Translational recoding: canonical translation mechanisms reinterpreted

Rodnina, Marina V.; Korniy, Natalia; Klimova, Mariia; Karki, Prajwal; Peng, Bee-Zen; Senyushkina, Tamara; Belardinelli, Riccardo; Maracci, Cristina; Wohlgemuth, Ingo; Samatova, Ekaterina; Peske, Frank

doi:10.1093/nar/gkz783

Cited by 73 publications

(84 citation statements)

References 159 publications

(194 reference statements)

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“…where N is a stretch of three identical nucleotides, W is either AAA or UUU, and Z ≠ G. The linker region is less well-defined, but typically is short (1 -12 nt long) and is thought to be important for determining the extent of -1 PRF in a virus-specific manner. The function of the downstream secondary structure is to induce elongating ribosomes to pause, a critical step for efficient -1 PRF to occur [reviewed in (9)]. The generally accepted mechanism of -1 PRF is that the mRNA secondary structure directs elongating ribosomes to pause with its A-and P- suggesting that it may present a target for small molecule therapeutics (7,8).…”

Section: Introductionmentioning

confidence: 99%

Structural and functional conservation of the programmed −1 ribosomal frameshift signal of SARS-CoV-2

Neupane

et al. 2020

Preprint

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17 years after the SARS-CoV epidemic, the world is facing the COVID-19 pandemic.COVID-19 is caused by a coronavirus named SARS-CoV-2. Given the most optimistic projections estimating that it will take more than a year to develop a vaccine, our best short term strategy may lie in identifying virus-specific targets for small molecule interventions. All coronaviruses utilize a molecular mechanism called -1 PRF to control the relative expression of their proteins. Prior analyses of SARS-CoV revealed that it utilizes a structurally unique three-stemmed mRNA pseudoknot to stimulate high rates of -1 PRF, that it also harbors a -1 PRF attenuation element. Altering -1 PRF activity negatively impacts virus replication, suggesting that this molecular mechanism may be therapeutically targeted. Here we present a comparative analysis of the original SARS-CoV and SARS-CoV-2 frameshift signals. Structural analyses reveal that the core -1 PRF signal, composed of the U UUA AAC slippery site and three-stemmed mRNA pseudoknot is highly conserved. In contrast, the upstream attenuator hairpin is less well conserved. Functional assays revealed that both elements promote similar rates of -1 PRF and that silent coding mutations in the slippery site strongly ablate -1 PRF activity. We suggest that molecules that were previously identified as inhibiting SARS-CoV mediated -1 PRF may serve as lead compounds to counter the current pandemic.

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Section: Introductionmentioning

confidence: 99%

Structural and functional conservation of the programmed −1 ribosomal frameshift signal of SARS-CoV-2

Neupane

et al. 2020

Preprint

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“…This complex mechanism requires special trans-acting protein factors (Sec insertion sequence binding protein 2 and Sec-specific translation elongation factor) and a cis-acting Sec insertion sequence (SECIS) element (a stem-loop structure located immediately downstream of the in-frame UGA codon at which Sec is incorporated) [9,44]. For the decoding of a stop codon by near cognate tRNA, genomic analyses, and profiling studies of human genes have found several potential readthrough candidates [9] some of which were confirmed experimentally. About 4% of malate dehydrogenase is physiologically extended by translational readthrough, with arginine and tryptophan being co-encoded by the UGA stop codon [45].…”

Section: Discussionmentioning

confidence: 99%

“…The first phenomenon does not alter the translational reading frame and extends the polypeptide C-terminally [9]. Stop codon can be decoded as a sense codon by either a near-cognate tRNA (tRNA with anticodons that have a single mismatch upon pairing to a stop codon) or the specialized cognate tRNAs (tRNAs with an anticodon that is complementary to the stop codon), such as tRNA Sec [9]. Both of these recoding events would result in the full-length ALDH3B2 expression (466 amino acids (aa), molecular weight around 53 kDa; longer variant shown in Figure 1).…”

Section: Introductionmentioning

confidence: 98%

“…Regulation of gene expression at the translational level can be achieved via the following three recoding events: stop-codon readthrough, ribosome frameshifting, and translational bypassing. The first phenomenon does not alter the translational reading frame and extends the polypeptide C-terminally [9]. Stop codon can be decoded as a sense codon by either a near-cognate tRNA (tRNA with anticodons that have a single mismatch upon pairing to a stop codon) or the specialized cognate tRNAs (tRNAs with an anticodon that is complementary to the stop codon), such as tRNA Sec [9].…”

Section: Introductionmentioning

confidence: 99%

“…In case of the ALDH3B2 gene, the ribosome could translate the first 16 mRNA codons up to the UGA stop codon. Then instead of terminating protein synthesis, the ribosome could slide over a non-coding gap and continue the synthesis after reaching the matching landing codon, which in case of ALDH3B2 would be first downstream AAG triplet, as the matching take-off and landing codon is the key bypassing signal [9]. Translational bypassing would result in the production of a protein a little bit shorter than the full-length isoform (466 aa), but longer than the short one (385 aa).…”

Section: Introductionmentioning

confidence: 99%

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Detection of ALDH3B2 in Human Placenta

Michorowska

Giebułtowicz

Wolinowska

et al. 2019

IJMS

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Aldehyde dehydrogenase 3B2 (ALDH3B2) gene contains a premature termination codon, which can be skipped or suppressed resulting in full-length protein expression. Alternatively, the longest putative open reading frame starting with the second in-frame start codon would encode short isoform. No unequivocal evidence of ALDH3B2 expression in healthy human tissues is available. The aim of this study was to confirm its expression in human placenta characterized by the highest ALDH3B2 mRNA abundance. ALDH3B2 DNA and mRNA were sequenced. The expression was investigated using western blot. The identity of the protein was confirmed using mass spectrometry (MS). The predicted tertiary and quaternary structures, subcellular localization, and phosphorylation sites were assessed using bioinformatic analyses. All DNA and mRNA isolates contained the premature stop codon. In western blot analyses, bands corresponding to the mass of full-length protein were detected. MS analysis led to the identification of two unique peptides, one of which is encoded by the nucleotide sequence located upstream the second start codon. Bioinformatic analyses suggest cytoplasmic localization and several phosphorylation sites. Despite premature stop codon in DNA and mRNA sequences, full-length ALDH3B2 was found. It can be formed as a result of premature stop codon readthrough, complex phenomenon enabling stop codon circumvention.

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Expression of the translation termination factor eRF1 is autoregulated by translational readthrough and 3'UTR intron‐mediated NMD in Neurospora crassa

et al. 2020

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Eukaryotic release factor 1 (eRF1) is a translation termination factor that binds to the ribosome at stop codons. The expression of eRF1 is strictly controlled, since its concentration defines termination efficiency and frequency of translational readthrough. Here, we show that eRF1 expression in Neurospora crassa is controlled by an autoregulatory circuit that depends on the specific 3'UTR structure of erf1 mRNA. The stop codon context of erf1 promotes readthrough that protects the mRNA from its 3'UTR‐induced nonsense‐mediated mRNA decay (NMD). High eRF1 concentration leads to inefficient readthrough, thereby allowing NMD‐mediated erf1 degradation. We propose that eRF1 expression is controlled by similar autoregulatory circuits in many fungi and seed plants and discuss the evolution of autoregulatory systems of different translation termination factors.

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Translational recoding: canonical translation mechanisms reinterpreted

Cited by 73 publications

References 159 publications

Structural and functional conservation of the programmed −1 ribosomal frameshift signal of SARS-CoV-2

Structural and functional conservation of the programmed −1 ribosomal frameshift signal of SARS-CoV-2

Detection of ALDH3B2 in Human Placenta

Expression of the translation termination factor eRF1 is autoregulated by translational readthrough and 3'UTR intron‐mediated NMD in Neurospora crassa

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