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Bacterial DNA excision repair pathways

Abstract

Bacteria are continuously exposed to numerous endogenous and exogenous DNA-damaging agents. To maintain genome integrity and ensure cell survival, bacteria have evolved several DNA repair pathways to correct different types of DNA damage and non-canonical bases, including strand breaks, nucleotide modifications, cross-links, mismatches and ribonucleotide incorporations. Recent advances in genome-wide screens, the availability of thousands of whole-genome sequences and advances in structural biology have enabled the rapid discovery and characterization of novel bacterial DNA repair pathways and new enzymatic activities. In this Review, we discuss recent advances in our understanding of base excision repair and nucleotide excision repair, and we discuss several new repair processes including the EndoMS mismatch correction pathway and the MrfAB excision repair system.

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Fig. 1: Examples of endogenous and exogenous sources of DNA damage encountered by bacteria.
Fig. 2: Advances in base excision repair.
Fig. 3: Azinomycin B and nitrogen mustard inter-strand cross-link repair.
Fig. 4: Overview of nucleotide excision repair.
Fig. 5: Structural insights into EndoMS restriction endonuclease activity.
Fig. 6: Role of MrfA in DNA repair.

References

  1. Friedberg, E. C. et al. DNA Repair and Mutagenesis: Second Edition (American Society for Microbiology, 2006).

  2. Wang, S. T. et al. The forespore line of gene expression in Bacillus subtilis. J. Mol. Biol. 358, 16–37 (2006).

    CAS  PubMed  Google Scholar 

  3. Setlow, P. I will survive: DNA protection in bacterial spores. Trends Microbiol. 15, 172–180 (2007).

    CAS  PubMed  Google Scholar 

  4. Park, J. S., Marr, M. T. & Roberts, J. W. E. coli transcription repair coupling factor (Mfd protein) rescues arrested complexes by promoting forward translocation. Cell 109, 757–767 (2002).

    CAS  PubMed  Google Scholar 

  5. Goranov, A. I., Kuester-Schoeck, E., Wang, J. D. & Grossman, A. D. Characterization of the global transcriptional responses to different types of DNA damage and disruption of replication in Bacillus subtilis. J. Bacteriol. 188, 5595–5605 (2006). This work characterizes the transcriptional response to MMC, and also shows that MMC slows replication fork progression in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Gupta, R., Barkan, D., Redelman-Sidi, G., Shuman, S. & Glickman, M. S. Mycobacteria exploit three genetically distinct DNA double-strand break repair pathways. Mol. Microbiol. 79, 316–330 (2011).

    CAS  PubMed  Google Scholar 

  7. Williams, J. S. & Kunkel, T. A. Ribonucleotides in DNA: origins, repair and consequences. DNA Repair. 19, 27–37 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Zgur-Bertok, D. DNA damage repair and bacterial pathogens. PLoS Pathog. 9, e1003711 (2013).

    PubMed  PubMed Central  Google Scholar 

  9. Matic, I. Mutation rate heterogeneity increases odds of survival in unpredictable environments. Mol. Cell 75, 421–425 (2019).

    CAS  PubMed  Google Scholar 

  10. Cooke, M. S., Evans, M. D., Dizdaroglu, M. & Lunec, J. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 17, 1195–1214 (2003).

    CAS  PubMed  Google Scholar 

  11. Kow, Y. W. & Dare, A. Detection of abasic sites and oxidative DNA base damage using an ELISA-like assay. Methods 22, 164–169 (2000).

    CAS  PubMed  Google Scholar 

  12. Thompson, P. S. & Cortez, D. New insights into abasic site repair and tolerance. DNA Repair. 90, 102866 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sagher, D. & Strauss, B. Insertion of nucleotides opposite purinic/apyrimidinic sites in deoxyribonucleic acid during in vitro synthesis: uniqueness of adenine nucleotides. Biochemistry 22, 4518–4526 (1983).

    CAS  PubMed  Google Scholar 

  14. Mullins, E. A., Rodriguez, A. A., Bradley, N. P. & Eichman, B. F. Emerging roles of DNA glycosylases and the base excision repair pathway. Trends Biochem. Sci. 44, 765–781 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Dronkert, M. L. & Kanaar, R. Repair of DNA interstrand cross-links. Mutat. Res. 486, 217–247 (2001). This is an excellent comprehensive review covering all aspects of DNA cross-linking agents, and the repair of cross-linking damage in organisms ranging from E. coli to human cells.

    CAS  PubMed  Google Scholar 

  16. Schroeder, J. W., Hirst, W. G., Szewczyk, G. A. & Simmons, L. A. The effect of local sequence context on mutational bias of genes encoded on the leading and lagging strands. Curr. Biol. 26, 692–697 (2016). This paper determines the mutation rate and mutation spectrum caused by a mismatch repair defect in B. subtilis, and shows that sequence context is the major driver of mutation rate in B. subtilis.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Schroeder, J. W., Randall, J. R., Hirst, W. G., O’Donnell, M. E. & Simmons, L. A. Mutagenic cost of ribonucleotides in bacterial DNA. Proc. Natl Acad. Sci. USA 114, 11733–11738 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Nick McElhinny, S. A. et al. Genome instability due to ribonucleotide incorporation into DNA. Nat. Chem. Biol. 6, 774–781 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Yao, N. Y., Schroeder, J. W., Yurieva, O., Simmons, L. A. & O’Donnell, M. E. Cost of rNTP/dNTP pool imbalance at the replication fork. Proc. Natl Acad. Sci. USA 110, 12942–12947 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Vaisman, A. et al. Investigating the mechanisms of ribonucleotide excision repair in Escherichia coli. Mutat. Res. Fundam. Mol. Mech. Mutagen. 761, 21–33 (2014).

    CAS  Google Scholar 

  21. Slauch, J. M. How does the oxidative burst of macrophages kill bacteria? Still an open question. Mol. Microbiol. 80, 580–583 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Fang, F. C. & Vazquez-Torres, A. Reactive nitrogen species in host–bacterial interactions. Curr. Opin. Immunol. 60, 96–102 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. van der Veen, S. & Tang, C. M. The BER necessities: the repair of DNA damage in human-adapted bacterial pathogens. Nat. Rev. Microbiol. 13, 83–94 (2015).

    PubMed  Google Scholar 

  24. LeVier, K., Phillips, R. W., Grippe, V. K., Roop, R. M. & Walker, G. C. Similar requirements of a plant symbiont and a mammalian pathogen for prolonged intracellular survival. Science 287, 2492–2493 (2000).

    CAS  PubMed  Google Scholar 

  25. Davies, B. W. et al. DNA damage and reactive nitrogen species are barriers to Vibrio cholerae colonization of the infant mouse intestine. PLoS Pathog. 7, e1001295 (2011). This paper shows how defects in DNA repair pathways prevent passage of Vibrio cholerae through the stomach and a failure to colonize the intestine.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Cimino, G. D., Gamper, H. B., Isaacs, S. T. & Hearst, J. E. Psoralens as photoactive probes of nucleic acid structure and function: organic chemistry, photochemistry, and biochemistry. Annu. Rev. Biochem. 54, 1151–1193 (1985).

    CAS  PubMed  Google Scholar 

  27. Barker, S., Weinfeld, M. & Murray, D. DNA-protein crosslinks: their induction, repair, and biological consequences. Mutat. Res. 589, 111–135 (2005).

    CAS  PubMed  Google Scholar 

  28. Procopio, R. E., Silva, I. R., Martins, M. K., Azevedo, J. L. & Araujo, J. M. Antibiotics produced by Streptomyces. Braz. J. Infect. Dis. 16, 466–471 (2012).

    PubMed  Google Scholar 

  29. Barak, Y., Cohen-Fix, O. & Livneh, Z. Deamination of cytosine-containing pyrimidine photodimers in UV-irradiated DNA. Significance for UV light mutagenesis. J. Biol. Chem. 270, 24174–24179 (1995).

    CAS  PubMed  Google Scholar 

  30. Prise, K. M., Pinto, M., Newman, H. C. & Michael, B. D. A review of studies of ionizing radiation-induced double-strand break clustering. Radiat. Res. Suppl. 156, 572–576 (2001).

    CAS  Google Scholar 

  31. Ward, J. F. Radiation mutagenesis: the initial DNA lesions responsible. Radiat. Res. Suppl. 142, 362–368 (1995).

    CAS  Google Scholar 

  32. Hata, T. et al. Mitomycin, a new antibiotic from Streptomyces. I. J. Antibiot. 9, 141–146 (1956).

    CAS  Google Scholar 

  33. Armstrong, R. W., Salvati, M. E. & Nguyen, M. Novel interstrand cross-links induced by the antitumor antibiotic carzinophilin/azinomycin B. J. Am. Chem. Soc. 114, 3144–3145 (1992).

    CAS  Google Scholar 

  34. Sleigh, M. J. The mechanism of DNA breakage by phleomycin in vitro. Nucleic Acids Res. 3, 891–901 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Rizvi, R. Y., Shahabuddin, Rahman, A. & Hadi, S. M. Effect of alkylation with streptozotocin on the secondary structure of DNA. Biosci. Rep. 6, 557–564 (1986).

    CAS  PubMed  Google Scholar 

  36. Baute, J. & Depicker, A. Base excision repair and its role in maintaining genome stability. Crit. Rev. Biochem. Mol. Biol. 43, 239–276 (2008). This work is an excellent and comprehensive review of BER across biology, and is a tremendous resource detailing lesion types, glycosylases and mechanisms of BER.

    CAS  PubMed  Google Scholar 

  37. Wallace, S. S. Base excision repair: a critical player in many games. DNA Repair. 19, 14–26 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Labahn, J. et al. Structural basis for the excision repair of alkylation-damaged DNA. Cell 86, 321–329 (1996).

    CAS  PubMed  Google Scholar 

  39. Dianov, G. & Lindahl, T. Reconstitution of the DNA base excision-repair pathway. Curr. Biol. 4, 1069–1076 (1994).

    CAS  PubMed  Google Scholar 

  40. Neeley, W. L. & Essigmann, J. M. Mechanisms of formation, genotoxicity, and mutation of guanine oxidation products. Chem. Res. Toxicol. 19, 491–505 (2006).

    CAS  PubMed  Google Scholar 

  41. Gruber, C. C. & Walker, G. C. Incomplete base excision repair contributes to cell death from antibiotics and other stresses. DNA Repair. 71, 108–117 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Michaels, M. L., Cruz, C., Grollman, A. P. & Miller, J. H. Evidence that MutY and MutM combine to prevent mutations by an oxidatively damaged form of guanine in DNA. Proc. Natl Acad. Sci. USA 89, 7022–7025 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Maki, H. & Sekiguchi, M. MutT protein specifically hydrolyses a potent mutagenic substrate for DNA synthesis. Nature 355, 273–275 (1992).

    CAS  PubMed  Google Scholar 

  44. Fowler, R. G. & Schaaper, R. M. The role of the mutT gene of Escherichia coli in maintaining replication fidelity. FEMS Microbiol. Rev. 21, 43–54 (1997).

    CAS  PubMed  Google Scholar 

  45. Lenhart, J. S., Schroeder, J. W., Walsh, B. W. & Simmons, L. A. DNA repair and genome maintenance in Bacillus subtilis. Microbiol. Mol. Biol. Rev. 76, 530–564 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Sugahara, M. et al. Crystal structure of a repair enzyme of oxidatively damaged DNA, MutM (Fpg), from an extreme thermophile, Thermus thermophilus HB8. EMBO J. 19, 3857–3869 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Fromme, J. C. & Verdine, G. L. Structural insights into lesion recognition and repair by the bacterial 8-oxoguanine DNA glycosylase MutM. Nat. Struct. Biol. 9, 544–552 (2002).

    CAS  PubMed  Google Scholar 

  48. Williams, S. D. & David, S. S. Evidence that MutY is a monofunctional glycosylase capable of forming a covalent Schiff base intermediate with substrate DNA. Nucleic Acids Res. 26, 5123–5133 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kreppel, A., Blank, I. D. & Ochsenfeld, C. Base-independent DNA base-excision repair of 8-oxoguanine. J. Am. Chem. Soc. 140, 4522–4526 (2018).

    CAS  PubMed  Google Scholar 

  50. Mullins, E. A. et al. The DNA glycosylase AlkD uses a non-base-flipping mechanism to excise bulky lesions. Nature 527, 254–258 (2015). This work solves the crystal structure and uses a modelling approach to demonstrate the first non-base-flipping mechanism for a DNA glycosylase.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Stivers, J. T. Site-specific DNA damage recognition by enzyme-induced base flipping. Prog. Nucleic Acid. Res. Mol. Biol. 77, 37–65 (2004).

    CAS  PubMed  Google Scholar 

  52. Parsons, Z. D., Bland, J. M., Mullins, E. A. & Eichman, B. F. A catalytic role for C–H/π interactions in base excision repair by Bacillus cereus DNA glycosylase AlkD. J. Am. Chem. Soc. 138, 11485–11488 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Mullins, E. A., Shi, R. & Eichman, B. F. Toxicity and repair of DNA adducts produced by the natural product yatakemycin. Nat. Chem. Biol. 13, 1002–1008 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Shi, R. et al. Selective base excision repair of DNA damage by the non-base-flipping DNA glycosylase AlkC. EMBO J. 37, 63–74 (2018).

    CAS  PubMed  Google Scholar 

  55. Mohni, K. N. et al. HMCES maintains genome integrity by shielding abasic sites in single-strand DNA. Cell 176, 144–153.e13 (2019).

    CAS  PubMed  Google Scholar 

  56. Thompson, P. S., Amidon, K. M., Mohni, K. N., Cortez, D. & Eichman, B. F. Protection of abasic sites during DNA replication by a stable thiazolidine protein–DNA cross-link. Nat. Struct. Mol. Biol. 26, 613–618 (2019). This work solves the crystal structure of E. coli YedK bound to and protecting an AP site, and provides a mechanism that is likely to be conserved with the human protein HEMCES.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Fang, Q. DNA–protein crosslinks processed by nucleotide excision repair and homologous recombination with base and strand preference in E. coli model system. Mutat. Res. 741–742, 1–10 (2013).

    PubMed  Google Scholar 

  58. Zeinert, R. et al. A legacy role for DNA binding of Lon protects against genotoxic stress. Preprint at bioRxiv https://doi.org/10.1101/317677 (2018).

    Article  Google Scholar 

  59. Sang, P. B., Srinath, T., Patil, A. G., Woo, E. J. & Varshney, U. A unique uracil-DNA binding protein of the uracil DNA glycosylase superfamily. Nucleic Acids Res. 43, 8452–8463 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Tu, J., Chen, R., Yang, Y., Cao, W. & Xie, W. Suicide inactivation of the uracil DNA glycosylase UdgX by covalent complex formation. Nat. Chem. Biol. 15, 615–622 (2019).

    CAS  PubMed  Google Scholar 

  61. Ahn, W. C. et al. Covalent binding of uracil DNA glycosylase UdgX to abasic DNA upon uracil excision. Nat. Chem. Biol. 15, 607–614 (2019).

    CAS  PubMed  Google Scholar 

  62. Chatterjee, N. & Walker, G. C. Mechanisms of DNA damage, repair, and mutagenesis. Env. Mol. Mutagen. 58, 235–263 (2017).

    CAS  Google Scholar 

  63. Patlan, A. G. et al. YwqL (EndoV), ExoA and PolA act in a novel alternative excision pathway to repair deaminated DNA bases in Bacillus subtilis. PLoS ONE 14, e0211653 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Tomasz, M. et al. Reaction of DNA with chemically or enzymatically activated mitomycin C: isolation and structure of the major covalent adduct. Proc. Natl Acad. Sci. USA 83, 6702–6706 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Cole, J. M., Acott, J. D., Courcelle, C. T. & Courcelle, J. Limited capacity or involvement of excision repair, double-strand breaks, or translesion synthesis for psoralen cross-link repair in Escherichia coli. Genetics 210, 99–112 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Cole, R. S. Repair of DNA containing interstrand crosslinks in Escherichia coli: sequential excision and recombination. Proc. Natl Acad. Sci. USA 70, 1064–1068 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Terawaki, A. & Greenberg, J. Effect of carzinophillin on bacterial deoxyribonucleic acid: formation of inter-strand cross-links in deoxyribonucleic acid and their disappearance during post-treatment incubation. Nature 209, 481–484 (1966).

    CAS  PubMed  Google Scholar 

  68. Mullins, E. A., Warren, G. M., Bradley, N. P. & Eichman, B. F. Structure of a DNA glycosylase that unhooks interstrand cross-links. Proc. Natl Acad. Sci. USA 114, 4400–4405 (2017). This work solves the structure of and provides a model for the mechanism of ICL repair by DNA glycosylase AlkZ on AZB adducts.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Wang, S. et al. Characterization of a novel DNA glycosylase from S. sahachiroi involved in the reduction and repair of azinomycin B induced DNA damage. Nucleic Acids Res. 44, 187–197 (2016).

    CAS  PubMed  Google Scholar 

  70. Zhao, Q. et al. Characterization of the azinomycin B biosynthetic gene cluster revealing a different iterative type I polyketide synthase for naphthoate biosynthesis. Chem. Biol. 15, 693–705 (2008).

    CAS  PubMed  Google Scholar 

  71. Bradley, N. P., Washburn, L. A., Christov, P. P., Watanabe, C. M. H. & Eichman, B. F. Escherichia coli YcaQ is a DNA glycosylase that unhooks DNA interstrand crosslinks. Nucleic Acids Res. 48, 7005–7017 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Sancar, A. & Reardon, J. T. Nucleotide excision repair in E. coli and man. Adv. Protein Chem. 69, 43–71 (2004).

    CAS  PubMed  Google Scholar 

  73. Vaisman, A. et al. Removal of misincorporated ribonucleotides from prokaryotic genomes: an unexpected role for nucleotide excision repair. PLoS Genet. 9, e1003878 (2013).

    PubMed  PubMed Central  Google Scholar 

  74. Van Houten, B. & Kad, N. Investigation of bacterial nucleotide excision repair using single-molecule techniques. DNA Repair. 20, 41–48 (2014).

    PubMed  PubMed Central  Google Scholar 

  75. Kraithong, T., Hartley, S., Jeruzalmi, D. & Pakotiprapha, D. A peek inside the machines of bacterial nucleotide excision repair. Int. J. Mol. Sci. 22, 952 (2021). This work is an excellent and comprehensive review covering the structural biology and biochemical mechanisms underlying bacterial NER.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Case, B. C., Hartley, S., Osuga, M., Jeruzalmi, D. & Hingorani, M. M. The ATPase mechanism of UvrA2 reveals the distinct roles of proximal and distal ATPase sites in nucleotide excision repair. Nucleic Acids Res. 47, 4136–4152 (2019). This work details the mechanism of proximal and distal site ATP usage by UvrA during the process of lesion recognition and dissociation from the lesion, allowing UvrB to form the pre-incision complex.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Pakotiprapha, D., Samuels, M., Shen, K., Hu, J. H. & Jeruzalmi, D. Structure and mechanism of the UvrA–UvrB DNA damage sensor. Nat. Struct. Mol. Biol. 19, 291–298 (2012). This manuscript shows that UvrA2 adopts a ‘closed groove’ conformation, which can only accommodate binding of undamaged (native) DNA in the UvrA2B2 lesion recognition stoichiometry.

    CAS  PubMed  Google Scholar 

  78. Lin, J. J. & Sancar, A. Reconstitution of nucleotide excision nuclease with UvrA and UvrB proteins from Escherichia coli and UvrC protein from Bacillus subtilis. J. Biol. Chem. 265, 21337–21341 (1990).

    CAS  PubMed  Google Scholar 

  79. Lin, J. J. & Sancar, A. Active site of (A)BC excinuclease. I. Evidence for 5′ incision by UvrC through a catalytic site involving Asp399, Asp438, Asp466, and His538 residues. J. Biol. Chem. 267, 17688–17692 (1992).

    CAS  PubMed  Google Scholar 

  80. Mazur, S. J. & Grossman, L. Dimerization of Escherichia coli UvrA and its binding to undamaged and ultraviolet light damaged DNA. Biochemistry 30, 4432–4443 (1991).

    CAS  PubMed  Google Scholar 

  81. Stracy, M. et al. Single-molecule imaging of UvrA and UvrB recruitment to DNA lesions in living Escherichia coli. Nat. Commun. 7, 12568 (2016). This paper examines the single-molecule dynamics of UvrA and UvrB in vivo, and shows that lesion recognition takes place in a two-step process with UvrA acting first followed by recruitment of UvrB.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kraithong, T. et al. Real-time investigation of the roles of ATP hydrolysis by UvrA and UvrB during DNA damage recognition in nucleotide excision repair. DNA Repair. 97, 103024 (2021).

    CAS  PubMed  Google Scholar 

  83. Orren, D. K. & Sancar, A. The (A)BC excinuclease of Escherichia coli has only the UvrB and UvrC subunits in the incision complex. Proc. Natl Acad. Sci. USA 86, 5237–5241 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Verhoeven, E. E., Wyman, C., Moolenaar, G. F. & Goosen, N. The presence of two UvrB subunits in the UvrAB complex ensures damage detection in both DNA strands. EMBO J. 21, 4196–4205 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Pakotiprapha, D. & Jeruzalmi, D. Small-angle X-ray scattering reveals architecture and A2B2 stoichiometry of the UvrA–UvrB DNA damage sensor. Proteins 81, 132–139 (2013).

    CAS  PubMed  Google Scholar 

  86. Lee, S. J., Sung, R. J. & Verdine, G. L. Mechanism of DNA lesion homing and recognition by the Uvr nucleotide excision repair system. Research 2019, 5641746 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Oh, E. Y. & Grossman, L. Helicase properties of the Escherichia coli UvrAB protein complex. Proc. Natl Acad. Sci. USA 84, 3638–3642 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Shi, Q., Thresher, R., Sancar, A. & Griffith, J. Electron microscopic study of (A)BC excinuclease. DNA is sharply bent in the UvrB–DNA complex. J. Mol. Biol. 226, 425–432 (1992).

    CAS  PubMed  Google Scholar 

  89. Delagoutte, E., Fuchs, R. P. & Bertrand-Burggraf, E. The isomerization of the UvrB–DNA preincision complex couples the UvrB and UvrC activities. J. Mol. Biol. 320, 73–84 (2002).

    CAS  PubMed  Google Scholar 

  90. Perera, A. V., Mendenhall, J. B., Courcelle, C. T. & Courcelle, J. Cho endonuclease functions during DNA interstrand cross-link repair in Escherichia coli. J. Bacteriol. 198, 3099–3108 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Mazon, G., Philippin, G., Cadet, J., Gasparutto, D. & Fuchs, R. P. The alkyltransferase-like ybaZ gene product enhances nucleotide excision repair of O6-alkylguanine adducts in E. coli. DNA Repair. 8, 697–703 (2009).

    CAS  PubMed  Google Scholar 

  92. Mielecki, D., Wrzesinski, M. & Grzesiuk, E. Inducible repair of alkylated DNA in microorganisms. Mutat. Res. Rev. Mutat. Res. 763, 294–305 (2015).

    CAS  PubMed  Google Scholar 

  93. Margison, G. P. et al. Alkyltransferase-like proteins. DNA Repair. 6, 1222–1228 (2007).

    CAS  PubMed  Google Scholar 

  94. Pearson, S. J., Ferguson, J., Santibanez-Koref, M. & Margison, G. P. Inhibition of O6-methylguanine-DNA methyltransferase by an alkyltransferase-like protein from Escherichia coli. Nucleic Acids Res. 33, 3837–3844 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Santos-Escobar, F., Leyva-Sanchez, H. C., Ramirez-Ramirez, N., Obregon-Herrera, A. & Pedraza-Reyes, M. Roles of Bacillus subtilis RecA, nucleotide excision repair, and translesion synthesis polymerases in counteracting CrVI-promoted DNA damage. J. Bacteriol. 201, e00073-19 (2019).

    PubMed  PubMed Central  Google Scholar 

  96. Rivas-Castillo, A. M., Yasbin, R. E., Robleto, E., Nicholson, W. L. & Pedraza-Reyes, M. Role of the Y-family DNA polymerases YqjH and YqjW in protecting sporulating Bacillus subtilis cells from DNA damage. Curr. Microbiol. 60, 263–267 (2010).

    CAS  PubMed  Google Scholar 

  97. Janel-Bintz, R., Napolitano, R. L., Isogawa, A., Fujii, S. & Fuchs, R. P. Processing closely spaced lesions during nucleotide excision repair triggers mutagenesis in E. coli. PLoS Genet. 13, e1006881 (2017).

    PubMed  PubMed Central  Google Scholar 

  98. Johnson, S. J. & Beese, L. S. Structures of mismatch replication errors observed in a DNA polymerase. Cell 116, 803–816 (2004).

    CAS  PubMed  Google Scholar 

  99. Su, S. S., Lahue, R. S., Au, K. G. & Modrich, P. Mispair specificity of methyl-directed DNA mismatch correction in vitro. J. Biol. Chem. 263, 6829–6835 (1988). This paper biochemically reconstitutes methyl-directed mismatch repair showing that for E. coli strand discrimination is signalled by the methylation state.

    CAS  PubMed  Google Scholar 

  100. Lenhart, J. S., Pillon, M. C., Guarne, A., Biteen, J. S. & Simmons, L. A. Mismatch repair in Gram-positive bacteria. Res. Microbiol. 167, 4–12 (2015).

    PubMed  Google Scholar 

  101. Modrich, P. Methyl-directed DNA mismatch correction. J. Biol. Chem. 264, 6597–6600 (1989).

    CAS  PubMed  Google Scholar 

  102. Putnam, C. D. Evolution of the methyl directed mismatch repair system in Escherichia coli. DNA Repair. 38, 32–41 (2016).

    CAS  PubMed  Google Scholar 

  103. Klocko, A. D. et al. Mismatch repair causes the dynamic release of an essential DNA polymerase from the replication fork. Mol. Microbiol. 82, 648–663 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Lenhart, J. S., Pillon, M. C., Guarne, A. & Simmons, L. A. Trapping and visualizing intermediate steps in the mismatch repair pathway in vivo. Mol. Microbiol. 90, 680–698 (2013).

    CAS  PubMed  Google Scholar 

  105. Lenhart, J. S., Sharma, A., Hingorani, M. M. & Simmons, L. A. DnaN clamp zones provide a platform for spatiotemporal coupling of mismatch detection to DNA replication. Mol. Microbiol. 87, 553–568 (2013).

    CAS  PubMed  Google Scholar 

  106. Liao, Y., Schroeder, J. W., Gao, B., Simmons, L. A. & Biteen, J. S. Single-molecule motions and interactions in live cells reveal target search dynamics in mismatch repair. Proc. Natl Acad. Sci. USA 112, E6898–E6906 (2015). This manuscript uses a single-molecule approach showing that MutS is recruited to search nascent DNA for mismatches at the replisome, and also shows that MutS tracks with replication forks in synchronized cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Lopez de Saro, F. J. & O’Donnell, M. Interaction of the beta sliding clamp with MutS, ligase, and DNA polymerase I. Proc. Natl Acad. Sci. USA 98, 8376–8380 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Dalrymple, B. P., Kongsuwan, K., Wijffels, G., Dixon, N. E. & Jennings, P. A. A universal protein–protein interaction motif in the eubacterial DNA replication and repair systems. Proc. Natl Acad. Sci. USA 98, 11627–11632 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Simmons, L. A., Davies, B. W., Grossman, A. D. & Walker, G. C. Beta clamp directs localization of mismatch repair in Bacillus subtilis. Mol. Cell 29, 291–301 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Chai, T., Terrettaz, C. & Collier, J. Spatial coupling between DNA replication and mismatch repair in Caulobacter crescentus. Nucleic Acids Res. 49, 3308–3321 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Kadyrov, F. A., Dzantiev, L., Constantin, N. & Modrich, P. Endonucleolytic function of MutLalpha in human mismatch repair. Cell 126, 297–308 (2006). This paper identifies the endonuclease active site in the human MutL homologue PMS2, and also demonstrates that the site is identical in organisms throughout biology including several bacterial MutL homologues.

    CAS  PubMed  Google Scholar 

  112. Pillon, M. C. et al. Structure of the endonuclease domain of MutL: unlicensed to cut. Mol. Cell 39, 145–151 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Pillon, M. C. et al. The sliding clamp tethers the endonuclease domain of MutL to DNA. Nucleic Acids Res. 43, 10746–10759 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Culligan, K. M., Meyer-Gauen, G., Lyons-Weiler, J. & Hays, J. B. Evolutionary origin, diversification and specialization of eukaryotic MutS homolog mismatch repair proteins. Nucleic Acids Res. 28, 463–471 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Sachadyn, P. Conservation and diversity of MutS proteins. Mutat. Res. 694, 20–30 (2010).

    CAS  PubMed  Google Scholar 

  116. Cole, S. T. et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544 (1998).

    CAS  PubMed  Google Scholar 

  117. Ishino, S. et al. Identification of a mismatch-specific endonuclease in hyperthermophilic Archaea. Nucleic Acids Res. 44, 2977–2986 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Castaneda-Garcia, A. et al. A non-canonical mismatch repair pathway in prokaryotes. Nat. Commun. 8, 14246 (2017). This work shows that EndoMS functions in mismatch correction in Mycobacterium, and shows conservation among other bacteria lacking the canonical mismatch repair proteins MutS and MutL.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Ishino, S. et al. Activation of the mismatch-specific endonuclease EndoMS/NucS by the replication clamp is required for high fidelity DNA replication. Nucleic Acids Res. 46, 6206–6217 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Takemoto, N., Numata, I., Su’etsugu, M. & Miyoshi-Akiyama, T. Bacterial EndoMS/NucS acts as a clamp-mediated mismatch endonuclease to prevent asymmetric accumulation of replication errors. Nucleic Acids Res. 46, 6152–6165 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Nakae, S. et al. Structure of the EndoMS–DNA complex as mismatch restriction endonuclease. Structure 24, 1960–1971 (2016).

    CAS  PubMed  Google Scholar 

  122. Zhang, L., Jiang, D., Wu, M., Yang, Z. & Oger, P. M. New Insights Into DNA repair revealed by NucS endonucleases from hyperthermophilic archaea. Front. Microbiol. 11, 1263 (2020).

    PubMed  PubMed Central  Google Scholar 

  123. Burby, P. E., Simmons, Z. W., Schroeder, J. W. & Simmons, L. A. Discovery of a dual protease mechanism that promotes DNA damage checkpoint recovery. PLoS Genet. 14, e1007512 (2018).

    PubMed  PubMed Central  Google Scholar 

  124. Burby, P. E. & Simmons, L. A. A bacterial DNA repair pathway specific to a natural antibiotic. Mol. Microbiol. 111, 338–353 (2019). This paper discovers a MMC repair pathway in B. subtilis mediated by newly characterized helicase MrfA and exonuclease MrfB.

    CAS  PubMed  Google Scholar 

  125. Burby, P. E., Simmons, Z. W. & Simmons, L. A. DdcA antagonizes a bacterial DNA damage checkpoint. Mol. Microbiol. 111, 237–253 (2019).

    CAS  PubMed  Google Scholar 

  126. Yakovleva, L. & Shuman, S. Mycobacterium smegmatis SftH exemplifies a distinctive clade of superfamily II DNA-dependent ATPases with 3′ to 5′ translocase and helicase activities. Nucleic Acids Res. 40, 7465–7475 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Bochman, M. L., Paeschke, K., Chan, A. & Zakian, V. A. Hrq1, a homolog of the human RecQ4 helicase, acts catalytically and structurally to promote genome integrity. Cell Rep. 6, 346–356 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Roske, J. J., Liu, S., Loll, B., Neu, U. & Wahl, M. C. A skipping rope translocation mechanism in a widespread family of DNA repair helicases. Nucleic Acids Res. 49, 504–518 (2021). This work solves the crystal structure for B. subtilis MrfA helicase, demonstrating a novel translocation mechanism.

    CAS  PubMed  Google Scholar 

  129. Amidon, K. M. & Eichman, B. F. Structural biology of DNA abasic site protection by SRAP proteins. DNA Repair. 94, 102903 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the referees for their helpful comments on this work. They also acknowledge that owing to space limitation many important studies and citations could not be included. Work in the authors’ laboratory was funded by the National Institutes of Health (NIH) grant GM131772 to L.A.S. K.J.W. was supported by funding from the NIH Cellular Biotechnology Training Grant (T32 GM008353) and a predoctoral fellowship from the National Science Foundation (NSF) (#DEG 1256260).

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Correspondence to Lyle A. Simmons.

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Nature Reviews Microbiology thanks Stewart Shuman; Umesh Varshney, who co-reviewed with Indu Kapoor; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Replication fork

Where the replicative machinery binds and synthesizes the leading and lagging DNA strands.

Photoreactivation

Direct reversal of pyrimidine dimers using photolyase.

Base excision repair

(BER). Repair of base damage and non-canonical bases using a DNA glycosylase.

Nucleotide excision repair

(NER). Repair of bulky, helix-distorting lesions within DNA following excision of an approximately 10–12-nucleotide patch.

Homologous recombination

Repair of a DNA break using homologous DNA.

Non-homologous end joining

The process by which two ends of DNA (from a double-stranded DNA break) with little to no homology are processed and joined together to repair the break.

Photoproducts

Bulky lesions resulting from UV damage.

δ-Elimination

Removal of the sugar moiety remaining after an apurinic/apyrimidinic (AP) site is created leaving behind phosphates on the 3′ and 5′ ends.

CH–π interactions

Non-covalent stacking interaction between the carbon–hydrogen bond of a nucleobase and an aromatic residue of a non-flipping DNA glycosylase that aids in cleavage of a glycosidic bond.

Nitrogen mustards

Non-specific DNA alkylating organic compounds.

Type II restriction systems

Enzymes that specifically recognize a site within DNA for methylation and cleavage.

π–π stacking

Non-covalent interactions between aromatic rings of a protein.

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Wozniak, K.J., Simmons, L.A. Bacterial DNA excision repair pathways. Nat Rev Microbiol 20, 465–477 (2022). https://doi.org/10.1038/s41579-022-00694-0

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