Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

DNA topoisomerase II and its growing repertoire of biological functions

Nature Reviews Cancer volume 9, pages 327–337 (2009)Cite this article

Key Points

  • Type II topoisomerases change DNA topology by generating transient DNA double strand breaks and are essential for all eukaryotic cells.

  • Mammalian cells have two topoisomerase II (TOP2) isoforms, TOP2α and TOP2β. TOP2α is essential for all cells, and is essential for separating replicated chromosomes. TOP2β is required for normal development, but is dispensable in some cell types. Type II topoisomerases are required for other processes such as transcription, and the precise roles of the two isoforms in these processes are a subject of current studies.

  • Type II topoisomerases use a two gate mechanism for carrying out topological changes in DNA. The enzyme requires ATP hydrolysis for its reaction. ATP hydrolysis is used for for conformational changes of the enzyme, and is not directly involved in DNA breakage or resealing.

  • Crystal structures of several domains of yeast Top2 have provided additional information about how the enzyme carries out its reactions. A recent structure of the breakage reunion domain of yeast Top2 bound to DNA has shown that the enzyme induces a large bend in the DNA that is cleaved by the enzyme.

  • Biological functions of TOP2 isoforms are modulated by a variety of protein–protein interactions. Some of these interactions may affect enzyme activity, stability and localization.

  • TOP2 activity is also modulated by post-translational modification. In addition to phosphorylation, a crucial post-translational modification of TOP2 is sumoylation. Failure to sumoylate TOP2α or to remove the SUMO modification disrupts the ability of TOP2α to separate replicated chromosomes.

  • TOP2β has a key role in the survival of some neural cells. TOP2β is important in transcriptional regulation, and it is likely that TOP2β enzyme activity is specifically required.

  • Some aspects of TOP2 function during the cell cycle are monitored by checkpoints. It has been hypothesized that a major role of checkpoints is to monitor the completion of decatenation. If so, then TOP2-dependent checkpoints may be crucial for normal chromosome segregation and genome stability.

Abstract

DNA topoisomerases are enzymes that disentangle the topological problems that arise in double-stranded DNA. Many of these can be solved by the generation of either single or double strand breaks. However, where there is a clear requirement to alter DNA topology by introducing transient double strand breaks, only DNA topoisomerase II (TOP2) can carry out this reaction. Extensive biochemical and structural studies have provided detailed models of how TOP2 alters DNA structure, and recent molecular studies have greatly expanded knowledge of the biological contexts in which TOP2 functions, such as DNA replication, transcription and chromosome segregation — processes that are essential for preventing tumorigenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mechanism of strand passage by type II topoisomerases.
Figure 2: Structure of eukaryotic topoisomerase II (TOP2).
Figure 3: Roles of topoisomerase II (TOP2) in replication.

Similar content being viewed by others

References

  1. Champoux, J. J. DNA topoisomerases: structure, function, and mechanism. Annu. Rev. Biochem. 70, 369–413 (2001).

    CAS  PubMed  Google Scholar 

  2. Wang, J. C. Moving one DNA double helix through another by a type II DNA topoisomerase: the story of a simple molecular machine. Q. Rev. Biophys. 31, 107–144 (1998).

    CAS  PubMed  Google Scholar 

  3. Sundin, O. & Varshavsky, A. Arrest of segregation leads to accumulation of highly intertwined catenated dimers: dissection of the final stages of SV40 DNA replication. Cell 25, 659–669 (1981). The first demonstration that replication specifically requires a type II topoisomerase.

    CAS  PubMed  Google Scholar 

  4. Sundin, O. & Varshavsky, A. Terminal stages of SV40 DNA replication proceed via multiply intertwined catenated dimers. Cell 21, 103–114 (1980).

    CAS  PubMed  Google Scholar 

  5. Bates, A. D. & Maxwell, A. DNA topology (Oxford University Press, Oxford, 2005).

    Google Scholar 

  6. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 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). The structure of the ATPase domain of yeast Top2. These authors also reported the structure of the ATPase domain of Top2 bound to a bisdioxopiperazines.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Wei, H., Ruthenburg, A. J., Bechis, S. K. & Verdine, G. L. Nucleotide-dependent domain movement in the ATPase domain of a human type IIA DNA topoisomerase. J. Biol. Chem. 280, 37041–37047 (2005).

    CAS  PubMed  Google Scholar 

  9. Dong, K. C. & Berger, J. M. Structural basis for gate-DNA recognition and bending by type IIA topoisomerases. Nature 450, 1201–1205 (2007). A landmark paper showing the structure of the breakage reunion domain of TOP2 bound to DNA.

    CAS  PubMed  Google Scholar 

  10. Corbett, K. D. & Berger, J. M. Structure, molecular mechanisms, and evolutionary relationships in DNA topoisomerases. Annu. Rev. Biophys. Biomol. Struct. 33, 95–118 (2004).

    CAS  PubMed  Google Scholar 

  11. Schoeffler, A. J. & Berger, J. M. DNA topoisomerases: harnessing and constraining energy to govern chromosome topology. Q. Rev. Biophys. 41, 41–101 (2008). A recent review that integrates structural and biochemical information on different classes of topoisomerases.

    CAS  PubMed  Google Scholar 

  12. Berger, J. M., Gamblin, S. J., Harrison, S. C. & Wang, J. C. Structure and mechanism of DNA topoisomerase II Nature 379, 225–232 (1996); erratum Nature 380,179 (1996). The first structure of the breakage reunion domain of a type II topoisomerase.

  13. Fass, D., Bogden, C. E. & Berger, J. M. Quaternary changes in topoisomerase II may direct orthogonal movement of two DNA strands. Nature Struct. Biol. 6, 322–326 (1999).

    CAS  PubMed  Google Scholar 

  14. Rybenkov, V. V., Ullsperger, C., Vologodskii, A. V. & Cozzarelli, N. R. Simplification of DNA topology below equilibrium values by type II topoisomerases. Science 277, 690–693 (1997). The discovery of the phenomenon of topologoy simplification by type IIA topoisomerases.

    CAS  PubMed  Google Scholar 

  15. Vologodskii, A. V. et al. Mechanism of topology simplification by type II DNA topoisomerases. Proc. Natl Acad. Sci. USA 98, 3045–3049 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Chang, C. J., Goulding, S., Earnshaw, W. C. & Carmena, M. RNAi analysis reveals an unexpected role for topoisomerase II in chromosome arm congression to a metaphase plate. J. Cell Sci. 116, 4715–4726 (2003).

    CAS  PubMed  Google Scholar 

  17. Akimitsu, N. et al. Induction of apoptosis by depletion of DNA topoisomerase II alpha in mammalian cells. Biochem. Biophys. Res. Comm. 307, 301–307 (2003).

    CAS  PubMed  Google Scholar 

  18. Toyoda, Y. & Yanagida, M. Coordinated requirements of human topo II and cohesin for metaphase centromere alignment under Mad2-dependent spindle checkpoint surveillance. Mol. Biol. Cell 17, 2287–2302 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Coelho, P. A. et al. Dual role of Topoisomerase II in centromere resolution and Aurora B activity. Plos Biol. 6, 1758–1777 (2008).

    CAS  Google Scholar 

  20. McPherson, J. P. & Goldenberg, G. J. Induction of apoptosis by deregulated expression of DNA topoisomerase IIα. Cancer Res. 58, 4519–4524 (1998).

    CAS  PubMed  Google Scholar 

  21. Mo, Y. Y., Ameiss, K. A. & Beck, W. T. Overexpression of human DNA topoisomerase II alpha by fusion to enhanced green fluorescent protein. Biotechniques 25, 1052–1057 (1998).

    CAS  PubMed  Google Scholar 

  22. Lucas, I., Germe, T., Chevrier-Miller, M. & Hyrien, O. Topoisomerase II can unlink replicating DNA by precatenane removal. EMBO J. 20, 6509–6519 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 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). Demonstration that precatenanes were a relevant topological form of replicating DNA.

    CAS  PubMed  Google Scholar 

  24. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 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); erratum 326, 812 (1987).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Bermejo, R. et al. Top1- and Top2-mediated topological transitions at replication forks ensure fork progression and stability and prevent DNA damage checkpoint activation. Genes Dev. 21, 1921–1936 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 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). The first analysis of a conditional TOP2 mutant in a eukaryotic cell. This paper confirmed the prediction of Sundin and Varshavsky that TOP2 is required to separate replicated chromosomes.

    CAS  PubMed  Google Scholar 

  29. Baxter, J. & Diffley, J. F. Topoisomerase II inactivation prevents the completion of DNA replication in budding yeast. Mol. Cell 30, 790–802 (2008). An elegant study assessing roles of Top2 in replication in yeast.

    CAS  PubMed  Google Scholar 

  30. Carpenter, A. J. & Porter, A. C. Construction, characterization, and complementation of a conditional-lethal DNA topoisomerase IIα mutant human cell line. Mol. Biol. Cell 15, 5700–5711 (2004). A novel approach to generating a conditional TOP2α allele in a human cell line.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    CAS  PubMed  Google Scholar 

  32. 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). A demonstration that TOP2α has preferential activity against positively supercoiled DNA. This result may be important for understanding a specific requirement for TOP2α during replication.

    CAS  PubMed  Google Scholar 

  33. Murray, A. W. & Szostak, J. W. Chromosome segregation in mitosis and meiosis. Annu. Rev. Cell Biol. 1, 289–315 (1985).

    CAS  PubMed  Google Scholar 

  34. Losada, A. & Hirano, T. Dynamic molecular linkers of the genome: the first decade of SMC proteins. Genes Dev. 19, 1269–1287 (2005).

    CAS  PubMed  Google Scholar 

  35. Diaz-Martinez, L. A., Gimenez-Abian, J. F. & Clarke, D. J. Chromosome cohesion — rings, knots, orcs and fellowship. J. Cell Sci. 121, 2107–2114 (2008).

    CAS  PubMed  Google Scholar 

  36. Michaelis, C., Ciosk, R. & Nasmyth, K. Cohesins: Chromosomal proteins that prevent premature separation of sister chromatids. Cell 91, 35–45 (1997).

    CAS  PubMed  Google Scholar 

  37. Huang, C. E., Milutinovich, M. & Koshland, D. Rings, bracelet or snaps: fashionable alternatives for Smc complexes. Phil. Trans. R. Soc. B Biol. Sci. 360, 537–542 (2005).

    CAS  Google Scholar 

  38. 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).

    PubMed  Google Scholar 

  39. Coelho, P. A., Queiroz-Machado, J. & Sunkel, C. E. Condensin-dependent localisation of topoisomerase II to an axial chromosomal structure is required for sister chromatid resolution during mitosis. J. Cell Sci. 116, 4763–4776 (2003).

    CAS  PubMed  Google Scholar 

  40. Rattner, J. B., Hendzel, M. J., Furbee, C. S., Muller, M. T. & BazettJones, D. P. Topoisomerase II α is associated with the mammalian centromere in a cell cycle and species-specific manner and is required for proper centromere/kinetochore structure. J. Cell Biol. 134, 1097–1107 (1996).

    CAS  PubMed  Google Scholar 

  41. Barthelmes, H. U., Grue, P., Feineis, S., Straub, T. & Boege, F. Active DNA topoisomerase II alpha is a component of the salt-stable centrosome core. J. Biol. Chem. 275, 38823–38830 (2000).

    CAS  PubMed  Google Scholar 

  42. Christensen, M. O. et al. Dynamics of human DNA topoisomerases II α and II β in living cells. J. Cell Biol. 157, 31–44 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Shimogawa, M. M., Widlund, P. O., Riffle, M., Ess, M. & Davis, T. N. Bir1 is required for the tension checkpoint. Mol. Biol. Cell 20, 915–923 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu, D., Vader, G., Vromans, M. J. M., Lampson, M. A. & Lens, S. M. A. Sensing chromosome bi-orientation by spatial separation of Aurora B kinase from kinetochore substrates. Science 323, 1350–1353 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Huang, H. M. et al. Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit. J. Cell Biol. 183, 667–680 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Porter, A. C. & Farr, C. J. Topoisomerase II: untangling its contribution at the centromere. Chromosome Res. 12, 569–583 (2004).

    CAS  PubMed  Google Scholar 

  47. 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). The biological significance of the modification of TOP2 with SUMO is described.

    CAS  PubMed  Google Scholar 

  48. Azuma, Y., Arnaoutov, A., Anan, T. & Dasso, M. PIASy mediates SUMO-2 conjugation of Topoisomerase-II on mitotic chromosomes. EMBO J. 24, 2172–2182 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Diaz-Martinez, L. A. et al. PIASgamma is required for faithful chromosome segregation in human cells. PLoS ONE 1, e53 (2006).

    PubMed  PubMed Central  Google Scholar 

  50. Roth, W. et al. PIASy-deficient mice display modest defects in IFN and Wnt signaling. J. Immunol. 173, 6189–6199 (2004).

    CAS  PubMed  Google Scholar 

  51. Wong, K. A. et al. Protein inhibitor of activated STAT y (PIASy) and a splice variant lacking exon 6 enhance sumoylation but are not essential for embryogenesis and adult life. Mol. Cell. Biol. 24, 5577–5586 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Dawlaty, M. M. et al. Resolution of sister centromeres requires RanBP2-mediated SUMOylation of topoisomerase IIα. Cell 133, 103–115 (2008). Convincing evidence that RANBP2 is required to sumoylate mammalian TOP2.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Belmont, A. S. Mitotic chromosome structure and condensation. Curr. Opin. Cell Biol. 18, 632–638 (2006).

    CAS  PubMed  Google Scholar 

  54. Xu, Y. X. & Manley, J. L. The prolyl isomerase Pin1 functions in mitotic chromosome condensation. Mol. Cell 26, 287–300 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  56. Adachi, Y., Kas, E. & Laemmli, U. K. Preferential, cooperative binding of DNA topoisomerase II to scaffold-associated regions. EMBO J. 8, 3997–4006 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Gasser, S. M., Laroche, T., Falquet, J., Boy de la Tour, E. & Laemmli, U. K. Metaphase chromosome structure. Involvement of topoisomerase II. J. Mol. Biol. 188, 613–629 (1986).

    CAS  PubMed  Google Scholar 

  58. Schultz, M. C., Brill, S. J., Ju, Q., Sternglanz, R. & Reeder, R. H. Topoisomerases and yeast rRNA transcription: negative supercoiling stimulates initiation and topoisomerase activity is required for elongation. Genes Dev. 6, 1332–1341 (1992).

    CAS  PubMed  Google Scholar 

  59. Goto, T. & Wang, J. C. Cloning of yeast TOP1, the gene encoding DNA topoisomerase I, and construction of mutants defective in both DNA topoisomerase I and DNA topoisomerase II. Proc. Natl Acad. Sci. USA 82, 7178–7182 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Gartenberg, M. R. & Wang, J. C. Positive supercoiling of DNA greatly diminishes mRNA synthesis in yeast. Proc. Natl Acad. Sci. USA 89, 11461–11465 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Salceda, J., Fernandez, X. & Roca, J. Topoisomerase II, not topoisomerase I, is the proficient relaxase of nucleosomal DNA. EMBO J. 25, 2575–2583 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Mondal, N. & Parvin, J. D. DNA topoisomerase IIα is required for RNA polymerase II transcription on chromatin templates. Nature 413, 435–438 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Kretzschmar, M., Meisterernst, M. & Roeder, R. G. Identification of human DNA topoisomerase I as a cofactor for activator-dependent transcription by RNA polymerase II. Proc. Natl Acad. Sci. USA 90, 11508–11512 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    CAS  PubMed  Google Scholar 

  66. Shykind, B. M., Kim, J., Stewart, L., Champoux, J. J. & Sharp, P. A. Topoisomerase I enhances TFIID–TFIIA complex assembly during activation of transcription. Genes Dev. 11, 397–407 (1997).

    CAS  PubMed  Google Scholar 

  67. Liu, L. F. & Wang, J. C. Supercoiling of the DNA template during transcription. Proc. Natl Acad. Sci. USA 84, 7024–7027 (1987). The transcriptional supercoiling model.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Wang, J. C. Cellular roles of DNA topoisomerases: a molecular perspective. Nature Rev. Mol. Cell Biol. 3, 430–440 (2002).

    CAS  Google Scholar 

  69. Ju, B. G. & Rosenfeld, M. G. A breaking strategy for topoisomerase IIβ/PARP-1-dependent regulated transcription. Cell Cycle 5, 2557–2560 (2006).

    CAS  PubMed  Google Scholar 

  70. Ju, B. G. et al. A topoisomerase IIβ-mediated dsDNA break required for regulated transcription. Science 312, 1798–1802 (2006). A demonstration that TOP2β has a crucial enzymatic role in transcription. Reference 56 is an important elaboration on the findings of this paper.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Lyu, Y. L. & Wang, J. C. Aberrant lamination in the cerebral cortex of mouse embryos lacking DNA topoisomerase IIβ. Proc. Natl Acad. Sci. USA 100, 7123–7128 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  75. Hartwell, L. H. & Weinert, T. A. Checkpoints: controls that ensure the order of cell cycle events. Science 246, 629–634 (1989).

    CAS  PubMed  Google Scholar 

  76. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Uemura, T. et al. DNA topoisomerase II is required for condensation and separation of mitotic chromosomes in S. pombe. Cell 50, 917–925 (1987).

    Google Scholar 

  79. Downes, C. S., Mullinger, A. M. & Johnson, R. T. Inhibitors of DNA topoisomerase II prevent chromatid separation in mammalian cells but do not prevent exit from mitosis. Proc. Natl Acad. Sci. USA 88, 8895–8899 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Clarke, D. J., Johnson, R. T. & Downes, C. S. Topoisomerase II inhibition prevents anaphase chromatid segregation in mammalian cells independently of the generation of DNA strand breaks. J. Cell Sci. 105 (Pt 2), 563–569 (1993).

    CAS  PubMed  Google Scholar 

  81. Clifford, B., Beljin, M., Stark, G. R. & Taylor, W. R. G2 arrest in response to topoisomerase II inhibitors: the role of p53. Cancer Res. 63, 4074–4081 (2003).

    CAS  PubMed  Google Scholar 

  82. Ishida, R. et al. Inhibition of intracellular topoisomerase II by antitumor bis(2,6-dioxopiperazine) derivatives: mode of cell growth inhibition distinct from that of cleavable complex-forming type inhibitors. Cancer Res. 51, 4909–4916 (1991).

    CAS  PubMed  Google Scholar 

  83. Downes, C. S. et al. A topoisomerase II-dependent G2 cycle checkpoint in mammalian cells. Nature 372, 467–470 (1994). The first paper demonstrating a mitotic delay induced by bisdioxopiperazines. This paper is important in understanding TOP2 checkpoints as it was the first to use a catalytic inhibitor of TOP2 rather than an agent that induces TOP2-mediated DNA damage.

    CAS  PubMed  Google Scholar 

  84. Deming, P. B. et al. The human decatenation checkpoint. Proc. Natl Acad. Sci. USA 98, 12044–12049 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Skoufias, D. A., Lacroix, F. B., Andreassen, P. R., Wilson, L. & Margolis, R. L. Inhibition of DNA decatenation, but not DNA damage, arrests cells at metaphase. Mol. Cell 15, 977–990 (2004).

    CAS  PubMed  Google Scholar 

  86. Andrews, C. A. et al. A mitotic topoisomerase II checkpoint in budding yeast is required for genome stability but acts independently of Pds1/securin. Genes Dev. 20, 1162–1174 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Damelin, M. & Bestor, T. H. Decatenation checkpoint deficiency destabilizes the stem cell genome. Cell Cycle 5, 345–346 (2006).

    CAS  PubMed  Google Scholar 

  88. Damelin, M., Sun, Y. E., Sodja, V. B. & Bestor, T. H. Decatenation checkpoint deficiency in stem and progenitor cells. Cancer Cell 8, 479–484 (2005).

    CAS  PubMed  Google Scholar 

  89. Luo, K. T., Yuan, J., Chen, J. J. & Lou, Z. K. Topoisomerase II α controls the decatenation checkpoint. Nature Cell Biol. 11, 204–U196 (2009).

    CAS  PubMed  Google Scholar 

  90. 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 alpha protein in vivo and is a substrate for casein kinase II in vitro. J. Biol. Chem. 269, 29746–29751 (1994).

    CAS  PubMed  Google Scholar 

  91. Wood, J. L. & Chen, J. J. DNA-damage checkpoints: location, location, location. Trends Cell Biol. 18, 451–455 (2008).

    CAS  PubMed  Google Scholar 

  92. Haggarty, S. J. et al. Small molecule modulation of the human chromatid decatenation checkpoint. Chem. Biol. 10, 1267–1279 (2003).

    CAS  PubMed  Google Scholar 

  93. Nitiss, J. L. in DNA Damage and Repair: Volume II: DNA repair in Higher Eukaryotes (eds Nickoloff, J. A. & Hoekstra, M. F.) 517–537 (Humana Press, Totawa, New Jersey, 1998).

    Google Scholar 

  94. Kingma, P. S. & Osheroff, N. The response of eukaryotic topoisomerases to DNA damage. Biochim. Biophys. Acta 1400, 223–232 (1998).

    CAS  PubMed  Google Scholar 

  95. Yamane, K., Wu, X. & Chen, J. A DNA damage-regulated BRCT-containing protein, TopBP1, is required for cell survival. Mol. Cell. Biol. 22, 555–566 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Wilstermann, A. M. & Osheroff, N. Base excision repair intermediates as topoisomerase II poisons. J. Biol. Chem. 276, 46290–46296 (2001).

    CAS  PubMed  Google Scholar 

  97. Nitiss, J. L. Targeting DNA topoisomerase II in cancer chemotherapy. Nature Rev. Cancer 8, 338–350 (2008).

    Google Scholar 

  98. Corbett, K. D. & Berger, J. M. Emerging roles for plant topoisomerase VI. Chem. Biol. 10, 107–111 (2003).

    CAS  PubMed  Google Scholar 

  99. Lichten, M. Meiotic recombination: breaking the genome to save it. Curr. Biol. 11, R253–256 (2001).

    CAS  PubMed  Google Scholar 

  100. Austin, C. A. & Marsh, K. L. Eukaryotic DNA topoisomerase II β. Bioessays 20, 215–226 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Keeney, S. et al. A mouse homolog of the Saccharomyces cerevisiae meiotic recombination DNA transesterase Spo11p. Genomics 61, 170–182 (1999).

    CAS  PubMed  Google Scholar 

  103. Romanienko, P. J. & Camerini-Otero, R. D. Cloning, characterization, and localization of mouse and human SPO11. Genomics 61, 156–169 (1999).

    CAS  PubMed  Google Scholar 

  104. 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).

    CAS  PubMed  Google Scholar 

  105. Harkins, T. T. & Lindsley, J. E. Pre-steady-state analysis of ATP hydrolysis by Saccharomyces cerevisiae DNA topoisomerase II. 1. A DNA-dependent burst in ATP hydrolysis. Biochemistry 37, 7292–7298 (1998).

    CAS  PubMed  Google Scholar 

  106. Berger, J. M., Gamblin, S. J., Harrison, S. C. & Wang, J. C. Structure and mechanism of DNA topoisomerase II. Nature 379, 225–232 (1996).

    CAS  PubMed  Google Scholar 

  107. Kurz, E. U., Leader, K. B., Kroll, D. J., Clark, M. & Gieseler, F. Modulation of human DNA topoisomerase IIα function by interaction with 14-3-3ɛ. J. Biol. Chem. 275, 13948–13954 (2000).

    CAS  PubMed  Google Scholar 

  108. Wang, Y., Azuma, Y., Moore, D., Osheroff, N. & Neufeld, K. L. Interaction between tumor suppressor adenomatous polyposis coli and topoisomerase II α: implication for the G2/M transition. Mol. Biol. Cell 19, 4076–4085 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Morrison, C. et al. Proteomic analysis of human metaphase chromosomes reveals topoisomerase II α as an Aurora B substrate. Nucleic Acids Res. 30, 5318–5327 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Lou, Z., Minter-Dykhouse, K. & Chen, J. BRCA1 participates in DNA decatenation. Nature Struct. Mol. Biol. 12, 589–593 (2005).

    CAS  Google Scholar 

  111. Oliveira, R. A., Coelho, P. A. & Sunkel, C. E. The condensin I subunit Barren/CAP-H is essential for the structural integrity of centromeric heterochromatin during mitosis. Mol. Cell. Biol. 25, 8971–8984 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Ackerman, P., Glover, C. V. & Osheroff, N. Phosphorylation of DNA topoisomerase II by casein kinase II: modulation of eukaryotic topoisomerase II activity in vitro. Proc. Natl Acad. Sci. USA 82, 3164–3168 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. DeVore, R. F., Corbett, A. H. & Osheroff, N. Phosphorylation of topoisomerase II by casein kinase II and protein kinase C: effects on enzyme-mediated DNA cleavage/religation and sensitivity to the antineoplastic drugs etoposide and 4′-(9-acridinylamino)methane-sulfon-m-anisidide. Cancer Res. 52, 2156–2161 (1992).

    CAS  PubMed  Google Scholar 

  114. Redwood, C., Davies, S. L., Wells, N. J., Fry, A. M. & Hickson, I. D. Casein kinase II stabilizes the activity of human topoisomerase IIα in a phosphorylation-independent manner. J. Biol. Chem. 273, 3635–3642 (1998).

    CAS  PubMed  Google Scholar 

  115. Cardenas, M. E. & Gasser, S. M. Regulation of topoisomerase II by phosphorylation: a role for casein kinase II. J. Cell Sci. 104 (Pt 2), 219–225 (1993).

    CAS  PubMed  Google Scholar 

  116. Isaacs, R. J. et al. Physiological regulation of eukaryotic topoisomerase II. Biochim. Biophys. Acta 1400, 121–137 (1998).

    CAS  PubMed  Google Scholar 

  117. Ahn, B. H., Kim, T. H. & Bae, Y. S. Mapping of the interaction domain of the protein kinase CKII β subunit with target proteins. Mol. Cells 12, 158–163 (2001).

    CAS  PubMed  Google Scholar 

  118. Wells, N. J. & Hickson, I. D. Human topoisomerase II alpha is phosphorylated in a cell-cycle phase-dependent manner by a proline-directed kinase. Eur. J. Biochem. 231, 491–497 (1995).

    CAS  PubMed  Google Scholar 

  119. Poot, R. A. et al. HuCHRAC, a human ISWI chromatin remodelling complex contains hACF1 and two novel histone-fold proteins. EMBO J. 19, 3377–3387 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Varga-Weisz, P. D. et al. Chromatin-remodelling factor CHRAC contains the ATPases ISWI and topoisomerase II. Nature 388, 598–602 (1997).

    CAS  PubMed  Google Scholar 

  121. Turner, J. G., Engel, R., Derderian, J. A., Jove, R. & Sullivan, D. M. Human topoisomerase IIα nuclear export is mediated by two CRM-1-dependent nuclear export signals. J. Cell Sci. 117, 3061–3071 (2004).

    CAS  PubMed  Google Scholar 

  122. Mirski, S. E. et al. Topoisomerase II binds importin α isoforms and exportin/CRM1 but does not shuttle between the nucleus and cytoplasm in proliferating cells. Exp. Cell Res. 313, 627–637 (2007).

    CAS  PubMed  Google Scholar 

  123. Tsai, S. C. et al. Histone deacetylase interacts directly with DNA topoisomerase II. Nature Genet. 26, 349–353 (2000).

    CAS  PubMed  Google Scholar 

  124. Johnson, C. A., Padget, K., Austin, C. A. & Turner, B. M. Deacetylase activity associates with topoisomerase II and is necessary for etoposide-induced apoptosis. J. Biol. Chem. 276, 4539–4542 (2001).

    CAS  PubMed  Google Scholar 

  125. Yun, J., Tomida, A., Andoh, T. & Tsuruo, T. Interaction between glucose-regulated destruction domain of DNA topoisomerase IIα and MPN domain of Jab1/CSN5. J. Biol. Chem. 279, 31296–31303 (2004).

    CAS  PubMed  Google Scholar 

  126. Matheos, D., Ruiz, M. T., Price, G. B. & Zannis-Hadjopoulos, M. Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication. Biochim. Biophys. Acta 1578, 59–72 (2002).

    CAS  PubMed  Google Scholar 

  127. Cowell, I. G. et al. Human topoisomerase IIα and IIβ interact with the C-terminal region of p53. Exp. Cell Res. 255, 86–94 (2000).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  129. Messenger, M. M. et al. Interactions between protein kinase CK2 and Pin1. Evidence for phosphorylation-dependent interactions. J. Biol. Chem. 277, 23054–23064 (2002).

    CAS  PubMed  Google Scholar 

  130. Cuvier, O., Stanojcic, S., Lemaitre, J. M. & Mechali, M. A topoisomerase II-dependent mechanism for resetting replicons at the S–M-phase transition. Genes Dev. 22, 860–865 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Wyles, J. P., Wu, Z., Mirski, S. E. & Cole, S. P. Nuclear interactions of topoisomerase II α and β with phospholipid scramblase 1. Nucleic Acids Res. 35, 4076–4085 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Navarro, M. S. & Bachant, J. RanBP2: a tumor suppressor with a new twist on TopoII, SUMO, and centromeres. Cancer Cell 13, 293–295 (2008).

    CAS  PubMed  Google Scholar 

  133. Zhou, K. et al. RNA helicase A interacts with dsDNA and topoisomerase IIalpha. Nucleic Acids Res. 31, 2253–2260 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  135. Agostinho, M. et al. Conjugation of human topoisomerase 2 alpha with small ubiquitin-like modifiers 2/3 in response to topoisomerase inhibitors: cell cycle stage and chromosome domain specificity. Cancer Res. 68, 2409–2418 (2008).

    CAS  PubMed  Google Scholar 

  136. Takahashi, Y. & Strunnikov, A. In vivo modeling of polysumoylation uncovers targeting of Topoisomerase II to the nucleolus via optimal level of SUMO modification. Chromosoma 117, 189–198 (2008).

    CAS  PubMed  Google Scholar 

  137. Huang, L. et al. Functional interaction of DNA topoisomerase II α with the β-catenin and T-cell factor-4 complex. Gastroenterology 133, 1569–1578 (2007).

    CAS  PubMed  Google Scholar 

  138. Yamane, K., Kawabata, M. & Tsuruo, T. A DNA-topoisomerase-II-binding protein with eight repeating regions similar to DNA-repair enzymes and to a cell-cycle regulator. Eur. J. Biochem. 250, 794–799 (1997).

    CAS  PubMed  Google Scholar 

  139. Lee, C. G., Hague, L. K., Li, H. & Donnelly, R. Identification of toposome, a novel multisubunit complex containing topoisomerase IIα. Cell Cycle 3, 638–647 (2004).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author thanks J. Berger, University of California Berkeley, USA, who kindly provided figures and also provided useful discussion, and also Y. Pommier, National Cancer Institute, Bethesda, for encouragement. Work in the author's laboratory is supported by grants from the National Cancer Institute (CA82313 and CA21765) and the American Lebanese Syrian Associated Charities (ALSAC).

Author information

Authors and Affiliations

  1. Molecular Pharmacology Department, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, 38105, Tennessee, USA

    John L. Nitiss

Authors
  1. John L. Nitiss
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

National Cancer Institute Drug Dictionary

etoposide

mAMSA

Glossary

Catenane

Circles linked as in a chain: the two links cannot be separated without breaking one of the two molecules.

TOPRIM domain

A conserved domain found in topoisomerases, primases and other DNA metabolic enzymes. The TOPRIM domain adopts a Rossman fold and is involved in divalent cation binding.

B-DNA

DNA exists in many possible conformations, but only A-DNA, B-DNA and Z-DNA have been observed in organisms. Which conformation DNA adopts depends, for example, on the sequence of the DNA, or the amount and direction of supercoiling. The B form is most common under the conditions found in cells.

Boltzmann distribution

A certain distribution function or probability measure for the distribution of the states of a system.

Precatenane

A structure related to a catenane that results from the interwinding of DNA strands behind a replication fork. Precatenanes interconvert with positive supercoils that arise in front of a replication fork.

Hypomorphs

Organisms expressing alleles that result in a reduction, but not the elimination, of wild-type levels of a gene product or activity, often causing a less severe phenotype than a loss-of-function (or null) allele.

Bisdioxopiperazines

A class of small molecules, including ICRF-159, ICRF-187 and MST-16, that inhibit the catalytic activity of TOP2 and do not stabilize the TOP2 cleaved complex. Bisdioxopiperazines are the most commonly used catalytic inhibitors of type II topoisomerases.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nitiss, J. DNA topoisomerase II and its growing repertoire of biological functions. Nat Rev Cancer 9, 327–337 (2009). https://doi.org/10.1038/nrc2608

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2608

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing