Mistranslation of the genetic code

Moghal, Adil; Mohler, Kyle; Ibba, Michael

doi:10.1016/j.febslet.2014.08.035

Cited by 44 publications

(31 citation statements)

References 74 publications

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“…For instance, in Mycobacterium smegmatis, artificially increasing specific amino acid substitutions at glutamate and aspartate tRNAs generates a mixed population of wild type and mistranslated RNA polymerase molecules [14], imparting greater resistance to rifampicin (an antibiotic that targets RNA polymerase). More generally, high global (rather than proteinspecific) mistranslation rates could confer a selective advantage by generating a "statistical proteome"-a bet-hedging strategy whereby a few cells with some mistranslated proteins (rather than all cells with one specific mistranslated protein as in the previous example) can survive an environmental stress [15,16]. Such a mixed proteome can occur both as a consequence of baseline mistranslation (as shown by proteome analyses [1]) or through artificial or stress-induced mistranslation.…”

Section: Introductionmentioning

confidence: 99%

Global mistranslation increases cell survival under stress in Escherichia coli

2020

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Mistranslation is typically deleterious for cells, although specific mistranslated proteins can confer a short-term benefit in a particular environment. However, given its large overall cost, the prevalence of high global mistranslation rates remains puzzling. Altering basal mistranslation levels of Escherichia coli in several ways, we show that generalized mistranslation enhances early survival under DNA damage, by rapidly activating the SOS response. Mistranslating cells maintain larger populations after exposure to DNA damage, and thus have a higher probability of sampling critical beneficial mutations. Both basal and artificially increased mistranslation increase the number of cells that are phenotypically tolerant and genetically resistant under DNA damage; they also enhance survival at high temperature. In contrast, decreasing the normal basal mistranslation rate reduces cell survival. This wideranging stress resistance relies on Lon protease, which is revealed as a key effector that induces the SOS response in addition to alleviating proteotoxic stress. The new links between error-prone protein synthesis, DNA damage, and generalised stress resistance indicate surprising coordination between intracellular stress responses and suggest a novel hypothesis to explain high global mistranslation rates. Author summaryCells make mistakes all the time. Protein synthesis is exceptionally error-prone, which is puzzling because such mistakes are usually harmful. Prior work shows that specific erroneous proteins can be beneficial under specific stresses. However, this cannot explain a high background error rate, because most mistakes will not be useful. We offer a solution to this conundrum: cells that make more mistakes accumulate a key quality-control enzyme, tripping the switch for a broad stress response (the "SOS" response, that repairs damaged DNA). In turn, this increases cell survival. The unexpected link between protein synthesis and DNA damage suggests surprising cross talk across important quality-control processes, and motivates a new hypothesis to explain how and why cells tolerate so many mistakes.

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Section: Introductionmentioning

confidence: 99%

Global mistranslation increases cell survival under stress in Escherichia coli

2020

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“…In addition, mixtures of these rare peptides produced by trypsin diggestion of proteomes are truly challenging to detect, even when the most sophysticated mass spectrometry instruments and software methods are used [26]. Moreover, radioactive and/or chemiluminescence methods normally used to quantify protein synthesis errors in cell cultures are not applicable to solid tumors or tissue biopsies [9,[27][28][29][30][31] complicating this issue even further. To circumvent those technical limitations, we have used highly sensitive MS/MS methods, and MS/ MS spectra searching engines that are able to identify rare peptides in proteins whose occurrence depends on the rules that govern mRNA decoding by the ribosome (knowledge based targeted searches).…”

Section: Introductionmentioning

confidence: 99%

Codon misreading tRNAs promote tumor growth in mice

et al. 2018

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Deregulation of tRNAs, aminoacyl-tRNA synthetases and tRNA modifying enzymes are common in cancer, raising the hypothesis that protein synthesis efficiency and accuracy (mistranslation) are compromised in tumors. We show here that human colon tumors and xenograft tumors produced in mice by two epithelial cancer cell lines mistranslate 2- to 4-fold more frequently than normal tissue. To clarify if protein mistranslation plays a role in tumor biology, we expressed mutant Ser-tRNAs that misincorporate Ser-at-Ala (frequent error) and Ser-at-Leu (infrequent error) in NIH3T3 cells and investigated how they responded to the proteome instability generated by the amino acid misincorporations. There was high tolerance to both misreading tRNAs, but the Ser-to-Ala misreading tRNA was a more potent inducer of cell transformation, stimulated angiogenesis and produced faster growing tumors in mice than the Ser-to-Leu misincorporating tRNA. Upregulation of the Akt pathway and the UPR were also observed. Most surprisingly, the relative expression of both misreading tRNAs increased during tumor growth, suggesting that protein mistranslation is advantageous in cancer contexts. These data highlight new features of protein synthesis deregulation in tumor biology.

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“…Translation fidelity is maintained in part through the accurate pairing of amino acids with cognate tRNAs and accurate selection of aminoacyl-tRNAs at the ribosome [1–3]. Despite these mechanisms, amino acid misincorporation occurs once in every 1,000 to 10,000 codons translated, resulting in around 15% of all proteins in the cell possessing at least one mistranslated amino acid [4, 5]. …”

Section: Introductionmentioning

confidence: 99%

MS-READ: Quantitative measurement of amino acid incorporation

Mohler

Aerni

Gassaway

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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Ribosomal protein synthesis results in the genetically programmed incorporation of amino acids into a growing polypeptide chain. Faithful amino acid incorporation that accurately reflects the genetic code is critical to the structure and function of proteins as well as overall proteome integrity. Errors in protein synthesis are generally detrimental to cellular processes yet emerging evidence suggest that proteome diversity generated through mistranslation may be beneficial under certain conditions. Cumulative translational error rates have been determined at the organismal level, however codon specific error rates and the spectrum of misincorporation errors from system to system remain largely unexplored. In particular, until recently technical challenges have limited the ability to detect and quantify comparatively rare amino acid misincorporation events, which occur orders of magnitude less frequently than canonical amino acid incorporation events. We now describe a technique for the quantitative analysis of amino acid incorporation that provides the sensitivity necessary to detect mistranslation events during translation of a single codon at frequencies as low as 1 in 10,000 for all 20 proteinogenic amino acids, as well as non-proteinogenic and modified amino acids.

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Mistranslation of the genetic code

Cited by 44 publications

References 74 publications

Global mistranslation increases cell survival under stress in Escherichia coli

Global mistranslation increases cell survival under stress in Escherichia coli

Codon misreading tRNAs promote tumor growth in mice

MS-READ: Quantitative measurement of amino acid incorporation

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