All tangled up: how cells direct, manage and exploit topoisomerase function

Article metrics

Abstract

Topoisomerases are complex molecular machines that modulate DNA topology to maintain chromosome superstructure and integrity. Although capable of stand-alone activity in vitro, topoisomerases are frequently linked to larger pathways and systems that resolve specific DNA superstructures and intermediates arising from cellular processes such as DNA repair, transcription, replication and chromosome compaction. Topoisomerase activity is indispensible to cells, but requires the transient breakage of DNA strands. This property has been exploited, often for significant clinical benefit, by various exogenous agents that interfere with cell proliferation. Despite decades of study, surprising findings involving topoisomerases continue to emerge with respect to their cellular function, regulation and utility as therapeutic targets.

Key Points

  • Topoisomerases are classified into several families, namely, types IA, IB, IC, IIA and IIB. These families have different cellular roles and preferential substrate specificities.

  • Topoisomerases are involved in a range of cellular nucleic acid transactions, including DNA replication, transcription, packaging, compaction, recombination and repair. Topoisomerases interact with various proteins in the cell to accomplish these tasks.

  • Post-translational modification of eukaryotic topoisomerases regulates their activation, localization and destruction.

  • Small molecules and proteins can inhibit topoisomerase activity at different stages of the topoisomerase catalytic cycle. Inhibition of topoisomerases has been exploited in therapeutics and in nature.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: DNA cleavage.
Figure 2: Type I topoisomerase mechanisms.
Figure 3: Type II topoisomerase mechanisms.
Figure 4: Topoisomerase functions during DNA replication.
Figure 5: Topoisomerase functions during transcription and DNA repair.
Figure 6: Inhibition or poisoning points for type II topoisomerases.

Change history

  • 07 December 2011

    In 'About the authors', James M. Berger's affiliation has been corrected from "California Institute for Quantitative Biology" to "California Institute for Quantitative Biosciences".

References

  1. 1

    Forterre, P., Gribaldo, S., Gadelle, D. & Serre, M. C. Origin and evolution of DNA topoisomerases. Biochimie 89, 427–446 (2007). A review that extensively covers the evolution of topoisomerases.

  2. 2

    Schoeffler, A. J. & Berger, J. M. DNA topoisomerases: harnessing and constraining energy to govern chromosome topology. Q. Rev. Biophys. 41, 41–101 (2008). A review that comprehensively describes the biochemical and structural nature of topoisomerases.

  3. 3

    Lima, C. D., Wang, J. C. & Mondragón, A. Three-dimensional structure of the 67K N-terminal fragment of E. coli DNA topoisomerase I. Nature 367, 138–146 (1994). A report detailing the first crystal structure of a type IA topoisomerase.

  4. 4

    Tse, Y. C., Kirkegaard, K. & Wang, J. C. Covalent bonds between protein and DNA. Formation of phosphotyrosine linkage between certain DNA topoisomerases and DNA. J. Biol. Chem. 255, 5560–5565 (1980).

  5. 5

    Brown, P. O. & Cozzarelli, N. R. Catenation and knotting of duplex DNA by type 1 topoisomerases: a mechanistic parallel with type 2 topoisomerases. Proc. Natl Acad. Sci. USA 78, 843–847 (1981).

  6. 6

    Wang, J. C. Interaction between DNA and an Escherichia coli protein omega. J. Mol. Biol. 55, 523–533 (1971). The first report of a purified topoisomerase activity.

  7. 7

    Hiasa, H., DiGate, R. J. & Marians, K. J. Decatenating activity of Escherichia coli DNA gyrase and topoisomerases I and III during oriC and pBR322 DNA replication in vitro. J. Biol. Chem. 269, 2093–2099 (1994).

  8. 8

    Wallis, J. W., Chrebet, G., Brodsky, G., Rolfe, M. & Rothstein, R. A hyper-recombination mutation in S. cerevisiae identifies a novel eukaryotic topoisomerase. Cell 58, 409–419 (1989). An article describing the discovery of eukaryotic topo III and its possible role in homologous recombination.

  9. 9

    Harmon, F. G., DiGate, R. J. & Kowalczykowski, S. C. RecQ helicase and topoisomerase III comprise a novel DNA strand passage function: a conserved mechanism for control of DNA recombination. Mol. Cell 3, 611–620 (1999). The first paper to link topo III and RecQ function.

  10. 10

    DiGate, R. J. & Marians, K. J. Identification of a potent decatenating enzyme from Escherichia coli. J. Biol. Chem. 263, 13366–13373 (1988). The first study to identify a decatenase activity for topo III.

  11. 11

    Lopez, C. R. et al. A role for topoisomerase III in a recombination pathway alternative to RuvABC. Mol. Microbiol. 58, 80–101 (2005).

  12. 12

    Kikuchi, A. & Asai, K. Reverse gyrase—a topoisomerase which introduces positive superhelical turns into DNA. Nature 309, 677–681 (1984). An investigation that identifies and characterizes reverse gyrase, a novel type IA topoisomerase that is found in thermophiles.

  13. 13

    Hsieh, T. & Plank, J. L. Reverse gyrase functions as a DNA renaturase. J. Biol. Chem. 281, 5640–5647 (2006).

  14. 14

    Redinbo, M. R., Stewart, L., Kuhn, P., Champoux, J. J. & Hol, W. G. Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA. Science 279, 1504–1513 (1998). A paper that reports the first eukaryotic type IB topoiosmerase structure. In this study, the enzyme is crystallized with and without DNA.

  15. 15

    Koster, D. A., Croquette, V., Dekker, C., Shuman, S. & Dekker, N. H. Friction and torque govern the relaxation of DNA supercoils by eukaryotic topoisomerase IB. Nature 434, 671–674 (2005). A report describing the detailed mechanism of topo IB, elucidated through elegant single-molecule experiments.

  16. 16

    Champoux, J. J. & Dulbecco, R. An activity from mammalian cells that untwists superhelical DNA—a possible swivel for DNA replication (polyoma-ethidium bromide-mouse-embryo cells-dye binding assay). Proc. Natl Acad. Sci. USA 69, 143–146 (1972). The first paper to report the discovery of topo IB.

  17. 17

    Madden, K. R., Stewart, L. & Champoux, J. J. Preferential binding of human topoisomerase I to superhelical DNA. EMBO J. 14, 5399–5409 (1995).

  18. 18

    Frohlich, R. F. et al. Tryptophan-205 of human topoisomerase I is essential for camptothecin inhibition of negative but not positive supercoil removal. Nucleic Acids Res. 35, 6170–6180 (2007).

  19. 19

    Patel, A., Yakovleva, L., Shuman, S. & Mondragón, A. Crystal structure of a bacterial topoisomerase IB in complex with DNA reveals a secondary DNA binding site. Structure 18, 725–733 (2010).

  20. 20

    Stewart, L., Redinbo, M. R., Qiu, X., Hol, W. G. & Champoux, J. J. A model for the mechanism of human topoisomerase I. Science 279, 1534–1541 (1998). Using structural information, the authors propose a detailed mechanism for type IB topoisomerase activity.

  21. 21

    Cheng, C., Kussie, P., Pavletich, N. & Shuman, S. Conservation of structure and mechanism between eukaryotic topoisomerase I and site-specific recombinases. Cell 92, 841–850 (1998).

  22. 22

    Krogh, B. O. & Shuman, S. A poxvirus-like type IB topoisomerase family in bacteria. Proc. Natl Acad. Sci. USA 99, 1853–1858 (2002).

  23. 23

    Forterre, P. DNA topoisomerase V: a new fold of mysterious origin. Trends Biotechnol. 24, 245–247 (2006).

  24. 24

    Taneja, B., Schnurr, B., Slesarev, A., Marko, J. F. & Mondragón, A. Topoisomerase V relaxes supercoiled DNA by a constrained swiveling mechanism. Proc. Natl Acad. Sci. USA 104, 14670–14675 (2007).

  25. 25

    Slesarev, A. I. et al. DNA topoisomerase V is a relative of eukaryotic topoisomerase I from a hyperthermophilic prokaryote. Nature 364, 735–737 (1993). The study that discovers topo IC.

  26. 26

    Taneja, B., Patel, A., Slesarev, A. & Mondragon, A. Structure of the N-terminal fragment of topoisomerase V reveals a new family of topoisomerases. EMBO J. 25, 398–408 (2006).

  27. 27

    Belova, G. I. et al. A type IB topoisomerase with DNA repair activities. Proc. Natl Acad. Sci. USA 98, 6015–6020 (2001).

  28. 28

    Aravind, L., Leipe, D. D. & Koonin, E. V. Toprim—a conserved catalytic domain in type IA and II topoisomerases, DnaG-type primases, OLD family nucleases and RecR proteins. Nucleic Acids Res. 26, 4205–4213 (1998). Work showing that many nucleotidyl transferases, topoisomerases and nucleases share a catalytic domain known as the Toprim domain.

  29. 29

    Berger, J. M., Fass, D., Wang, J. C. & Harrison, S. C. Structural similarities between topoisomerases that cleave one or both DNA strands. Proc. Natl Acad. Sci. USA 95, 7876–7881 (1998). A paper that identifies similarities between the DNA interaction regions of type IA and type II topoisomerases, suggesting that the enzymes have a common DNA cleavage mechanism.

  30. 30

    Liu, L. F., Liu, C. C. & Alberts, B. M. Type II DNA topoisomerases: enzymes that can unknot a topologically knotted DNA molecule via a reversible double-strand break. Cell 19, 697–707 (1980).

  31. 31

    Brown, P. O. & Cozzarelli, N. R. A sign inversion mechanism for enzymatic supercoiling of DNA. Science 206, 1081–1083 (1979).

  32. 32

    Mizuuchi, K., Fisher, L. M., O'Dea, M. H. & Gellert, M. DNA gyrase action involves the introduction of transient double-strand breaks into DNA. Proc. Natl Acad. Sci. USA 77, 1847–1851 (1980).

  33. 33

    Gellert, M., Mizuuchi, K., O'Dea, M. H. & Nash, H. A. DNA gyrase: an enzyme that introduces superhelical turns into DNA. Proc. Natl Acad. Sci. USA 73, 3872–3876 (1976). The first investigation to discover a type II topoisomerase.

  34. 34

    Goto, T. & Wang, J. C. Yeast DNA topoisomerase II. An ATP-dependent type II topoisomerase that catalyzes the catenation, decatenation, unknotting, and relaxation of double-stranded DNA rings. J. Biol. Chem. 257, 5866–5872 (1982).

  35. 35

    Hsieh, T. & Brutlag, D. ATP-dependent DNA topoisonmerase from D. melanogaster reversibly catenates duplex DNA rings. Cell 21, 115–125 (1980).

  36. 36

    Peng, H. & Marians, K. J. Decatenation activity of topoisomerase IV during oriC and pBR322 DNA replication in vitro. Proc. Natl Acad. Sci. USA 90, 8571–8575 (1993).

  37. 37

    Zechiedrich, E. & Cozzarelli, N. Roles of topoisomerase IV and DNA gyrase in DNA unlinking during replication in Escherichia coli. Genes Dev. 9, 2859–2869 (1995). A study that defines distinct roles of topo IV and gyrase during bacterial DNA replication.

  38. 38

    Crisona, N. J., Strick, T. R., Bensimon, D., Croquette, V. & Cozzarelli, N. R. Preferential relaxation of positively supercoiled DNA by E. coli topoisomerase IV in single-molecule and ensemble measurements. Genes Dev. 14, 2881–2892 (2000).

  39. 39

    McClendon, A. K., Rodriguez, A. C. & Osheroff, N. Human topoisomerase II α rapidly relaxes positively supercoiled DNA: implications for enzyme action ahead of replication forks. J. Biol. Chem. 280, 39337–39345 (2005).

  40. 40

    Baxter, J. et al. Positive supercoiling of mitotic DNA drives decatenation by topoisomerase II in eukaryotes. Science 331, 1328–1332 (2011). A paper that suggests that positive supercoiling drives topoisomerase II decatenation activity.

  41. 41

    Dong, K. C. & Berger, J. M. Structural basis for gate-DNA recognition and bending by type IIA topoisomerases. Nature 450, 1201–1205 (2007). The first DNA-bound type IIA topoisomerase structure, described in this article, shows a bent DNA conformation, confirming previous models.

  42. 42

    Laponogov, I. et al. Structural basis of gate-DNA breakage and resealing by type II topoisomerases. PLoS ONE 5, e11338 (2010). A paper reporting the structure of a ternary topo–DNA–quinolone complex, showing that the quinolone intercalates between the +1 and −1 bases at each of two active sites.

  43. 43

    Vologodskii, A. V. et al. Mechanism of topology simplification by type II DNA topoisomerases. Proc. Natl Acad. Sci. USA 98, 3045–3049 (2001). An article that proposes a model for DNA bending by type II topoisomerases to account for topology simplification below the expected thermodynamic equilibrium value.

  44. 44

    Charvin, G., Bensimon, D. & Croquette, V. Single-molecule study of DNA unlinking by eukaryotic and prokaryotic type-II topoisomerases. Proc. Natl Acad. Sci. USA 100, 9820–9825 (2003).

  45. 45

    Roca, J. & Wang, J. C. The probabilities of supercoil removal and decatenation by yeast DNA topoisomerase II. Genes Cells 1, 17–27 (1996).

  46. 46

    Bergerat, A. et al. An atypical topoisomerase II from archaea with implications for meiotic recombination. Nature 386, 414–417 (1997).

  47. 47

    Malik, S. B., Ramesh, M. A., Hulstrand, A. M. & Logsdon, J. M. Jr. Protist homologs of the meiotic Spo11 gene and topoisomerase VI reveal an evolutionary history of gene duplication and lineage-specific loss. Mol. Biol. Evol. 24, 2827–2841 (2007).

  48. 48

    Bergerat, A., Gadelle, D. & Forterre, P. Purification of a DNA topoisomerase II from the hyperthermophilic archaeon Sulfolobus shibatae. A thermostable enzyme with both bacterial and eucaryal features. J. Biol. Chem. 269, 27663–27669 (1994). A report detailing the discovery of the first type IIB topoisomerase.

  49. 49

    Corbett, K. D. & Berger, J. M. Structure of the topoisomerase VI-B subunit: implications for type II topoisomerase mechanism and evolution. EMBO J. 22, 151–163 (2003).

  50. 50

    Nichols, M. D., DeAngelis, K., Keck, J. L. & Berger, J. M. Structure and function of an archaeal topoisomerase VI subunit with homology to the meiotic recombination factor Spo11. EMBO J. 18, 6177–6188 (1999).

  51. 51

    Corbett, K. D., Benedetti, P. & Berger, J. M. Holoenzyme assembly and ATP-mediated conformational dynamics of topoisomerase VI. Nature Struct. Mol. Biol. 14, 611–619 (2007). The first paper to describe a full-length type IIB topoisomerase structure. The study described also uses small-angle X-ray scattering to image nucleotide-mediated conformational changes in the enzyme.

  52. 52

    Keeney, S., Giroux, C. N. & Kleckner, N. Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell 88, 375–384 (1997). Together with reference 46, work linking a topo II-like protein, Spo11 of S. cerevisiae , to the formation of double-strand DNA breaks during meiosis.

  53. 53

    Luijsterburg, M. S., White, M. F., van Driel, R. & Dame, R. T. The major architects of chromatin: architectural proteins in bacteria, archaea and eukaryotes. Crit. Rev. Biochem. Mol. Biol. 43, 393–418 (2008).

  54. 54

    Boles, T. C., White, J. H. & Cozzarelli, N. R. Structure of plectonemically supercoiled DNA. J. Mol. Biol. 213, 931–951 (1990).

  55. 55

    Zechiedrich, E. L. et al. Roles of topoisomerases in maintaining steady-state DNA supercoiling in Escherichia coli. J. Biol. Chem. 275, 8103–8113 (2000).

  56. 56

    McClelland, M. et al. Complete genome sequence of Salmonella enterica serovar Typhimurium LT2. Nature 413, 852–856 (2001).

  57. 57

    Champion, K. & Higgins, N. P. Growth rate toxicity phenotypes and homeostatic supercoil control differentiate Escherichia coli from Salmonella enterica serovar Typhimurium. J. Bacteriol. 189, 5839–5849 (2007). An article showing that distinct differences in overall supercoiling densities between two closely related species are directly linked to small differences in gyrase.

  58. 58

    Tretter, E. M., Lerman, J. C. & Berger, J. M. A naturally chimeric type IIA topoisomerase in Aquifex aeolicus highlights an evolutionary path for the emergence of functional paralogs. Proc. Natl Acad. Sci. USA 107, 22055–22059 (2010).

  59. 59

    Brochier-Armanet, C. & Forterre, P. Widespread distribution of archaeal reverse gyrase in thermophilic bacteria suggests a complex history of vertical inheritance and lateral gene transfers. Archaea 2, 83–93 (2007).

  60. 60

    Forterre, P., Mirambeau, G., Jaxel, C., Nadal, M. & Duguet, M. High positive supercoiling in vitro catalyzed by an ATP and polyethylene glycol-stimulated topoisomerase from Sulfolobus acidocaldarius. EMBO J. 4, 2123–2128 (1985).

  61. 61

    Perugino, G., Valenti, A., D'Amaro, A., Rossi, M. & Ciaramella, M. Reverse gyrase and genome stability in hyperthermophilic organisms. Biochem. Soc. Trans. 37, 69–73 (2009).

  62. 62

    Charbonnier, F. & Forterre, P. Comparison of plasmid DNA topology among mesophilic and thermophilic eubacteria and archaebacteria. J. Bacteriol. 176, 1251–1259 (1994).

  63. 63

    Tadesse, S., Mascarenhas, J., Koesters, B., Hasilik, A. & Graumann, P. L. Genetic interaction of the SMC complex with topoisomerase IV in Bacillus subtilis. Microbiology 151, 1–9 (2005).

  64. 64

    Hayama, R. & Marians, K. J. Physical and functional interaction between the condensin MukB and the decatenase topoisomerase IV in Escherichia coli. Proc. Natl Acad. Sci. USA 107, 18826–18831 (2010).

  65. 65

    Li, Y. et al. Escherichia coli condensin MukB stimulates topoisomerase IV activity by a direct physical interaction. Proc. Natl Acad. Sci. USA 107, 18832–18837 (2010).

  66. 66

    Bhat, M. A., Philp, A. V., Glover, D. M. & Bellen, H. J. Chromatid segregation at anaphase requires the barren product, a novel chromosome-associated protein that interacts with Topoisomerase II. Cell 87, 1103–1114 (1996).

  67. 67

    Maeshima, K. & Laemmli, U. K. A two-step scaffolding model for mitotic chromosome assembly. Dev. Cell 4, 467–480 (2003).

  68. 68

    Hirano, T. At the heart of the chromosome: SMC proteins in action. Nature Rev. Mol. Cell Biol. 7, 311–322 (2006).

  69. 69

    Bhalla, N., Biggins, S. & Murray, A. W. Mutation of YCS4, a budding yeast condensin subunit, affects mitotic and nonmitotic chromosome behavior. Mol. Biol. Cell 13, 632–645 (2002).

  70. 70

    Hartung, F. et al. An archaebacterial topoisomerase homolog not present in other eukaryotes is indispensable for cell proliferation of plants. Curr. Biol. 12, 1787–1791 (2002).

  71. 71

    Sugimoto-Shirasu, K., Stacey, N. J., Corsar, J., Roberts, K. & McCann, M. C. DNA topoisomerase VI is essential for endoreduplication in Arabidopsis. Curr. Biol. 12, 1782–1786 (2002).

  72. 72

    Yin, Y. et al. A crucial role for the putative Arabidopsis topoisomerase VI in plant growth and development. Proc. Natl Acad. Sci. USA 99, 10191–10196 (2002).

  73. 73

    Breuer, C. et al. BIN4, a novel component of the plant DNA topoisomerase VI complex, is required for endoreduplication in Arabidopsis. Plant Cell 19, 3655–3668 (2007).

  74. 74

    Lee, H. O., Davidson, J. M. & Duronio, R. J. Endoreplication: polyploidy with purpose. Genes Dev. 23, 2461–2477 (2009).

  75. 75

    Sugimoto-Shirasu, K. et al. RHL1 is an essential component of the plant DNA topoisomerase VI complex and is required for ploidy-dependent cell growth. Proc. Natl Acad. Sci. USA 102, 18736–18741 (2005).

  76. 76

    Rosa, I. D. et al. Adaptation of topoisomerase I paralogs to nuclear and mitochondrial DNA. Nucleic Acids Res. 37, 6414–6428 (2009).

  77. 77

    Zhang, H. & Pommier, Y. Mitochondrial topoisomerase I sites in the regulatory D-Loop region of mitochondrial DNA. Biochemistry 47, 11196–11203 (2008).

  78. 78

    Kaguni, J. M. & Kornberg, A. Topoisomerase I confers specificity in enzymatic replication of the Escherichia coli chromosomal origin. J. Biol. Chem. 259, 8578–8583 (1984).

  79. 79

    Hiasa, H. & Marians, K. J. Topoisomerase IV can support oriC DNA replication in vitro. J. Biol. Chem. 269, 16371–16375 (1994).

  80. 80

    Abdurashidova, G. et al. Functional interactions of DNA topoisomerases with a human replication origin. EMBO J. 26, 998–1009 (2007).

  81. 81

    Lyu, Y. L. et al. Role of topoisomerase IIβ in the expression of developmentally regulated genes. Mol. Cell. Biol. 26, 7929–7941 (2006).

  82. 82

    Yang, X., Li, W., Prescott, E. D., Burden, S. J. & Wang, J. C. DNA topoisomerase IIβ and neural development. Science 287, 131–134 (2000).

  83. 83

    Ju, B. G. et al. A topoisomerase IIβ-mediated dsDNA break required for regulated transcription. Science 312, 1798–1802 (2006). A paper that links topo II β-dependent double-strand DNA breaks with the DNA damage and repair enzyme PARP1 in transcription regulation.

  84. 84

    Rampakakis, E. & Zannis-Hadjopoulos, M. Transient dsDNA breaks during pre-replication complex assembly. Nucleic Acids Res. 37, 5714–5724 (2009).

  85. 85

    Wang, X., Lesterlin, C., Reyes-Lamothe, R., Ball, G. & Sherratt, D. J. Replication and segregation of an Escherichia coli chromosome with two replication origins. Proc. Natl Acad. Sci. USA 108, e243–e250 (2011).

  86. 86

    Khodursky, A. B. et al. Analysis of topoisomerase function in bacterial replication fork movement: use of DNA microarrays. Proc. Natl Acad. Sci. USA 97, 9419–9424 (2000).

  87. 87

    Hiasa, H. & Marians, K. J. Two distinct modes of strand unlinking during θ-type DNA replication. J. Biol. Chem. 271, 21529–21535 (1996).

  88. 88

    Brill, S. J., DiNardo, S., Voelkel-Meiman, K. & Sternglanz, R. Need for DNA topoisomerase activity as a swivel for DNA replication for transcription of ribosomal RNA. Nature 326, 414–416 (1987).

  89. 89

    Kim, R. A. & Wang, J. C. Function of DNA topoisomerases as replication swivels in Saccharomyces cerevisiae. J. Mol. Biol. 208, 257–267 (1989).

  90. 90

    Yang, L., Wold, M. S., Li, J. J., Kelly, T. J. & Liu, L. F. Roles of DNA topoisomerases in simian virus 40 DNA replication in vitro. Proc. Natl Acad. Sci. USA 84, 950–954 (1987).

  91. 91

    Kegel, A. et al. Chromosome length influences replication-induced topological stress. Nature 471, 392–396 (2011). A report presenting the finding that chromosome length determines the need for release and development of superhelical tension in eukaryotes.

  92. 92

    Champoux, J. & Been, M. in Mechanistic Studies of DNA Replication and Recombination: ICN–UCLA Symposia on Molecular and Cellular Biology Vol.19 (ed. Alberts, B. M.) 809–815 (Academic, New York, 1980).

  93. 93

    Peter, B. J., Ullsperger, C., Hiasa, H., Marians, K. J. & Cozzarelli, N. R. The structure of supercoiled intermediates in DNA replication. Cell 94, 819–827 (1998). Work showing that replication-dependent supercoiling is spread throughout both nascent and unreplicated DNA, and supercoiling is not localized.

  94. 94

    Holm, C., Goto, T., Wang, J. C. & Botstein, D. DNA topoisomerase II is required at the time of mitosis in yeast. Cell 41, 553–563 (1985).

  95. 95

    Uemura, T. & Yanagida, M. Isolation of type I and II DNA topoisomerase mutants from fission yeast: single and double mutants show different phenotypes in cell growth and chromatin organization. EMBO J. 3, 1737–1744 (1984).

  96. 96

    Baxter, J. & Diffley, J. F. Topoisomerase II inactivation prevents the completion of DNA replication in budding yeast. Mol. Cell 30, 790–802 (2008). A study that shows that topo II depletion and inhibition kill eukaryotic cells by two distinct mechanisms.

  97. 97

    Uemura, T. et al. DNA topoisomerase II is required for condensation and separation of mitotic chromosomes in S. pombe. Cell 50, 917–925 (1987). Research demonstrating that, in addition to their role in chromosome decatenation, type II topoisomerases are required for condensation of chromosomes prior to segregation.

  98. 98

    Adams, D. E., Shekhtman, E. M., Zechiedrich, E. L., Schmid, M. B. & Cozzarelli, N. R. The role of topoisomerase IV in partitioning bacterial replicons and the structure of catenated intermediates in DNA replication. Cell 71, 277–288 (1992). The first paper to report that topo IV is responsible for unlinking of daughter chromosomes prior to cell division in bacteria.

  99. 99

    Holm, C., Stearns, T. & Botstein, D. DNA topoisomerase II must act at mitosis to prevent nondisjunction and chromosome breakage. Mol. Cell. Biol. 9, 159–168 (1989).

  100. 100

    DiNardo, S., Voelkel, K. & Sternglanz, R. DNA topoisomerase II mutant of Saccharomyces cerevisiae: topoisomerase II is required for segregation of daughter molecules at the termination of DNA replication. Proc. Natl Acad. Sci. USA 81, 2616–2620 (1984). A study that identifies the essential role of type II topoisomerases for resolving sister chromosmes after DNA replication prior to cell segregation in eukaryotes.

  101. 101

    Uemura, T. & Yanagida, M. Mitotic spindle pulls but fails to separate chromosomes in type II DNA topoisomerase mutants: uncoordinated mitosis. EMBO J. 5, 1003–1010 (1986).

  102. 102

    Nurse, P., Levine, C., Hassing, H. & Marians, K. J. Topoisomerase III can serve as the cellular decatenase in Escherichia coli. J. Biol. Chem. 278, 8653–8660 (2003). A paper showing that overexpression of topo III compensates for the loss of topo IV and thus can act as the main cellular decatenase.

  103. 103

    Suski, C. & Marians, K. J. Resolution of converging replication forks by RecQ and topoisomerase III. Mol. Cell 30, 779–789 (2008). An article that provides the first evidence that RecQ helicases and topo III collaborate to resolve converging replication forks.

  104. 104

    Chang, M. et al. RMI1/NCE4, a suppressor of genome instability, encodes a member of the RecQ helicase/Topo III complex. EMBO J. 24, 2024–2033 (2005).

  105. 105

    Xu, D. et al. RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability. Genes Dev. 22, 2843–2855 (2008). A study that identifies another single-stranded-DNA-binding protein, RMI1, that associates with the topo III–RecQ helicase complex. The interaction of RMI1 with the topo III–RecQ helicase complex diminishes and regulates sister chromosome exchange during homologous recombination.

  106. 106

    Chan, K. L., North, P. S. & Hickson, I. D. BLM is required for faithful chromosome segregation and its localization defines a class of ultrafine anaphase bridges. EMBO J. 26, 3397–3409 (2007). A study finding that ultrafine anaphase bridges form at a higher frequency when the helicase BLM is absent, suggesting a role for BLM dependent topo III localization for appropriate segregation of sister chromosomes.

  107. 107

    Confalonieri, F. et al. Reverse gyrase: a helicase-like domain and a type I topoisomerase in the same polypeptide. Proc. Natl Acad. Sci. USA 90, 4753–4757 (1993).

  108. 108

    Déclais, A. C., Marsault, J., Confalonieri, F., de La Tour, C. B. & Duguet, M. Reverse gyrase, the two domains intimately cooperate to promote positive supercoiling. J. Biol. Chem. 275, 19498–19504 (2000).

  109. 109

    Valjavec-Gratian, M., Henderson, T. A. & Hill, T. M. Tus-mediated arrest of DNA replication in Escherichia coli is modulated by DNA supercoiling. Mol. Microbiol. 58, 758–773 (2005).

  110. 110

    Fachinetti, D. et al. Replication termination at eukaryotic chromosomes is mediated by Top2 and occurs at genomic loci containing pausing elements. Mol. Cell 39, 595–605 (2010).

  111. 111

    Crozat, E. & Grainge, I. FtsK DNA translocase: the fast motor that knows where it's going. Chembiochem 11, 2232–2243 (2010).

  112. 112

    Bigot, S. & Marians, K. J. DNA chirality-dependent stimulation of topoisomerase IV activity by the C-terminal AAA+ domain of FtsK. Nucleic Acids Res. 38, 3031–3040 (2010).

  113. 113

    Espeli, O., Lee, C. & Marians, K. J. A physical and functional interaction between Escherichia coli FtsK and topoisomerase IV. J. Biol. Chem. 278, 44639–44644 (2003).

  114. 114

    Madabhushi, R. & Marians, K. J. Actin homolog MreB affects chromosome segregation by regulating topoisomerase IV in Escherichia coli. Mol. Cell 33, 171–180 (2009).

  115. 115

    Coelho, P. A. et al. Dual role of topoisomerase II in centromere resolution and aurora B activity. PLoS Biol. 6, e207 (2008).

  116. 116

    Li, H., Wang, Y. & Liu, X. Plk1-dependent phosphorylation regulates functions of DNA topoisomerase IIα in cell cycle progression. J. Biol. Chem. 283, 6209–6221 (2008).

  117. 117

    Espeli, O., Levine, C., Hassing, H. & Marians, K. J. Temporal regulation of topoisomerase IV activity in E. coli. Mol. Cell 11, 189–201 (2003).

  118. 118

    Kang, S., Han, J., Park, J., Skarstad, K. & Wang, D. H. SeqA protein stimulates the relaxing and decatenating activities of topoisomerase IV. J. Biol. Chem. 278, 48779–48785 (2003).

  119. 119

    Liu, L. F. & Wang, J. C. Supercoiling of the DNA template during transcription. Proc. Natl Acad. Sci. USA 84, 7024–7027 (1987). A paper presenting the first evidence of DNA supercoiling induced by a translocating motor protein.

  120. 120

    Wu, H. Y., Shyy, S. H., Wang, J. C. & Liu, L. F. Transcription generates positively and negatively supercoiled domains in the template. Cell 53, 433–440 (1988). An article providing experimental evidence that transcription results in the formation of positive supercoils ahead of the RNA polymerase, and negative supercoils behind it.

  121. 121

    Blot, N., Mavathur, R., Geertz, M., Travers, A. & Muskhelishvili, G. Homeostatic regulation of supercoiling sensitivity coordinates transcription of the bacterial genome. EMBO Rep. 7, 710–715 (2006).

  122. 122

    Drolet, M., Bi, X. & Liu, L. F. Hypernegative supercoiling of the DNA template during transcription elongation in vitro. J. Biol. Chem. 269, 2068–2074 (1994).

  123. 123

    Tuduri, S. et al. Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription. Nature Cell Biol. 11, 1315–1324 (2009).

  124. 124

    Drolet, M. et al. Overexpression of RNase H partially complements the growth defect of an Escherichia coli ΔtopA mutant: R-loop formation is a major problem in the absence of DNA topoisomerase I. Proc. Natl Acad. Sci. USA 92, 3526–3530 (1995).

  125. 125

    Massé, E. & Drolet, M. Relaxation of transcription-induced negative supercoiling is an essential function of Escherichia coli DNA topoisomerase I. J. Biol. Chem. 274, 16654–16658 (1999).

  126. 126

    Cheng, B., Zhu, C. X., Ji, C., Ahumada, A. & Tse-Dinh, Y. C. Direct interaction between Escherichia coli RNA polymerase and the zinc ribbon domains of DNA topoisomerase I. J. Biol. Chem. 278, 30705–30710 (2003).

  127. 127

    Merino, A., Madden, K. R., Lane, W. S., Champoux, J. J. & Reinberg, D. DNA topoisomerase I is involved in both repression and activation of transcription. Nature 365, 227–232 (1993).

  128. 128

    Mondal, N. et al. Elongation by RNA polymerase II on chromatin templates requires topoisomerase activity. Nucleic Acids Res. 31, 5016–5024 (2003).

  129. 129

    Durand-Dubief, M., Persson, J., Norman, U., Hartsuiker, E. & Ekwall, K. Topoisomerase I regulates open chromatin and controls gene expression in vivo. EMBO J. 29, 2126–2134 (2010).

  130. 130

    Lotito, L. et al. Global transcription regulation by DNA topoisomerase I in exponentially growing Saccharomyces cerevisiae cells: activation of telomere-proximal genes by TOP1 deletion. J. Mol. Biol. 377, 311–322 (2008).

  131. 131

    Rossi, F. et al. Specific phosphorylation of SR proteins by mammalian DNA topoisomerase I. Nature 381, 80–82 (1996). The first report of a topo IB-associated kinase activity for SR proteins.

  132. 132

    Juge, F., Fernando, C., Fic, W. & Tazi, J. The SR protein B52/SRp55 is required for DNA topoisomerase I recruitment to chromatin, mRNA release and transcription shutdown. PLoS Genet. 6, e1001124 (2010).

  133. 133

    Malanga, M., Czubaty, A., Girstun, A., Staron, K. & Althaus, F. R. Poly(ADP-ribose) binds to the splicing factor ASF/SF2 and regulates its phosphorylation by DNA topoisomerase I. J. Biol. Chem. 283, 19991–19998 (2008).

  134. 134

    Mcnamara, S., Wang, H., Hanna, N. & Miller, W. Topoisomerase IIβ negatively modulates retinoic acid receptor a function: a novel mechanism of retinoic acid resistance. Mol. Cell. Biol. 28, 2066–2077 (2008).

  135. 135

    Peciña, A. et al. Targeted stimulation of meiotic recombination. Cell 111, 173–184 (2002).

  136. 136

    Keeney, S. Spo11 and the formation of DNA double-strand breaks in meiosis. Genome Dyn. Stab. 2, 81–123 (2008).

  137. 137

    Neale, M. J., Pan, J. & Keeney, S. Endonucleolytic processing of covalent protein-linked double-strand breaks. Nature 436, 1053–1057 (2005). An article describing how Spo11 is removed from chromosome ends to permit homologous recombination to occur in S. cerevisiae.

  138. 138

    Li, W. & Ma, H. Double-stranded DNA breaks and gene functions in recombination and meiosis. Cell Res. 16, 402–412 (2006).

  139. 139

    Baudat, F., Manova, K., Yuen, J. P., Jasin, M. & Keeney, S. Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Mol. Cell 6, 989–998 (2000).

  140. 140

    Hartsuiker, E. et al. Ctp1 CtIP and Rad32 Mre11 nuclease activity are required for Rec12 Spo11 removal, but Rec12 Spo11 removal is dispensable for other MRN-dependent meiotic functions. Mol. Cell. Biol. 29, 1671–1681 (2009).

  141. 141

    Lu, W. J., Chapo, J., Roig, I. & Abrams, J. M. Meiotic recombination provokes functional activation of the p53 regulatory network. Science 328, 1278–1281 (2010). A recent paper that highlights the role of p53 in SPO11-mediated homologous recombination.

  142. 142

    Cliby, W. A. S. Phase and G2 arrests induced by topoisomerase I poisons are dependent on ATR kinase function. J. Biol. Chem. 277, 1599–1606 (2002).

  143. 143

    Treszezamsky, A. D. et al. BRCA1- and BRCA2-deficient cells are sensitive to etoposide-induced DNA double-strand breaks via topoisomerase II. Cancer Res. 67, 7078–7081 (2007).

  144. 144

    Lin, C. P., Ban, Y., Lyu, Y. L. & Liu, L. F. Proteasome-dependent processing of topoisomerase I-DNA adducts into DNA double strand breaks at arrested replication forks. J. Biol. Chem. 284, 28084–28092 (2009).

  145. 145

    Mao, Y., Sun, M., Desai, S. D. & Liu, L. F. SUMO-1 conjugation to topoisomerase I: a possible repair response to topoisomerase-mediated DNA damage. Proc. Natl Acad. Sci. USA 97, 4046–4051 (2000).

  146. 146

    Mao, Y., Desai, S. D., Ting, C. Y., Hwang, J. & Liu, L. F. 26 S proteasome-mediated degradation of topoisomerase II cleavable complexes. J. Biol. Chem. 276, 40652–40658 (2001).

  147. 147

    Pouliot, J. J., Yao, K. C., Robertson, C. A. & Nash, H. A. Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes. Science 286, 552–555 (1999). A paper reporting the discovery of yeast Tdp1, a repair protein that removes covalently attached topo IB from DNA ends.

  148. 148

    Nitiss, K. C., Malik, M., He, X., White, S. W. & Nitiss, J. L. Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage. Proc. Natl Acad. Sci. USA 103, 8953–8958 (2006).

  149. 149

    Cortes Ledesma, F., El Khamisy, S. F., Zuma, M. C., Osborn, K. & Caldecott, K. W. A human 5′-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage. Nature 461, 674–678 (2009).

  150. 150

    Zeng, Z., Cortes-Ledesma, F., El Khamisy, S. F. & Caldecott, K. W. TDP2/TTRAP is the major 5′-tyrosyl DNA phosphodiesterase activity in vertebrate cells and is critical for cellular resistance to topoisomerase II-induced DNA damage. J. Biol. Chem. 286, 403–409 (2011).

  151. 151

    Mao, Y., Desai, S. D. & Liu, L. F. SUMO-1 conjugation to human DNA topoisomerase II isozymes. J. Biol. Chem. 275, 26066–26073 (2000).

  152. 152

    Desai, S. D., Liu, L. F., Vazquez-Abad, D. & D'Arpa, P. Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. J. Biol. Chem. 272, 24159–24164 (1997).

  153. 153

    Sordet, O. et al. Hyperphosphorylation of RNA polymerase II in response to topoisomerase I cleavage complexes and its association with transcription- and BRCA1-dependent degradation of topoisomerase I. J. Mol. Biol. 381, 540–549 (2008).

  154. 154

    Desai, S. D. et al. Transcription-dependent degradation of topoisomerase I-DNA covalent complexes. Mol. Cell. Biol. 23, 2341–2350 (2003).

  155. 155

    Xiao, H. et al. The topoisomerase IIβ circular clamp arrests transcription and signals a 26S proteasome pathway. Proc. Natl Acad. Sci. USA 100, 3239–3244 (2003).

  156. 156

    Datta, A. & Jinks-Robertson, S. Association of increased spontaneous mutation rates with high levels of transcription in yeast. Science 268, 1616–1619 (1995).

  157. 157

    Lippert, M. J. et al. Role for topoisomerase 1 in transcription-associated mutagenesis in yeast. Proc. Natl Acad. Sci. USA 108, 698–703 (2011).

  158. 158

    Takahashi, T., Burguiere-Slezak, G., Van der Kemp, P. A. & Boiteux, S. Topoisomerase 1 provokes the formation of short deletions in repeated sequences upon high transcription in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 108, 692–697 (2011). Together with reference 157, the first reports on transcription-mediated genomic deletions that are a result of topo IB action.

  159. 159

    Kim, N. et al. Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I. Science 332, 1561–1564 (2011). A recent paper that is the first to report the mutagenic role of topo IB in the removal of genomically misincorpated ribonucleotides.

  160. 160

    Wang, Y., Knudsen, B. R., Bjergbaek, L., Westergaard, O. & Andersen, A. H. Stimulated activity of human topoisomerases IIα and IIβ on RNA-containing substrates. J. Biol. Chem. 274, 22839–22846 (1999).

  161. 161

    Deweese, J. E. & Osheroff, N. Coordinating the two protomer active sites of human topoisomerase IIα: nicks as topoisomerase II poisons. Biochemistry 48, 1439–1441 (2009).

  162. 162

    Sayer, J., Jerina, D. & Shuman, S. Individual nucleotide bases, not base pairs, are critical for triggering site-specific DNA cleavage by vaccinia topoisomerase. J. Biol. Chem. 39718–39726 (2004).

  163. 163

    Kingma, P. S. & Osheroff, N. Apurinic sites are position-specific topoisomerase II poisons. J. Biol. Chem. 272, 1148–1155 (1997).

  164. 164

    Kingma, P. S. & Osheroff, N. Spontaneous DNA damage stimulates topoisomerase II-mediated DNA cleavage. J. Biol. Chem. 272, 7488–7493 (1997).

  165. 165

    Ira, G., Malkova, A., Liberi, G., Foiani, M. & Haber, J. E. Srs2 and Sgs1-Top3 suppress crossovers during double-strand break repair in yeast. Cell 115, 401–411 (2003). An investigation which shows that interactions between RecQ helicases and topo III restrict crossover events during repair of double-strand breaks.

  166. 166

    Wu, L. & Hickson, I. D. The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 426, 870–874 (2003). A report demonstrating that topo III and a RecQ helicase interact to resolve double Holliday junctions, resulting in limited crossover during homologous recombination.

  167. 167

    Plank, J. L., Wu, J. & Hsieh, T. S. Topoisomerase IIIα and Bloom's helicase can resolve a mobile double Holliday junction substrate through convergent branch migration. Proc. Natl Acad. Sci. USA 103, 11118–11123 (2006). A study which finds that topo III collaborates with a RecQ-like helicase and RPA to remove double Holliday junctions, using a convergent migration mechanism to collapse the junctions and produce non-crossover products.

  168. 168

    Harmon, F. G., Brockman, J. P. & Kowalczykowski, S. C. RecQ helicase stimulates both DNA catenation and changes in DNA topology by topoisomerase III. J. Biol. Chem. 278, 42668–42678 (2003). The first paper to show the ability of a RecQ helicase to stimulate topo III, and to suggest that the interaction is important for recombination.

  169. 169

    Singh, T. R. et al. BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase–double Holliday junction dissolvasome. Genes Dev. 22, 2856–2868 (2008).

  170. 170

    Cejka, P. et al. DNA end resection by Dna2–Sgs1–RPA and its stimulation by Top3–Rmi1 and Mre11–Rad50–Xrs2. Nature 467, 112–116 (2010). A demonstration that nucleases required for end resectioning may be recruited to broken ends by topo III in vivo.

  171. 171

    Niu, H. et al. Mechanism of the ATP-dependent DNA end-resection machinery from Saccharomyces cerevisiae. Nature 467, 108–111 (2010).

  172. 172

    Wells, N. J., Addison, C. M., Fry, A. M., Ganapathi, R. & Hickson, I. D. Serine 1524 is a major site of phosphorylation on human topoisomerase II α protein in vivo and is a substrate for casein kinase II in vitro. J. Biol. Chem. 269, 29746–29751 (1994).

  173. 173

    Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840 (2009).

  174. 174

    Ryu, H., Furuta, M., Kirkpatrick, D., Gygi, S. P. & Azuma, Y. PIASy-dependent SUMOylation regulates DNA topoisomerase II α activity. J. Cell Biol. 191, 783–794 (2010).

  175. 175

    Dawlaty, M. M. et al. Resolution of sister centromeres requires RanBP2-mediated SUMOylation of topoisomerase IIα. Cell 133, 103–115 (2008).

  176. 176

    Bachant, J., Alcasabas, A., Blat, Y., Kleckner, N. & Elledge, S. J. The SUMO-1 isopeptidase Smt4 is linked to centromeric cohesion through SUMO-1 modification of DNA topoisomerase II. Mol. Cell 9, 1169–1182 (2002).

  177. 177

    Shapiro, P. et al. Extracellular signal-regulated kinase activates topoisomerase IIα through a mechanism independent of phosphorylation. Mol. Cell. Biol. 19, 3551–3560 (1999).

  178. 178

    Plo, I. et al. Overexpression of the atypical protein kinase C ζ reduces topoisomerase II catalytic activity, cleavable complexes formation, and drug-induced cytotoxicity in monocytic U937 leukemia cells. J. Biol. Chem. 277, 31407–31415 (2002).

  179. 179

    Kimura, K., Saijo, M., Tanaka, M. & Enomoto, T. Phosphorylation-independent stimulation of DNA topoisomerase II α activity. J. Biol. Chem. 271, 10990–10995 (1996).

  180. 180

    Bernard, P. & Couturier, M. Cell killing by the F plasmid CcdB protein involves poisoning of DNA-topoisomerase II complexes. J. Mol. Biol. 226, 735–745 (1992).

  181. 181

    Smith, A. B. & Maxwell, A. A strand-passage conformation of DNA gyrase is required to allow the bacterial toxin, CcdB, to access its binding site. Nucleic Acids Res. 34, 4667–4676 (2006).

  182. 182

    Vizán, J., Hernández-Chico, C., del Castillo, I. & Moreno, F. The peptide antibiotic microcin B17 induces double-strand cleavage of DNA mediated by E. coli DNA gyrase. EMBO J. 10, 467–476 (1991).

  183. 183

    Hegde, S. et al. A fluoroquinolone resistance protein from Mycobacterium tuberculosis that mimics DNA. Science 308, 1480–1483 (2005). The study that identifies and structurally characterizes a DNA-mimic protein in Mycobacterium tuberculosis that provides quinolone resistance to gyrase.

  184. 184

    Staker, B. L. et al. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc. Natl Acad. Sci. USA 99, 15387–15392 (2002).

  185. 185

    Lewis, R. J. et al. The nature of inhibition of DNA gyrase by the coumarins and the cyclothialidines revealed by X-ray crystallography. EMBO J. 15, 1412–1420 (1996).

  186. 186

    Tsai, F. T. et al. The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin. Proteins 28, 41–52 (1997).

  187. 187

    Classen, S., Olland, S. & Berger, J. M. Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187. Proc. Natl Acad. Sci. USA 100, 10629–10634 (2003).

  188. 188

    Corbett, K. D. & Berger, J. M. Structural basis for topoisomerase VI inhibition by the anti-Hsp90 drug radicicol. Nucleic Acids Res. 34, 4269–4277 (2006).

  189. 189

    Edwards, M. J. et al. A crystal structure of the bifunctional antibiotic simocyclinone D8, bound to DNA gyrase. Science 326, 1415–1418 (2009).

  190. 190

    Bax, B. D. et al. Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 466, 935–940 (2010). Work showing that bacterial type IIA topoisomerases are inhibited by a novel compound that binds across the dimer interface and intercalates into the DNA.

  191. 191

    Cheng, B. et al. Asp-to-Asn substitution at the first position of the DxD TOPRIM motif of recombinant bacterial topoisomerase I is extremely lethal to E. coli. J. Mol. Biol. 385, 558–567 (2009). A paper reporting how a single active-site mutation turns a type IA topo into a highly lethal machine, suggesting that this previously unrealized drug target may become a viable future target.

  192. 192

    Dwyer, D. J., Kohanski, M. A., Hayete, B. & Collins, J. J. Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli. Mol. Syst. Biol. 3, 91 (2007).

  193. 193

    Kohanski, M. A., Dwyer, D. J., Hayete, B., Lawrence, C. A. & Collins, J. J. A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130, 797–810 (2007).

  194. 194

    Wang, X., Zhao, X., Malik, M. & Drlica, K. Contribution of reactive oxygen species to pathways of quinolone-mediated bacterial cell death. J. Antimicrob. Chemother. 65, 520–524 (2010).

  195. 195

    Bowman, K. J., Newell, D. R., Calvert, A. H. & Curtin, N. J. Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro. Br. J. Cancer 84, 106–112 (2001). An article which shows that the PARP1 inhibitor NU1025 enhances the toxicity of the topo IB inhibitor camptothecin, suggesting that this kind of synergy with topo inhibitors may be a promising approach for the treatment of cancer and microbial infections.

  196. 196

    Wesierska-Gadek, J., Schloffer, D., Gueorguieva, M., Uhl, M. & Skladanowski, A. Increased susceptibility of poly(ADP-ribose) polymerase-1 knockout cells to antitumor triazoloacridone C-1305 is associated with permanent G2 cell cycle arrest. Cancer Res. 64, 4487–4497 (2004).

  197. 197

    Munoz-Gamez, J. A. et al. Inhibition of poly (ADP-ribose) polymerase-1 enhances doxorubicin activity against liver cancer cells. Cancer Lett. 301, 47–56.

  198. 198

    Austin, C., Sng, J., Patel, S. & Fisher, L. Novel HeLa topoisomerase II is the IIβ isoform: complete coding sequence and homology with other type II topoisomerases. Biochim. Biophys. Acta 1172, 283–291 (1993).

  199. 199

    Linka, R. M. et al. C-terminal regions of topoisomerase IIα and IIβ determine isoform-specific functioning of the enzymes in vivo. Nucleic Acids Res. 35, 3810–3822 (2007).

  200. 200

    Ye, J. et al. TRF2 and apollo cooperate with topoisomerase 2 α to protect human telomeres from replicative damage. Cell 142, 230–242 (2010).

  201. 201

    Niimi, A., Suka, N., Harata, M., Kikuchi, A. & Mizuno, S. Co-localization of chicken DNA topoisomerase IIa, but not β, with sites of DNA replication and possible involvement of a C-terminal region of a through its binding to PCNA. Chromosoma 110, 102–114 (2001).

  202. 202

    Grue, P. et al. Essential mitotic functions of DNA topoisomerase IIα are not adopted by topoisomerase IIβ in human H69 cells. J. Biol. Chem. 273, 33660–33666 (1998).

  203. 203

    Peng, H. & Marians, K. J. Escherichia coli topoisomerase IV. Purification, characterization, subunit structure, and subunit interactions. J. Biol. Chem. 268, 24481–24490 (1993).

  204. 204

    Kato, J. et al. New topoisomerase essential for chromosome segregation in E. coli. Cell 63, 393–404 (1990). The discovery of topo IV and its importance for chromosome segregation in E. coli.

  205. 205

    Kampranis, S. C. & Maxwell, A. Conversion of DNA gyrase into a conventional type II topoisomerase. Proc. Natl Acad. Sci. USA 93, 14416–14421 (1996).

  206. 206

    Corbett, K. D., Schoeffler, A. J., Thomsen, N. D. & Berger, J. M. The structural basis for substrate specificity in DNA topoisomerase IV. J. Mol. Biol. 351, 545–561 (2005).

  207. 207

    Hsieh, T.-J., Farh, L., Huang, W. M. & Chan, N.-L. Structure of the topoisomerase IV C-terminal domain: a broken β-propeller implies a role as geometry facilitator in catalysis. J. Biol. Chem. 279, 55587–55593 (2004).

  208. 208

    Corbett, K. D., Shultzaberger, R. K. & Berger, J. M. The C-terminal domain of DNA gyrase A adopts a DNA-bending β-pinwheel fold. Proc. Natl Acad. Sci. USA 101, 7293–7298 (2004). The first high-resolution structure of the C-terminal domain from bacterial type IIA topoisomerase.

  209. 209

    Ruthenburg, A. J., Graybosch, D. M., Huetsch, J. C. & Verdine, G. L. A superhelical spiral in the Escherichia coli DNA gyrase A C-terminal domain imparts unidirectional supercoiling bias. J. Biol. Chem. 280, 26177–26184 (2005).

  210. 210

    Changela, A., DiGate, R. J. & Mondragón, A. Crystal structure of a complex of a type IA DNA topoisomerase with a single-stranded DNA molecule. Nature 411, 1077–1081 (2001).

  211. 211

    Schmidt, B., Burgin, A., Deweese, J., Osheroff, N. & Berger, J. A novel and unified two-metal mechanism for DNA cleavage by type II and IA topoisomerases. Nature 465, 641–644 (2010).

Download references

Acknowledgements

The authors thank K. Drlica for thoughtful discussions and editing. This work was supported by a US National Science Foundation pre-doctoral fellowship (to S.M.V.) and the US National Cancer Institute (grant CA077373 to J.M.B.).

Author information

Correspondence to James M. Berger.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Related links

Related links

FURTHER INFORMATION

James M. Berger's homepage

Glossary

Supercoil

The result of duplex DNA twisting on itself in three-dimensional space.

Paralogues

Homologous genes separated by a duplication event that have evolved new functions.

Domains of life

The three major evolutionary branches (Bacteria, Archaea and Eukarya) of modern-day cellular lineages.

Negatively supercoiled DNA

DNA that is under-twisted (wound to <10.5 base pairs per turn). Negative supercoiling destabilizes the DNA, allowing complementary strands to be more easily denatured. By contrast, DNA becomes more resistant to denaturation when positively supercoiled (wound to >10.5 base pairs per turn).

Superfamily 2 helicase

A member of a diverse group of ATP-dependent nucleic acid helicases and translocases that share a conserved domain architecture. Many members of this family can locally melt or unwind short duplex regions.

Abasic lesions

Regions of DNA damage in which the nucleobase has been excised from the sugar backbone.

Catenanes

Topologically interlinked duplex DNA rings.

Plectonemic supercoiling

The natural tendency of supercoiled DNA to wrap back on itself, forming intramolecularly wound structures known as plectonemes. Because DNA is itself a chiral molecule, negatively and positively supercoiled states cause the DNA to coil in opposite directions (in the form of right- and left-handed supertwists, respectively).

Superhelical densities

Measurements of the over- or under-twistedness of DNA, generally expressed as the ratio by which the twist of the supercoiled state differs from that of the relaxed state.

ATP-binding-cassette ATPases

(ABC ATPases). A family of proteins that include membrane-bound transporters, DNA repair factors and structural maintenance of chromosomes (SMC) proteins. ABC ATPases possess a conserved ATPase site that is often formed at dimer interfaces. ATP binding results in conformational changes (often dimerization) that affect the associated partner proteins and substrates.

Origin

A chromosomal site for replisome assembly.

Origin recognition complex

A multisubunit protein complex that localizes to origins to initiate DNA replication in eukaryotes.

Poly(ADP-ribose) polymerase 1

An enzyme that adds chains of ADP-ribose to proteins as a response to DNA damage and cell death.

Precatenanes

Entangled daughter duplexes that are formed behind a replication fork during strand synthesis.

Hemicatenane

A junction between two double-stranded DNA molecules, in which one strand of one DNA molecule forms a duplex with the complementary strand on the other DNA molecule.

Scissile phosphate

The phosphate at which a nucleic acid backbone is broken by nucleophilic attack.

E3 ligases

Enzymes that attach ubiquitin or ubiquitin-like proteins to target proteins.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vos, S., Tretter, E., Schmidt, B. et al. All tangled up: how cells direct, manage and exploit topoisomerase function. Nat Rev Mol Cell Biol 12, 827–841 (2011) doi:10.1038/nrm3228

Download citation

Further reading