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Lessons from 50 years of SOS DNA-damage-induced mutagenesis

Nature Reviews Molecular Cell Biology volume 8, pages 587–594 (2007)Cite this article

Abstract

This historical perspective integrates 50 years of research on SOS mutagenesis in Escherichia coli with the proverbial '3R' functions—replication, repair and recombination—that feature DNA polymerase V. Genetic and biochemical data are assimilated to arrive at a current picture of UV-damage-induced mutagenesis. An unprecedented DNA polymerase V transactivation mechanism, which involves the RecA protein, sheds new light on unresolved issues that have persisted over time, prompting us to reflect on evolving molecular concepts regarding DNA structures and polymerase-switching mechanisms.

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Figure 1: Evolution of translesion synthesis models.
Figure 2: Prospective translesion synthesis models.

References

  1. Weigle, J. J. Induction of mutation in a bacterial virus. Proc. Natl Acad. Sci. USA 39, 628–636 (1953).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Witkin, E. M. The radiation sensitivity of Escherichia coli B: a hypothesis relating filament formation and prophage induction. Proc. Natl Acad. Sci. USA 57, 1275–1279 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Radman, M. in Molecular and Environmental Aspects of Mutagenesis (eds Prakash, L., Sherman, F., Miller, M., Lawrence, C. & Tabor, H. W.) 128–142 (Thomas, Springfield, 1974).

    Google Scholar 

  4. Courcelle, J., Khodursky, A., Peter, B., Brown, P. O. & Hanawalt, P. C. Comparative gene expression profiles following UV exposure in wild-type and SOS-deficient Escherichia coli. Genetics 158, 41–64 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Kenyon, C. J. & Walker, G. C. DNA-damaging agents stimulate gene expression at specific loci in Escherichia coli. Proc. Natl Acad. Sci. USA 77, 2819–2823 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bagg, A., Kenyon, C. J. & Walker, G. C. Inducibility of a gene product required for UV and chemical mutagenesis in Escherichia coli. Proc. Natl Acad. Sci. USA 78, 5749–5753 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bonner, C. A. et al. Purification and characterization of an inducible Escherichia coli DNA polymerase capable of insertion and bypass at abasic lesions in DNA. J. Biol. Chem. 263, 18946–18952 (1988).

    CAS  PubMed  Google Scholar 

  8. Bonner, C. A., Hays, S., McEntee, K. & Goodman, M. F. DNA polymerase II is encoded by the DNA damage-inducible dinA gene of Escherichia coli. Proc. Natl Acad. Sci. USA 87, 7663–7667 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Iwasaki, H., Nakata, A., Walker, G. C. & Shinagawa, H. The Escherichia coli polB gene, which encodes DNA polymerase II, is regulated by the SOS system. J. Bacteriol. 172, 6268–6273 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wagner, J. et al. The dinB gene encodes a novel E. coli DNA polymerase, DNA pol IV, involved in mutagenesis. Mol. Cell 4, 281–286 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Kato, T. & Shinoura, Y. Isolation and characterization of mutants of Escherichia coli deficient in induction of mutations by ultraviolet light. Mol. Gen. Genet. 156, 121–131 (1977).

    CAS  PubMed  Google Scholar 

  12. Steinborn, G. Uvm mutants of Escherichia coli K12 deficient in UV mutagenesis. I. Isolation of uvm mutants and their phenotypical characterization in DNA repair and mutagenesis. Mol. Gen. Genet. 165, 87–93 (1978).

    Article  CAS  PubMed  Google Scholar 

  13. Steinborn, G. Uvm mutants of Escherichia coli K12 deficient in UV mutagenesis. II. Further evidence for a novel function in error-prone repair. Mol. Gen. Genet. 175, 203–208 (1979).

    Article  CAS  PubMed  Google Scholar 

  14. Tang, M. J. et al. UmuD′2C is an error-prone DNA polymerase, Escherichia coli pol V. Proc. Natl Acad. Sci. USA 96, 8919–8924 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reuven, N. B., Arad, G., Maor-Shoshani, A. & Livneh, Z. The mutagenesis protein UmuC is a DNA polymerase activated by UmuD′, RecA, and SSB and is specialized for translesion replication. J. Biol. Chem. 274, 31763–31766 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Witkin, E. M. Ultraviolet mutagenesis and inducible DNA repair in Escherichia coli. Bacteriol. Rev. 40, 869–907 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Cox, M. M. Motoring along with the bacterial RecA protein. Nature Rev. Mol. Cell Biol. 8, 127–138 (2007).

    Article  CAS  Google Scholar 

  18. Heller, R. C. & Marians, K. J. Replisome assembly and the direct restart of stalled replication forks. Nature Rev. Mol. Cell Biol. 7, 932–943 (2006).

    Article  CAS  Google Scholar 

  19. Mahdi, A. A., Buckman, C., Harris, L. & Lloyd, R. G. Rep and PriA helicase activities prevent RecA from provoking unnecessary recombination during replication fork repair. Genes Dev. 20, 2135–2147 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Foster, P. L. Adaptive mutation in Escherichia coli. Cold Spring Harb. Symp. Quant. Biol. 65, 21–29 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yeiser, B., Pepper, E. D., Goodman, M. F. & Finkel, S. E. SOS-induced DNA polymerases enhance long-term survival and evolutionary fitness. Proc. Natl Acad. Sci. USA 99, 8737–8741 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gudas, L. J. & Pardee, A. B. DNA synthesis inhibition and the induction of protein X in Escherichia coli. J. Mol. Biol. 101, 459–477 (1976).

    Article  CAS  PubMed  Google Scholar 

  23. Gudas, L. J. & Pardee, A. B. Model for regulation of Escherichia coli DNA repair functions. Proc. Natl Acad. Sci. USA 72, 2330–2334 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Walker, G. C. & Dobson, P. P. Mutagenesis and repair deficiencies of Escherichia coli umuC mutants are suppressed by the plasmid pKM101. Mol. Gen. Genet. 172, 17–24 (1979).

    Article  CAS  PubMed  Google Scholar 

  25. Bridges, B. A., Mottershead, R. P. & Sedgwick, S. G. Mutagenic DNA repair in Escherichia coli. III. Requirement for a function of DNA polymerase III in ultraviolet-light mutagenesis. Mol. Gen. Genet. 144, 53–58 (1976).

    Article  CAS  PubMed  Google Scholar 

  26. Bridges, B. A. & Woodgate, R. The two-step model of bacterial UV mutagenesis. Mutation Research 150, 133–139 (1985).

    Article  CAS  PubMed  Google Scholar 

  27. Nohmi, T., Battista, J. R., Dodson, L. A. & Walker, G. C. RecA-mediated cleavage activates UmuD for mutagenesis: mechanistic relationship between transcriptional derepression and posttranslational activation. Proc. Natl Acad. Sci. USA 85, 1816–1820 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Burckhardt, S. E., Woodgate, R., Scheuermann, R. H. & Echols, H. UmuD mutagenesis protein of Escherichia coli: overproduction, purification, and cleavage by RecA. Proc. Natl Acad. Sci. USA 85, 1811–1815 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shinagawa, H., Iwasaki, H., Kato, T. & Nakata, A. RecA protein-dependent cleavage of UmuD protein and SOS mutagenesis. Proc. Natl Acad. Sci. USA 85, 1806–1810 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dutreix, M. et al. New recA mutations that dissociate the various RecA protein activities in Escherichia coli provide evidence for an additional role for RecA protein in UV mutagenesis. J. Bacteriol. 171, 2415–2423 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sweasy, J. B., Witkin, E. M., Sinha, N. & Roegner-Maniscalco, V. RecA protein of Escherichia coli has a third essential role in SOS mutator activity. J. Bacteriol. 172, 3030–3036 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Woodgate, R., Rajagopalan, M., Lu, C. & Echols, H. UmuC mutagenesis protein of Escherichia coli: purification and interaction with UmuD and UmuD′. Proc. Natl Acad. Sci. USA 86, 7301–7305 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rajagopalan, M. et al. Activity of the purified mutagenesis proteins UmuC, UmuD′, and RecA in replicative bypass of an abasic DNA lesion by DNA polymerase III. Proc. Natl Acad. Sci. USA 89, 10777–10781 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bruck, I., Woodgate, R., McEntee, K. & Goodman, M. F. Purification of a soluble UmuD′C complex from Escherichia coli: cooperative binding of UmuD′C to single-stranded DNA. J. Biol. Chem. 271, 10767–10774 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Shen, X., Woodgate, R. & Goodman, M. F. Escherichia coli DNA polymerase V subunit exchange: a post-SOS mechanism to curtail error-prone DNA synthesis. J. Biol. Chem. 278, 52546–52550 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Tang, M. et al. Biochemical basis of SOS-induced mutagenesis in Escherichia coli: reconstitution of in vitro lesion bypass dependent on the UmuD′2C mutagenic complex and RecA protein. Proc. Natl Acad. Sci. USA 95, 9755–9760 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kuzminov, A. Recombinational repair of DNA damage in Escherichia coli and bacteriophage l. Microbiol. Mol. Biol. Rev. 63, 751–813 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Reuven, N. B., Arad, G., Stasiak, A. Z., Stasiak, A. & Livneh, Z. Lesion bypass by the Escherichia coli DNA polymerase V requires assembly of a RecA nucleoprotein filament. J. Biol. Chem. 276, 5511–5517 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Fujii, S., Gasser, V. & Fuchs, R. P. The biochemical requirements of DNA polymerase V-mediated translesion synthesis revisited. J. Mol. Biol. 341, 405–417 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Schlacher, K. et al. DNA polymerase V and RecA protein, a minimal mutasome. Mol. Cell 17, 561–572 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Schlacher, K., Cox, M. M., Woodgate, R. & Goodman, M. F. RecA acts in trans to allow replication of damaged DNA by DNA polymerase V. Nature 442, 883–887 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Moore, P. D., Bose, K. K., Rabkin, S. D. & Strauss, B. S. Sites of termination of in vitro DNA synthesis on ultraviolet- and N-acetylaminofluorene-treated phi X174 templates by prokaryotic and eukaryotic DNA polymerases. Proc. Natl Acad. Sci. USA 78, 110–114 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Echols, H. & Goodman, M. F. Mutation induced by DNA damage: a many protein affair. Mutat. Res. 236, 301–311 (1990).

    Article  CAS  PubMed  Google Scholar 

  44. Dutreix, M., Burnett, B., Bailone, A., Radding, C. M. & Devoret, R. A partially deficient mutant, RecA1730, that fails to form normal nucleoprotein filaments. Mol. Gen. Genet. 232, 489–497 (1992).

    Article  CAS  PubMed  Google Scholar 

  45. Pham, P., Bertram, J. G., O'Donnell, M., Woodgate, R. & Goodman, M. F. A model for SOS-lesion targeted mutations in E. coli involving pol V, RecA, SSB and β sliding clamp. Nature 409, 366–370 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Bailone, A., Sommer, S., Knezevic, J., Dutreix, M. & Devoret, R. A RecA protein mutant deficient in its interaction with the UmuDC complex. Biochemie 73, 479–484 (1991).

    Article  CAS  Google Scholar 

  47. Doudney, C. O. Complexity of the ultraviolet mutation frequency response curve in Escherichia coli B/r: SOS induction, one-lesion and two-lesion mutagenesis. J. Bacteriol. 128, 815–826 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Sedgwick, S. G. Misrepair of overlapping daughter strand gaps as a possible mechanism for UV induced mutagenesis in UVR strains of Escherichia coli: a general model for induced mutagenesis by misrepair (SOS repair) of closely spaced DNA lesions. Mutat. Res. 41, 185–200 (1976).

    Article  CAS  PubMed  Google Scholar 

  49. Svoboda, D. L., Smith, C. A., Taylor, J. S. & Sancar, A. Effect of sequence, adduct type, and opposing lesions on the binding and repair of ultraviolet photodamage by DNA photolyase and (A)BC excinuclease. J. Biol. Chem. 268, 10694–10700 (1993).

    CAS  PubMed  Google Scholar 

  50. Rupp, W. D. & Howard-Flanders, P. Discontinuities in the DNA synthesized in an excision-defective strain of Escherichia coli following ultraviolet irradiation. J. Mol. Biol. 31, 291–304 (1968).

    Article  CAS  PubMed  Google Scholar 

  51. Cox, M. M. et al. The importance of repairing stalled replication forks. Nature 404, 37–41 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Postow, L., Crisona, N. J., Peter, B. J., Hardy, C. D. & Cozzarelli, N. R. Topological challenges to DNA replication: conformations at the fork. Proc. Natl Acad. Sci. USA 98, 8219–8226 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Higgins, N. P., Kato, K. & Strauss, B. A model for replication repair in mammalian cells. J. Mol. Biol. 101, 417–425 (1976).

    Article  CAS  PubMed  Google Scholar 

  54. Courcelle, J. Recs preventing wrecks. Mutat. Res. 577, 217–227 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Caillet-Fauquet, P. & Maenhaut-Michel, G. Nature of the SOS mutator activity: genetic characterization of untargeted mutagenesis in Escherichia coli. Mol. Gen. Genet. 213, 491–498 (1988).

    Article  CAS  PubMed  Google Scholar 

  56. Fijalkowska, I. J., Dunn, R. L. & Schaaper, R. M. Genetic requirements and mutational specificity of the Escherichia coli SOS mutator activity. J. Bacteriol. 179, 7435–7445 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kawamoto, T. et al. Dual roles for DNA polymerase η in homologous DNA recombination and translesion DNA synthesis. Mol. Cell 20, 793–799 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. McIlwraith, M. J. et al. Human DNA polymerase η promotes DNA synthesis from strand invasion intermediates of homologous recombination. Mol. Cell 20, 783–792 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Friedberg, E. C., Lehmann, A. R. & Fuchs, R. P. Trading places: how do DNA polymerases switch during translesion DNA synthesis? Mol. Cell 18, 499–505 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Bunting, K. A., Roe, S. M. & Pearl, L. H. Structural basis for recruitment of translesion DNA polymerase Pol IV/DinB to the β-clamp. EMBO J. 22, 5883–5892 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Indiani, C., McInerney, P., Georgescu, R., Goodman, M. F. & O'Donnell, M. A sliding-clamp toolbelt binds high- and low-fidelity DNA polymerases simultaneously. Mol. Cell 19, 805–815 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Napolitano, R., Janel-Bintz, R., Wagner, J. & Fuchs, R. P. All three SOS-inducible DNA polymerases (Pol II, Pol IV and Pol V) are involved in induced mutagenesis. EMBO J. 19, 6259–6265 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Little, J. W., Edmiston, S. H., Pacelli, L. Z. & Mount, D. W. Cleavage of the Escherichia coli LexA protein by the RecA protease. Proc. Natl Acad. Sci. USA 77, 3225–3229 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fernandez de Henestrosa, A. R. et al. Identification of additional genes belonging to the LexA-regulon in Escherichia coli. Mol. Microbiol. 35, 1560–1572 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Opperman, T., Murli, S., Smith, B. T. & Walker, G. C. A model for umuDC-dependent prokaryotic DNA damage checkpoint. Proc. Natl Acad. Sci. USA 96, 9218–9223 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sommer, S., Boudsocq, F., Devoret, R. & Bailone, A. Specific RecA amino acid changes affect RecA-UmuD′C interaction. Mol. Microbiol. 28, 281–291 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Goodman, M. F. & Tippin, B. The expanding polymerase universe. Nature Rev. Mol. Cell Biol. 1, 101–109 (2000).

    Article  CAS  Google Scholar 

  68. Ling, H., Boudsocq, F., Woodgate, R. & Yang, W. Crystal structure of a Y-family DNA polymerase in action: a mechanism for error-prone and lesion-bypass replication. Cell 107, 91–102 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Tang, M. et al. Roles of E. coli DNA polymerases IV and V in lesion-targeted and untargeted SOS mutagenesis. Nature 404, 1014–1018 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Shen, X. et al. Efficiency and accuracy of SOS-induced DNA polymerases replicating benzo[a]pyrene-7,8-diol 9,10-epoxide A and G adducts. J. Biol. Chem. 277, 5265–5274 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. LeClerc, J. E., Borden, A. & Lawrence, C. W. The thymine-thymine pyrimidine-pyrimidone(6-4) ultraviolet light photoproduct is highly mutagenic and specifically induces 3′ thymine-to-cytosine transitions in Escherichia coli. Proc. Natl Acad. Sci. USA 88, 9685–9689 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Register, J. C. & Griffith, J. The direction of RecA protein assembly onto single strand DNA is the same as the direction of strand assimilation during strand exchange. J. Biol. Chem. 260, 12308–12312 (1985).

    CAS  PubMed  Google Scholar 

  73. Egelman, E. H. & Stasiak, A. Structure of helical RecA–DNA complexes. Complexes formed in the presence of ATP-γ-S or ATP. J. Mol. Biol. 191, 677–697 (1986).

    Article  CAS  PubMed  Google Scholar 

  74. Spies, M. & Kowalczykowski, S. C. The RecA binding locus of RecBCD is a general domain for recruitment of DNA strand exchange proteins. Mol. Cell 21, 573–580 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. VanLoock, M. S. et al. Complexes of RecA with LexA and RecX differentiate between active and inactive RecA nucleoprotein filaments. J. Mol. Biol. 333, 345–354 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Schlacher, K., Pham, P., Cox, M. M. & Goodman, M. F. Roles of DNA polymerase V and RecA protein in SOS damage-induced mutation. Chem. Rev. 106, 406–419 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Flores, M. J., Sanchez, N. & Michel, B. A fork-clearing role for UvrD. Mol. Microbiol. 57, 1664–1675 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Bridges, B. A. Error-prone DNA repair and translesion DNA synthesis. II: The inducible SOS hypothesis. DNA Repair 4, 725–739 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Perry, K. L., Elledge, S. J., Mitchell, B. B., Marsh, L. & Walker, G. C. umuDC and mucAB operons whose products are required for UV light- and chemical-induced mutagenesis: UmuD, MucA, and LexA proteins share homology. Proc. Natl Acad. Sci. USA 82, 4331–4335 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors' work on SOS mutagenesis carried out from 1988 onwards is supported by grants from the National Institutes of Health. We are indebted to the many contributors to the SOS field and would like to single out a few of the 'old timers': E. Witkin, M. Radman, G. Walker and R. Devoret, with a special heartfelt thanks to H. Echols. E. Witkin kindly provided reminiscences of how SOS began and evolved. We thank J. Petruska for comments on the manuscript. We especially thank students and colleagues I. Bruck, M. Tang, X. Shen, P. Pham, M. Cox and R. Woodgate, who devoted much effort and creative thinking to these studies.

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  1. Katharina Schlacher and Myron F. Goodman are at the University of Southern California, 1050 Childs Way, RIH 201B, Los Angeles, California 90089-2910, USA.,

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Schlacher, K., Goodman, M. Lessons from 50 years of SOS DNA-damage-induced mutagenesis. Nat Rev Mol Cell Biol 8, 587–594 (2007). https://doi.org/10.1038/nrm2198

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