Recognition of 3′ nucleotide context and stop codon readthrough are determined during mRNA translation elongation

Biziaev, Nikita; Sokolova, Elizaveta; Yanvarev, Dmitry V.; Toropygin, I. Yu.; Shuvalov, Alexey; Егорова, Т. В.; Alkalaeva, Elena

doi:10.1016/j.jbc.2022.102133

Cited by 20 publications

(13 citation statements)

References 54 publications

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“…Previously we identified UGA_CUAG as a mammalian readthrough-prone extended stop signal ( 9 , 45 ). This readthrough motif was subsequently corroborated using different approaches by several groups ( 8 , 51 , 56 , 57 ). Only 23 human genes contain this stop signal; however, their readthrough efficiencies vary by >10-fold, with DUS4L having the lowest readthrough efficiency (∼1.5%) and OPRL1 the highest (∼17%) ( 46 ).…”

Section: Introductionmentioning

confidence: 67%

Monitoring translation in all reading frames downstream of weak stop codons provides mechanistic insights into the impact of nucleotide and cellular contexts

Loughran

O'Loughlin

et al. 2022

Nucleic Acids Research

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A stop codon entering the ribosome A-site is normally decoded by release factors that induce release of the polypeptide. Certain factors influence the efficiency of the termination which is in competition with elongation in either the same (readthrough) or an alternative (frameshifting) reading frame. To gain insight into the competition between these processes, we monitored translation in parallel from all three reading frames downstream of stop codons while changing the nucleotide context of termination sites or altering cellular conditions (polyamine levels). We found that P-site codon identity can have a major impact on the termination efficiency of the OPRL1 stop signal, whereas for the OAZ1 ORF1 stop signal, the P-site codon mainly influences the reading frame of non-terminating ribosomes. Changes to polyamine levels predominantly influence the termination efficiency of the OAZ1 ORF1 stop signal. In contrast, increasing polyamine levels stimulate readthrough of the OPRL1 stop signal by enhancing near-cognate decoding rather than by decreasing termination efficiency. Thus, by monitoring the four competing processes occurring at stop codons we were able to determine which is the most significantly affected upon perturbation. This approach may be useful for the interrogation of other recoding phenomena where alternative decoding processes compete with standard decoding.

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Section: Introductionmentioning

confidence: 67%

Monitoring translation in all reading frames downstream of weak stop codons provides mechanistic insights into the impact of nucleotide and cellular contexts

Loughran

O'Loughlin

et al. 2022

Nucleic Acids Research

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“…However, refactoring alone is not sufficient as evidenced by the 32% success rate. We also speculate that codon optimization may lead to detrimental, context-dependent transcription and translation effects (Kent et al 2018;Biziaev et al 2022;Jiang et al 2023) that cannot yet be predicted and avoided.…”

Section: Conclusion and Remaining Challengesmentioning

confidence: 96%

Bacterial natural product discovery by heterologous expression

Kadjo,

Eustaquio

2023

Preprint

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Natural products have found important applications in the pharmaceutical and agricultural sectors. In bacteria, the genes that encode the biosynthesis of natural products are often colocalized in the genome, forming biosynthetic gene clusters. It has been predicted that only 3% of natural products encoded in bacterial genomes have been discovered thus far, in part because gene clusters may be poorly expressed under laboratory conditions. Heterologous expression can help realize bioinformatics predictions into products. However, challenges remain such as gene cluster prioritization, cloning of the complete gene cluster, appropriate expression, product identification, and isolation of products in practical yields. Here we reviewed the literature from the past five years (January 2018 to June 2023) to identify studies that discovered natural products by heterologous expression. From the 50 studies identified, we present analyses of the rationale for gene cluster prioritization, cloning methods, biosynthetic class, source taxa, and host choice. Combined, the 50 studies led to the discovery of 63 new families of natural products, supporting heterologous expression as a promising way to access novel chemistry. However, the success rate of natural product detection varied from 11% to 32% based on four large-scale studies that were identified. The low success rate makes it apparent that much remains to be improved. The potential reasons for failure and points to be considered to improve the chances of success are discussed.

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“…On the other hand, it is known from other translation systems that the read-through of stop codons by near-cognate tRNAs is a competing process for translation termination [ 23 ]. The likelihood of read-through is determined by the availability of RF, concentration of near-cognate tRNAs, and is also dependent on the codon context [ 24 , 25 ]. Consequently, the loss of RFs greatly increases the probability of ribosomes reading through a stop codon [ 23 , 26 ].…”

Section: Ongoing Questionsmentioning

confidence: 99%

Decoding the Enigma: Translation Termination in Human Mitochondria

Krüger,

Kovalchuk,

Shiriaev

et al. 2024

Human Molecular Genetics

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Mitochondrial translation is a complex process responsible for the synthesis of essential proteins involved in oxidative phosphorylation, a fundamental pathway for cellular energy production. Central to this process is the termination phase, where dedicated factors play a pivotal role in ensuring accurate and timely protein production. This review provides a comprehensive overview of the current understanding of translation termination in human mitochondria, emphasizing structural features and molecular functions of two mitochondrial termination factors mtRF1 and mtRF1a.

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Recognition of 3′ nucleotide context and stop codon readthrough are determined during mRNA translation elongation

Cited by 20 publications

References 54 publications

Monitoring translation in all reading frames downstream of weak stop codons provides mechanistic insights into the impact of nucleotide and cellular contexts

Monitoring translation in all reading frames downstream of weak stop codons provides mechanistic insights into the impact of nucleotide and cellular contexts

Bacterial natural product discovery by heterologous expression

Decoding the Enigma: Translation Termination in Human Mitochondria

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