Global mistranslation increases cell survival under stress in Escherichia coli

Autoři: Laasya Samhita aff001;  Parth K. Raval aff001;  Deepa Agashe aff001
Působiště autorů: National Centre for Biological Sciences, Tata Institute of Fundamental research, Bangalore, India aff001
Vyšlo v časopise: Global mistranslation increases cell survival under stress in Escherichia coli. PLoS Genet 16(3): e32767. doi:10.1371/journal.pgen.1008654
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008654


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 wide-ranging 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.

Klíčová slova:

Antibiotics – Cellular stress responses – DNA damage – DNA repair – Mutagenesis – Point mutation – Proteases – Transfer RNA


1. Mordret E, Yehonadav A, Barnabas GD, Cox J, Dahan O, Geiger T, et al. Systematic detection of amino acid substitutions in proteome reveals a mechanistic basis of ribosome errors. bioRxiv. 2018.

2. Ellis N, Gallant J. An estimate of the global error frequency in translation. Mol Gen Genet. 1982;188(2):169–72. doi: 10.1007/bf00332670 6759868

3. Ruan B, Palioura S, Sabina J, Marvin-Guy L, Kochhar S, Larossa RA, et al. Quality control despite mistranslation caused by an ambiguous genetic code. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(43):16502–7. doi: 10.1073/pnas.0809179105 18946032

4. Jakubowski H, Goldman E. Editing of errors in selection of amino acids for protein synthesis. Microbiol Rev. 1992;56(3):412–29. 1406490

5. Zaher HS, Green R. Fidelity at the molecular level: lessons from protein synthesis. Cell. 2009;136(4):746–62. doi: 10.1016/j.cell.2009.01.036 19239893

6. Wohlgemuth I, Pohl C, Rodnina MV. Optimization of speed and accuracy of decoding in translation. EMBO J. 2010;29(21):3701–9. doi: 10.1038/emboj.2010.229 20842102

7. Banerjee K, Kolomeisky AB, Igoshin OA. Elucidating interplay of speed and accuracy in biological error correction. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(20):5183–8. doi: 10.1073/pnas.1614838114 28465435

8. Zhang J, Ieong KW, Johansson M, Ehrenberg M. Accuracy of initial codon selection by aminoacyl-tRNAs on the mRNA-programmed bacterial ribosome. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(31):9602–7. doi: 10.1073/pnas.1506823112 26195797

9. Mikkola R, Kurland CG. Selection of laboratory wild-type phenotype from natural isolates of Escherichia coli in chemostats. Mol Biol Evol. 1992;9(3):394–402. doi: 10.1093/oxfordjournals.molbev.a040731 1584010

10. Rajon E, Masel J. Evolution of molecular error rates and the consequences for evolvability. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(3):1082–7. doi: 10.1073/pnas.1012918108 21199946

11. Bratulic S, Gerber F, Wagner A. Mistranslation drives the evolution of robustness in TEM-1 beta-lactamase. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(41):12758–63. doi: 10.1073/pnas.1510071112 26392536

12. Netzer N, Goodenbour JM, David A, Dittmar KA, Jones RB, Schneider JR, et al. Innate immune and chemically triggered oxidative stress modifies translational fidelity. Nature. 2009;462(7272):522–6. doi: 10.1038/nature08576 19940929

13. Mohler K, Ibba M. Translational fidelity and mistranslation in the cellular response to stress. Nat Microbiol. 2017;2:17117. doi: 10.1038/nmicrobiol.2017.117 28836574

14. Javid B, Sorrentino F, Toosky M, Zheng W, Pinkham JT, Jain N, et al. Mycobacterial mistranslation is necessary and sufficient for rifampicin phenotypic resistance. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(3):1132–7. doi: 10.1073/pnas.1317580111 24395793

15. Woese CR. On the evolution of the genetic code. Proceedings of the National Academy of Sciences of the United States of America. 1965;54(6):1546–52. doi: 10.1073/pnas.54.6.1546 5218910

16. Moghal A, Mohler K, Ibba M. Mistranslation of the genetic code. FEBS Lett. 2014;588(23):4305–10. doi: 10.1016/j.febslet.2014.08.035 25220850

17. Jones TE, Alexander RW, Pan T. Misacylation of specific nonmethionyl tRNAs by a bacterial methionyl-tRNA synthetase. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(17):6933–8. doi: 10.1073/pnas.1019033108 21482813

18. Ribas de Pouplana L, Santos MA, Zhu JH, Farabaugh PJ, Javid B. Protein mistranslation: friend or foe? Trends Biochem Sci. 2014;39(8):355–62. doi: 10.1016/j.tibs.2014.06.002 25023410

19. Fan Y, Wu J, Ung MH, De Lay N, Cheng C, Ling J. Protein mistranslation protects bacteria against oxidative stress. Nucleic acids research. 2015;43(3):1740–8. doi: 10.1093/nar/gku1404 25578967

20. Bacher JM, Schimmel P. An editing-defective aminoacyl-tRNA synthetase is mutagenic in aging bacteria via the SOS response. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(6):1907–12. doi: 10.1073/pnas.0610835104 17264207

21. Paredes JA, Carreto L, Simoes J, Bezerra AR, Gomes AC, Santamaria R, et al. Low level genome mistranslations deregulate the transcriptome and translatome and generate proteotoxic stress in yeast. BMC Biol. 2012;10:55. doi: 10.1186/1741-7007-10-55 22715922

22. <SOS_editing defective synthetase_paul schimmel.pdf>.

23. Al Mamun AAM, Gautam S, Humayun MZ. Hypermutagenesis in mutA cells is mediated by mistranslational corruption of polymerase, and is accompanied by replication fork collapse. Molecular Microbiology. 2006;62(6):1752–63. doi: 10.1111/j.1365-2958.2006.05490.x 17427291

24. Krisko A, Radman M. Phenotypic and genetic consequences of protein damage. PLoS genetics. 2013;9(9):e1003810. doi: 10.1371/journal.pgen.1003810 24068972

25. Samhita L, Shetty S, Varshney U. Unconventional initiator tRNAs sustain Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(32):13058–63. doi: 10.1073/pnas.1207868109 22829667

26. Kramer EB, Farabaugh PJ. The frequency of translational misreading errors in E. coli is largely determined by tRNA competition. RNA. 2007;13(1):87–96. doi: 10.1261/rna.294907 17095544

27. Samhita L, Virumae K, Remme J, Varshney U. Initiation with elongator tRNAs. Journal of bacteriology. 2013;195(18):4202–9. doi: 10.1128/JB.00637-13 23852868

28. Dittmar KA, Sorensen MA, Elf J, Ehrenberg M, Pan T. Selective charging of tRNA isoacceptors induced by amino-acid starvation. EMBO Rep. 2005;6(2):151–7. doi: 10.1038/sj.embor.7400341 15678157

29. Svenningsen SL, Kongstad M, Stenum TS, Munoz-Gomez AJ, Sorensen MA. Transfer RNA is highly unstable during early amino acid starvation in Escherichia coli. Nucleic acids research. 2017;45(2):793–804. doi: 10.1093/nar/gkw1169 27903898

30. Zhong J, Xiao C, Gu W, Du G, Sun X, He QY, et al. Transfer RNAs Mediate the Rapid Adaptation of Escherichia coli to Oxidative Stress. PLoS genetics. 2015;11(6):e1005302. doi: 10.1371/journal.pgen.1005302 26090660

31. Gualerzi CO, Pon CL. Initiation of mRNA translation in bacteria: structural and dynamic aspects. Cell Mol Life Sci. 2015;72(22):4341–67. doi: 10.1007/s00018-015-2010-3 26259514

32. Nagase T, Ishii S, Imamoto F. Differential transcriptional control of the two tRNA(fMet) genes of Escherichia coli K-12. Gene. 1988;67(1):49–57. doi: 10.1016/0378-1119(88)90007-8 2843439

33. Winther KS, Gerdes K. Enteric virulence associated protein VapC inhibits translation by cleavage of initiator tRNA. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(18):7403–7. doi: 10.1073/pnas.1019587108 21502523

34. Watanabe K, Miyagawa R, Tomikawa C, Mizuno R, Takahashi A, Hori H, et al. Degradation of initiator tRNAMet by Xrn1/2 via its accumulation in the nucleus of heat-treated HeLa cells. Nucleic acids research. 2013;41(8):4671–85. doi: 10.1093/nar/gkt153 23471000

35. Bochner BR, Gadzinski P, Panomitros E. Phenotype microarrays for high-throughput phenotypic testing and assay of gene function. Genome Res. 2001;11(7):1246–55. doi: 10.1101/gr.186501 11435407

36. Samhita L, Nanjundiah V, Varshney U. How many initiator tRNA genes does Escherichia coli need? Journal of bacteriology. 2014;196(14):2607–15. doi: 10.1128/JB.01620-14 24816600

37. Karkhanis VA, Mascarenhas AP, Martinis SA. Amino acid toxicities of Escherichia coli that are prevented by leucyl-tRNA synthetase amino acid editing. Journal of bacteriology. 2007;189(23):8765–8. doi: 10.1128/JB.01215-07 17890314

38. Agarwal D, Gregory ST, O'Connor M. Error-prone and error-restrictive mutations affecting ribosomal protein S12. J Mol Biol. 2011;410(1):1–9. doi: 10.1016/j.jmb.2011.04.068 21575643

39. Chumpolkulwong N, Hori-Takemoto C, Hosaka T, Inaoka T, Kigawa T, Shirouzu M, et al. Effects of Escherichia coli ribosomal protein S12 mutations on cell-free protein synthesis. Eur J Biochem. 2004;271(6):1127–34. doi: 10.1111/j.1432-1033.2004.04016.x 15009191

40. O'Connor M, Thomas CL, Zimmermann RA, Dahlberg AE. Decoding fidelity at the ribosomal A and P sites: influence of mutations in three different regions of the decoding domain in 16S rRNA. Nucleic acids research. 1997;25(6):1185–93. doi: 10.1093/nar/25.6.1185 9092628

41. Michel B. After 30 years of study, the bacterial SOS response still surprises us. PLoS biology. 2005;3(7):e255. doi: 10.1371/journal.pbio.0030255 16000023

42. Little JW, Harper JE. Identification of the lexA gene product of Escherichia coli K-12. Proceedings of the National Academy of Sciences of the United States of America. 1979;76(12):6147–51. doi: 10.1073/pnas.76.12.6147 160562

43. Radman M. SOS repair hypothesis: phenomenology of an inducible DNA repair which is accompanied by mutagenesis. Basic Life Sci. 1975;5A:355–67. doi: 10.1007/978-1-4684-2895-7_48 1103845

44. Uranga LA, Reyes ED, Patidar PL, Redman LN, Lusetti SL. The cohesin-like RecN protein stimulates RecA-mediated recombinational repair of DNA double-strand breaks. Nat Commun. 2017;8:15282. doi: 10.1038/ncomms15282 28513583

45. Dwyer DJ, Belenky PA, Yang JH, MacDonald IC, Martell JD, Takahashi N, et al. Antibiotics induce redox-related physiological alterations as part of their lethality. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(20):E2100–9. doi: 10.1073/pnas.1401876111 24803433

46. Rodríguez-Rosado AI, Valencia EY, Rodríguez-Rojas A, Costas C, Galhardo RS, Blázquez J, et al. Reactive oxygen species are major contributors to SOS-mediated mutagenesis induced by fluoroquinolones. BioRxiv. 2018.

47. Breidenstein EB, Bains M, Hancock RE. Involvement of the lon protease in the SOS response triggered by ciprofloxacin in Pseudomonas aeruginosa PAO1. Antimicrobial agents and chemotherapy. 2012;56(6):2879–87. doi: 10.1128/AAC.06014-11 22450976

48. Tsilibaris V, Maenhaut-Michel G, Van Melderen L. Biological roles of the Lon ATP-dependent protease. Res Microbiol. 2006;157(8):701–13. doi: 10.1016/j.resmic.2006.05.004 16854568

49. Evans CR, Fan Y, Ling J. Increased mistranslation protects E. coli from protein misfolding stress due to activation of a RpoS-dependent heat shock response. FEBS Lett. 2019.

50. Yanagida H, Gispan A, Kadouri N, Rozen S, Sharon M, Barkai N, et al. The Evolutionary Potential of Phenotypic Mutations. PLoS genetics. 2015;11(8):e1005445. doi: 10.1371/journal.pgen.1005445 26244544

51. Cowen LE, Lindquist S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science. 2005;309(5744):2185–9. doi: 10.1126/science.1118370 16195452

52. Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S. Prions are a common mechanism for phenotypic inheritance in wild yeasts. Nature. 2012;482(7385):363–8. doi: 10.1038/nature10875 22337056

53. Drummond DA, Wilke CO. The evolutionary consequences of erroneous protein synthesis. Nat Rev Genet. 2009;10(10):715–24. doi: 10.1038/nrg2662 19763154

54. Govers SK, Mortier J, Adam A, Aertsen A. Protein aggregates encode epigenetic memory of stressful encounters in individual Escherichia coli cells. PLoS biology. 2018;16(8):e2003853. doi: 10.1371/journal.pbio.2003853 30153247

55. Hoffman KS, Berg MD, Shilton BH, Brandl CJ, O'Donoghue P. Genetic selection for mistranslation rescues a defective co-chaperone in yeast. Nucleic acids research. 2017;45(6):3407–21. doi: 10.1093/nar/gkw1021 27899648

56. Neidhardt FC, VanBogelen RA. Positive regulatory gene for temperature-controlled proteins in Escherichia coli. Biochem Biophys Res Commun. 1981;100(2):894–900. doi: 10.1016/s0006-291x(81)80257-4 7023474

57. Malik M, Capecci J, Drlica K. Lon protease is essential for paradoxical survival of Escherichia coli exposed to high concentrations of quinolone. Antimicrobial agents and chemotherapy. 2009;53(7):3103–5. doi: 10.1128/AAC.00019-09 19414573

58. Yamaguchi Y, Tomoyasu T, Takaya A, Morioka M, Yamamoto T. Effects of disruption of heat shock genes on susceptibility of Escherichia coli to fluoroquinolones. BMC Microbiol. 2003;3:16. doi: 10.1186/1471-2180-3-16 12911840

59. van der Veen S, Hain T, Wouters JA, Hossain H, de Vos WM, Abee T, et al. The heat-shock response of Listeria monocytogenes comprises genes involved in heat shock, cell division, cell wall synthesis, and the SOS response. Microbiology. 2007;153(Pt 10):3593–607. doi: 10.1099/mic.0.2007/006361-0 17906156

60. Layton JC, Foster PL. Error-prone DNA polymerase IV is regulated by the heat shock chaperone GroE in Escherichia coli. Journal of bacteriology. 2005;187(2):449–57. doi: 10.1128/JB.187.2.449-457.2005 15629916

61. Baharoglu Z, Mazel D. SOS, the formidable strategy of bacteria against aggressions. FEMS Microbiol Rev. 2014;38(6):1126–45. doi: 10.1111/1574-6976.12077 24923554

62. Ganai RA, Johansson E. DNA Replication-A Matter of Fidelity. Mol Cell. 2016;62(5):745–55. doi: 10.1016/j.molcel.2016.05.003 27259205

63. Cycon M, Mrozik A, Piotrowska-Seget Z. Antibiotics in the Soil Environment-Degradation and Their Impact on Microbial Activity and Diversity. Front Microbiol. 2019;10:338. doi: 10.3389/fmicb.2019.00338 30906284

64. Schwartz MH, Waldbauer JR, Zhang L, Pan T. Global tRNA misacylation induced by anaerobiosis and antibiotic exposure broadly increases stress resistance in Escherichia coli. Nucleic acids research. 2016.

65. Dorr T, Lewis K, Vulic M. SOS response induces persistence to fluoroquinolones in Escherichia coli. PLoS genetics. 2009;5(12):e1000760. doi: 10.1371/journal.pgen.1000760 20011100

66. Aertsen A, Van Houdt R, Vanoirbeek K, Michiels CW. An SOS response induced by high pressure in Escherichia coli. Journal of bacteriology. 2004;186(18):6133–41. doi: 10.1128/JB.186.18.6133-6141.2004 15342583

Článek vyšel v časopise

PLOS Genetics

2020 Číslo 3

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Zvyšte si kvalifikaci online z pohodlí domova

Citikolin v neuroprotekci a neuroregeneraci – od výzkumu do klinické praxe
nový kurz
Autoři: MUDr. Petr Výborný, CSc., FEBO

Zánětlivá bolest zad a axiální spondylartritida – Diagnostika a referenční strategie
Autoři: MUDr. Monika Gregová, Ph.D., MUDr. Kristýna Bubová

Diagnostika a léčba deprese pro ambulantní praxi
Autoři: MUDr. Jan Hubeňák, Ph.D

Význam nemocničního alert systému v době SARS-CoV-2
Autoři: doc. MUDr. Helena Lahoda Brodská, Ph.D., prim. MUDr. Václava Adámková

Snímatelné zubní náhrady a fixační krémy
Autoři: doc. MUDr. Hana Hubálková, Ph.D.

Všechny kurzy
Kurzy Doporučená témata Časopisy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se