Impacts of uORF codon identity and position on translation regulation

Lin, Yizhu; May, Gemma E.; Kready, Hunter; Nazzaro, Lauren; Mao, Mao; Spealman, Pieter; Creeger, Yehuda; McManus, C. Joel

doi:10.1093/nar/gkz681

Cited by 58 publications

(55 citation statements)

References 51 publications

(67 reference statements)

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“…The strength and consistency over time of these anchoring stacking and H-bond interactions will be crucial for the strength and sequence sensitivity of the CAR interaction with the mRNA. Since the CAR interactions depend on both the wobble anticodon nucleotide and mRNA +1 codon, this implies a dependency between adjacent codons consistent with previous observations that translation efficiency can be a property of adjacent codons (40)(41)(42).…”

Section: Wobble Anticodon Nucleotide Anchors the C1054-a1196-r146 Intsupporting

confidence: 87%

A Ribosome Interaction Surface Sensitive to mRNA GCN Periodicity

Scopino

Williams

Elsayed

et al. 2020

Preprint

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GCN codons are over-represented in initial codons of ORFs of prokaryote and eukaryote mRNAs. We describe a ribosome rRNA-protein surface that interacts with an mRNA GCN codon when next-in-line for the ribosome A site. The interaction surface is comprised of the edges of two stacked rRNA bases: the Watson-Crick edge of 16S/18S rRNA C1054 and adjacent Hoogsteen edge of A1196 (Escherichia coli 16S rRNA numbering). Also part of the interaction surface, the planar guanidinium group of a conserved Arginine (R146 of yeast ribosomal protein Rps3) is stacked adjacent to A1196. On its other side, the interaction surface is anchored to the ribosome A site through base stacking of C1054 with the wobble anticodon base of the A-site tRNA. Using Molecular Dynamics simulations of a 495-residue subsystem of translocating ribosomes, we observe base pairing of C1054 to nucleotide G at position 1 of the next-in-line codon, consistent with previous cryo-EM observations, and hydrogen bonding of A1196 and R146 to C at position 2. Hydrogen bonding to both of these codon positions is significantly weakened when C at position 2 is changed to G, A or U. These sequence-sensitive mRNAribosome interactions at the C1054-A1196-R146 (CAR) surface potentially contribute to GCNmediated regulation of protein translation.Video S1. Example of neutral dynamics for translocation stage II; +1 codon GCU (mp4) Video S2. Example of neutral dynamics for translocation stage II; +1 codon GGU (mp4) AUTHOR INFORMATION

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Section: Wobble Anticodon Nucleotide Anchors the C1054-a1196-r146 Intsupporting

confidence: 87%

A Ribosome Interaction Surface Sensitive to mRNA GCN Periodicity

Scopino

Williams

Elsayed

et al. 2020

Preprint

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“…Because of the broad role of uORFs on downstream translation (Johnstone et al , 2016; Lin et al , 2019), we hypothesized that the detected mutation could be at the origin of the observed PSD. To validate this hypothesis, we first confirmed the presence of the mutation in the five sequenced patients by Sanger sequencing (Supplementary Fig 1) and genotyped it in one additional affected related (individual IV-7) for whom DNA was available.…”

Section: Resultsmentioning

confidence: 99%

“…Even if the flanking sequence of the new ATG does not completely match to the consensus predicted Kozak sequence ((G/A)NNAUGG), it seems similar to the one flanking the natural PROS1 ATG, suggesting that the new ATG could be identified by the translational machinery and thus used in the cells (Kozak, 1997, 1990). Several works have previously demonstrated that uAUG and uORF are cis-regulatory elements in 5‘UTR that are able to control protein expression by altering the translation efficiency and could subsequently be associated with risk of diseases (Dvir et al ., 2013; Lin et al ., 2019; Orr et al ., 2019; von Bohlen et al ., 2017). Many previously ignored uORFs are now known to act as major post-transcriptional regulatory elements or to be translated to produce bioactive peptides or proteins (Jones et al , 2017; Orr et al , 2019).…”

Section: Discussionmentioning

confidence: 99%

A novel rare c. -39C>T mutation in thePROS15’UTR causing PS deficiency by creating a new upstream translation initiation codon and inhibiting the production of the natural protein

Labrouche-Colomer

Soukarieh

Proust

et al. 2020

Preprint

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SummaryInherited Protein S deficiency (PSD) (MIM176880) is a rare automosal dominant disorder caused by rare mutations, mainly located in the coding sequence of the structural PROS1 gene, and associated with an increased risk of venous thromboembolism. To identify the molecular defect underlying PSD observed in an extended French pedigree with 7 PSD affected members in who no candidate deleterious PROS1 mutation was detected by Sanger sequencing of PROS1 exons and their flanking intronic regions or via a MLPA approach, a whole genome sequencing strategy was adopted. This led to the identification of a never reported C to T substitution at c.-39 from the natural ATG codon of the PROS1 gene that completely segregates with PSD in the whole family. This substitution ACG->ATG creates a new start codon upstream of the main ATG. We experimentally demonstrated that the variant generates a novel overlapping ORF and inhibits the translation of the wild type protein from the main ORF in HeLa cells. This work describes the first example of 5’UTR PROS1 mutation causing PSD through the creation of an upstream ORF, a mutation that is not predicted to be deleterious by standard annotation softwares.

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“…In this context the repression imposed by uORFs on the initiation of translation of the main ORF is relieved, thus allowing the production of specific proteins in response to stress. The mode of action of each uORF appears dictated by its initiation codon context, secondary structure and coding capacities [83,84]. Moreover, the overall regulation of a given mRNA will depend on the specific combination and organisation of uORFs in its 5 terminal region [85].…”

Section: Regulation By Uorfmentioning

confidence: 99%

Translational Regulations in Response to Endoplasmic Reticulum Stress in Cancers

Jaud

Philippe

Bella

et al. 2020

Cells

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During carcinogenesis, almost all the biological processes are modified in one way or another. Among these biological processes affected, anomalies in protein synthesis are common in cancers. Indeed, cancer cells are subjected to a wide range of stresses, which include physical injuries, hypoxia, nutrient starvation, as well as mitotic, oxidative or genotoxic stresses. All of these stresses will cause the accumulation of unfolded proteins in the Endoplasmic Reticulum (ER), which is a major organelle that is involved in protein synthesis, preservation of cellular homeostasis, and adaptation to unfavourable environment. The accumulation of unfolded proteins in the endoplasmic reticulum causes stress triggering an unfolded protein response in order to promote cell survival or to induce apoptosis in case of chronic stress. Transcription and also translational reprogramming are tightly controlled during the unfolded protein response to ensure selective gene expression. The majority of stresses, including ER stress, induce firstly a decrease in global protein synthesis accompanied by the induction of alternative mechanisms for initiating the translation of mRNA, later followed by a translational recovery. After a presentation of ER stress and the UPR response, we will briefly present the different modes of translation initiation, then address the specific translational regulatory mechanisms acting during reticulum stress in cancers and highlight the importance of translational control by ER stress in tumours.

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Impacts of uORF codon identity and position on translation regulation

Cited by 58 publications

References 51 publications

A Ribosome Interaction Surface Sensitive to mRNA GCN Periodicity

A Ribosome Interaction Surface Sensitive to mRNA GCN Periodicity

A novel rare c. -39C>T mutation in thePROS15’UTR causing PS deficiency by creating a new upstream translation initiation codon and inhibiting the production of the natural protein

Translational Regulations in Response to Endoplasmic Reticulum Stress in Cancers

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