-Liang Chew ◽  
Mark D. Biggin
Keyword(s):  
Translational Control ◽  
Rna Structure ◽  
Open Reading Frames ◽  
Sequence Length ◽  
Strongly Correlated ◽  
Protein Coding ◽  
Biochemical Processes ◽  
Sequence Features ◽  
Upstream Open Reading Frames ◽  
Control Translation

ABSTRACTBACKGROUNDGeneral translationalcis-elements are present in the mRNAs of all genes and affect the recruitment, assembly, and progress of preinitiation complexes and the ribosome under many physiological states. These elements are: mRNA folding, upstream open reading frames, specific nucleotides flanking the initiating AUG codon, protein coding sequence length, and codon usage. The quantitative contributions of these sequence features and how and why they coordinate together to control translation rates are not well understood.RESULTSHere we show that these sequence features specify 42%–81% of the variance in translation rates inS.cerevisiae, S.pombe, Arabidopsis thaliana, M.musculus, andH.Sapiens. We establish that control by RNA secondary structure is chiefly mediated by highly folded 25–60 nucleotide segments within mRNA 5’ regions; that changes in tri-nucleotide frequencies between highly and poorly translated 5’ regions are correlated between all species; and that control by distinct biochemical processes is extensively correlated as is regulation by a single process acting in different parts of the same mRNA.CONCLUSIONSOur work shows that the general features control a much larger fraction of the variance in translation rates than previously realized. We provide a more detailed and accurate understanding of the aspects of RNA structure that direct translation in diverse eukaryotes. In addition, we note that the strongly correlated regulation between and withincis-control features will cause more even densities of translational complexes along each mRNA and therefore more efficient use of the translation machinery by the cell.

scholarly journals Improved ribosome-footprint and mRNA measurements provide insights into dynamics and regulation of yeast translation

2015 ◽  
Author(s):  
David E Weinberg ◽  
Premal Shah ◽  
Stephen W Eichhorn ◽  
Jeffrey A Hussmann ◽  
Joshua B Plotkin ◽  
...  
Keyword(s):  
Translational Control ◽  
Nucleotide Composition ◽  
Ribosome Profiling ◽  
Open Reading Frames ◽  
Untranslated Regions ◽  
Coding Regions ◽  
Genome Wide ◽  
Upstream Open Reading Frames ◽  
Improved Methods ◽  
Reading Frames

Ribosome-footprint profiling provides genome-wide snapshots of translation, but technical challenges can confound its analysis. Here, we use improved methods to obtain ribosome-footprint profiles and mRNA abundances that more faithfully reflect gene expression in Saccharomyces cerevisiae. Our results support proposals that both the beginning of coding regions and codons matching rare tRNAs are more slowly translated. They also indicate that emergent polypeptides with as few as three basic residues within a 10-residue window tend to slow translation. With the improved mRNA measurements, the variation attributable to translational control in exponentially growing yeast was less than previously reported, and most of this variation could be predicted with a simple model that considered mRNA abundance, upstream open reading frames, cap-proximal structure and nucleotide composition, and lengths of the coding and 5′- untranslated regions. Collectively, our results reveal key features of translational control in yeast and provide a framework for executing and interpreting ribosome- profiling studies.

The first and fourth upstream open reading frames in GCN4 mRNA have similar initiation efficiencies but respond differently in translational control to change in length and sequence

1988 ◽  
Vol 8 (12) ◽  
pp. 5439-5447
Author(s):  
P P Mueller ◽  
B M Jackson ◽  
P F Miller ◽  
A G Hinnebusch
Keyword(s):  
Translational Control ◽  
Normal Growth ◽  
Open Reading Frames ◽  
Regulatory Function ◽  
Coding Sequences ◽  
Lacz Fusions ◽  
Upstream Open Reading Frames ◽  
Reading Frames ◽  
Starvation Conditions

The third and fourth AUG codons in GCN4 mRNA efficiently repress translation of the GCN4-coding sequences under normal growth conditions. The first AUG codon is approximately 30-fold less inhibitory and is required under amino acid starvation conditions to override the repressing effects of AUG codons 3 and 4. lacZ fusions constructed to functional, elongated versions of the first and fourth upstream open reading frames (URFs) were used to show that AUG codons 1 and 4 function similarly as efficient translational start sites in vivo, raising the possibility that steps following initiation distinguish the regulatory properties of URFs 1 and 4. In accord with this idea, we observed different consequences of changing the length and termination site of URF1 versus changing those of URFs 3 and 4. The latter were lengthened considerably, with little or no effect on regulation. In fact, the function of URFs 3 and 4 was partially reconstituted with a completely heterologous URF. By contrast, certain mutations that lengthen URF1 impaired its positive regulatory function nearly as much as removing its AUG codon did. The same mutations also made URF1 a much more inhibitory element when it was present alone in the mRNA leader. These results strongly suggest that URFs 1 and 4 both function in regulation as translated coding sequences. To account for the phenotypes of the URF1 mutations, we suggest the most ribosomes normally translate URF1 and that the mutations reduce the number of ribosomes that are able to complete URF1 translation and resume scanning downstream. This effect would impair URF1 positive regulatory function if ribosomes must first translate URF1 in order to overcome the strong translational block at the 3'-proximal URFs. Because URF1-lacZ fusions were translated at the same rate under repressing and derepressing conditions, it appears that modulating initiation at URF1 is not the means that is used to restrict the regulatory consequences of URF1 translation to starvation conditions.

Genome editing of upstream open reading frames enables translational control in plants

2018 ◽  
Vol 36 (9) ◽  
pp. 894-898 ◽  
Author(s):  
Huawei Zhang ◽  
Xiaomin Si ◽  
Xiang Ji ◽  
Rong Fan ◽  
Jinxing Liu ◽  
...  
Keyword(s):  
Genome Editing ◽  
Translational Control ◽  
Open Reading Frames ◽  
Upstream Open Reading Frames ◽  
Reading Frames

scholarly journals Role of two upstream open reading frames in the translational control of oncogene mdm2

Oncogene ◽  
1999 ◽  
Vol 18 (41) ◽  
pp. 5631-5637 ◽  
Author(s):  
Cheryl Y Brown ◽  
Gregory J Mize ◽  
Mario Pineda ◽  
Donna L George ◽  
David R Morris
Keyword(s):  
Translational Control ◽  
Open Reading Frames ◽  
Upstream Open Reading Frames ◽  
Reading Frames

scholarly journals Translational Control of theXenopus laevisConnexin-41 5′-Untranslated Region by Three Upstream Open Reading Frames

2000 ◽  
Vol 275 (40) ◽  
pp. 30787-30793 ◽  
Author(s):  
Hedda A. Meijer ◽  
Wim J. A. G. Dictus ◽  
Eelco D. Keuning ◽  
Adri A. M. Thomas
Keyword(s):  
Translational Control ◽  
Untranslated Region ◽  
Open Reading Frames ◽  
Upstream Open Reading Frames ◽  
Reading Frames

scholarly journals Genome-wide identification of Arabidopsis non-AUG-initiated upstream ORFs with evolutionarily conserved regulatory sequences that control protein expression levels

2021 ◽  
Author(s):  
Yuta Hiragori ◽  
Hiro Takahashi ◽  
Noriya Hayashi ◽  
Shun Sasaki ◽  
Kodai Nakao ◽  
...  
Keyword(s):  
Regulatory Peptides ◽  
Inhibitory Effect ◽  
Ribosome Profiling ◽  
Open Reading Frames ◽  
Regulatory Sequences ◽  
Dependent Manner ◽  
Protein Coding ◽  
Genome Wide ◽  
Evolutionarily Conserved ◽  
Upstream Open Reading Frames

Upstream open reading frames (uORFs) are short ORFs found in the 5′-UTRs of many eukaryotic transcripts and can influence the translation of protein-coding main ORFs (mORFs). Recent genome-wide ribosome profiling studies have revealed that thousands of uORFs initiate translation at non-AUG start codons. However, the physiological significance of these non-AUG uORFs has so far been demonstrated for only a few of them. It is conceivable that physiologically important non-AUG uORFs are evolutionarily conserved across species. In this study, using a combination of bioinformatics and experimental approaches, we searched the Arabidopsis genome for non-AUG-initiated uORFs with conserved sequences that control the expression of the mORF-encoded proteins. As a result, we identified four novel regulatory non-AUG uORFs. Among these, two exerted repressive effects on mORF expression in an amino acid sequence-dependent manner. These two non-AUG uORFs are likely to encode regulatory peptides that cause ribosome stalling, thereby enhancing their repressive effects. In contrast, one of the identified regulatory non-AUG uORFs promoted mORF expression by alleviating the inhibitory effect of a downstream AUG-initiated uORF. These findings provide insights into the mechanisms that enable non-AUG uORFs to play regulatory roles despite their low translation initiation efficiencies.

scholarly journals uORF-Tools – Workflow for the determination of translation-regulatory upstream open reading frames

2018 ◽  
Author(s):  
Anica Scholz ◽  
Florian Eggenhofer ◽  
Rick Gelhausen ◽  
Björn Grüning ◽  
Kathi Zarnack ◽  
...  
Keyword(s):  
Ribosome Profiling ◽  
Open Reading Frames ◽  
Annotation File ◽  
Inhibitory Effects ◽  
Protein Coding ◽  
Reading Frame ◽  
Upstream Open Reading Frames ◽  
Induced Changes ◽  
Reading Frames

AbstractRibosome profiling (ribo-seq) provides a means to analyze active translation by determining ribosome occupancy in a transcriptome-wide manner. The vast majority of ribosome protected fragments (RPFs) resides within the protein-coding sequence of mRNAs. However, commonly reads are also found within the transcript leader sequence (TLS) (aka 5’ untranslated region) preceding the main open reading frame (ORF), indicating the translation of regulatory upstream ORFs (uORFs). Here, we present a workflow for the identification of translation-regulatory uORFs. Specifically, uORF-Tools identifies uORFs within a given dataset and generates a uORF annotation file. In addition, a comprehensive human uORF annotation file, based on 35 ribo-seq files, is provided, which can serve as an alternative input file for the workflow. To assess the translation-regulatory activity of the uORFs, stimulus-induced changes in the ratio of the RPFs residing in the main ORFs relative to those found in the associated uORFs are determined. The resulting output file allows for the easy identification of candidate uORFs, which have translation-inhibitory effects on their associated main ORFs. uORF-Tools is available as a free and open Snakemake workflow at https://github.com/Biochemistry1-FFM/uORF-Tools. It is easily installed and all necessary tools are provided in a version-controlled manner, which also ensures lasting usability. uORF-Tools is designed for intuitive use and requires only limited computing times and resources.

scholarly journals RNA G-quadruplexes mark repressive upstream open reading frames in human mRNAs

2017 ◽  
Author(s):  
Pierre Murat ◽  
Giovanni Marsico ◽  
Barbara Herdy ◽  
Avazeh Ghanbarian ◽  
Guillem Portella ◽  
...  
Keyword(s):  
Secondary Structures ◽  
Ribosome Profiling ◽  
Open Reading Frames ◽  
Untranslated Regions ◽  
Translation Regulation ◽  
Physical Interaction ◽  
Protein Coding ◽  
Upstream Open Reading Frames ◽  
Nucleotide Resolution ◽  
Reading Frames

ABSTRACTRNA secondary structures in the 5’ untranslated regions (UTRs) of mRNAs have been characterised as key determinants of translation initiation. However the role of non-canonical secondary structures, such as RNA G-quadruplexes (rG4s), in modulating translation of human mRNAs and the associated mechanisms remain largely unappreciated. Here we use a ribosome profiling strategy to investigate the translational landscape of human mRNAs with structured 5’ untranslated regions (5’-UTR). We found that inefficiently translated mRNAs, containing rG4-forming sequences in their 5’-UTRs, have an accumulation of ribosome footprints in their 5’-UTRs. We show that rG4-forming sequences are determinants of 5’-UTR translation, suggesting that the folding of rG4 structures thwarts the translation of protein coding sequences (CDS) by stimulating the translation of repressive upstream open reading frames (uORFs). To support our model, we demonstrate that depletion of two rG4s-specialised DEAH-box helicases, DHX36 and DHX9, shifts translation towards rG4-containing uORFs reducing the translation of selected transcripts comprising proto-oncogenes, transcription factors and epigenetic regulators. Transcriptome-wide identification of DHX9 binding sites using individual-nucleotide resolution UV crosslinking and immunoprecipitation (iCLIP) demonstrate that translation regulation is mediated through direct physical interaction between the helicase and its rG4 substrate. Our findings unveil a previously unknown role for non-canonical structures in governing 5’-UTR translation and suggest that the interaction of helicases with rG4s could be considered as a target for future therapeutic intervention.

scholarly journals Conserved Upstream Open Reading Frame Nascent Peptides That Control Translation

2020 ◽  
Vol 54 (1) ◽  
pp. 237-264
Author(s):  
Thomas E. Dever ◽  
Ivaylo P. Ivanov ◽  
Matthew S. Sachs
Keyword(s):  
Gene Expression ◽  
Open Reading Frames ◽  
Upstream Open Reading Frame ◽  
Messenger Rnas ◽  
Regulate Gene Expression ◽  
Reading Frame ◽  
Ribosome Stalling ◽  
Evolutionarily Conserved ◽  
Upstream Open Reading Frames ◽  
Control Translation

Cells utilize transcriptional and posttranscriptional mechanisms to alter gene expression in response to environmental cues. Gene-specific controls, including changing the translation of specific messenger RNAs (mRNAs), provide a rapid means to respond precisely to different conditions. Upstream open reading frames (uORFs) are known to control the translation of mRNAs. Recent studies in bacteria and eukaryotes have revealed the functions of evolutionarily conserved uORF-encoded peptides. Some of these uORF-encoded nascent peptides enable responses to specific metabolites to modulate the translation of their mRNAs by stalling ribosomes and through ribosome stalling may also modulate the level of their mRNAs. In this review, we highlight several examples of conserved uORF nascent peptides that stall ribosomes to regulate gene expression in response to specific metabolites in bacteria, fungi, mammals, and plants.

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