Skip to main content

Advertisement

SpringerLink
Log in

DNA topoisomerase I in oncology: Dr Jekyll or Mr Hyde?

  • Review
  • Published:
Pathology & Oncology Research

Abstract

Mammalian DNA topoisomerase I is a multifunctional enzyme which is essential for embryonal development. In addition to its classical DNA nick-ing-closing activities which are needed for relaxation of supercoiled DNA, topoisomerase I can phosphorylate certain splicing factors. The enzyme is also involved in transcriptional regulation through its ability to associate with other proteins in the TFIID-, and possibly TFIIH-, transcription complexes, and is implicated in the recognition of DNA lesions. Finally, topoisomerase I is a recombinase which can mediate illegitimate recombination. A crucial reaction intermediate during relaxation of DNA is the formation of a DNA-topoisomerase I complex (the cleavable complex) where topoisomerase I is covalently linked to a 3′-end of DNA thereby creating a single stranded DNA break. Cleavable complexes are also formed in the vicinity of DNA lesions and in the presence of the antitumor agent, camptothecin. While formation of cleavable complexes may be necessary for the initial stages of the DNA damage response, these complexes are also potentially dangerous to the cell due to their ability to mediate illegitimate recombination, which can lead to genomic instability and oncogenesis. Thus the levels and stability of these complexes have to be strictly regulated. This is obtained by maintaining the enzyme levels relatively constant, by limiting the stability of the cleavable complexes through physical interaction with the oncogene suppressor protein p53 and by degradation of the topoisomerase I by the proteasome system. Emerging evidence suggest that these regulatory functions are perturbed in tumor cells, explaining at the same time why topoisomerase I activities so often are increased in certain human tumors, and why these cells are sensitized to the cytotoxic effects of camptothecins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rossi F, Labourier E, Forne T, et al: Specific phosphorylation of SR proteins by mammalian DNA topoisomerase I. Nature 381:80–82, 1996.

    Article  PubMed  CAS  Google Scholar 

  2. Wang JC: Interaction between DNA and anEscherichia coli protein omega. J Mol Biol.14:523–533, 1971.

    Article  Google Scholar 

  3. Champoux JJ, Dulbecco R: An activity from mammalian cells that untwists superhelical DNA; a possible swivel for DNA replication. Proc Natl Acad Sci USA 69:143–146, 1972.

    Article  PubMed  CAS  Google Scholar 

  4. Pulleyblank DE, Morgan AR: Partial purification of “omega” protein from calf thymus. Biochemistry14:5205–5209, 1975.

    Article  PubMed  CAS  Google Scholar 

  5. Durnford JM, Champoux JJ: The DNA untwisting enzyme fromSaccharomyces cerevisiae. Partial purification and characterization. J Biol Chem 253:1086–1089, 1978.

    PubMed  CAS  Google Scholar 

  6. Javaherian K, Tse YC, Vega J: Drosophila topoisomerase I: isolation, purification and characterization. Nucleic Acids Res 10:6945–6955, 1982.

    Article  PubMed  CAS  Google Scholar 

  7. Liu LF: HeLa toposiomerase I. Methods Enzymol 100:133–137, 1983.

    Article  PubMed  CAS  Google Scholar 

  8. Riou GF, Gabillot M, Douc-Rasy S, et al: A type I DNA topoisomerase fromTrypanosoma cruzi. Eur J Biochem 134:479- 484, 1983.

    Article  PubMed  CAS  Google Scholar 

  9. Shuman S, Moss B: Identification of a vaccinia virus gene encoding a type I DNA topoisomerase. Proc Natl Acad Sci USA 84:7478–7482, 1987.

    Article  PubMed  CAS  Google Scholar 

  10. Wallis JW, Chrebet G, Brodsky G, et al: A hyper-recombination mutation in S.cerevisiae identifies a novel eukaryotic topoisomerase. Cell 58:409–419, 1989.

    Article  PubMed  CAS  Google Scholar 

  11. Hanai R, Caron PR, Wang JC: Human TOP3: a single-copy gene encoding DNA topoisomerase III. Proc Natl Acad Sci USA 93:3653–3657, 1996.

    Article  PubMed  CAS  Google Scholar 

  12. Stewart L, Ireton GC, Parker LH,et al: Biochemical and biophysical analyses of recombinant forms of human topoisomerase I. J Biol Chem 271:7593–7601, 1996.

    Article  PubMed  CAS  Google Scholar 

  13. Redinbo MR, Stewart L, Kuhn P, et al: Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA. Science279:504–513, 1998.

    Article  Google Scholar 

  14. Alsner J, Svejstrup JQ, Kjeldsen E, et al: Identification of an N- terminal domain of eukaryotic DNA topoisomerase I dispensable for catalytic activity but essential forin vivo function. J Biol Chem 26:2408–2411, 1992.

    Google Scholar 

  15. Labourier E, Rossi F, Gallouzi IE, et al: Interaction between the N-terminal domain of human DNA topoisomerase I and the arginine-serine domain of its substrate determines phosphorylation of SF2/ASF splicing factor. Nucleic Acids Res 26:2955- 2962, 1998.

    Article  PubMed  CAS  Google Scholar 

  16. Rossi F, Labourier E, Gallouzi IE, et al: The C-terminal domain but not the tyrosine 723 of human DNA topoisomerase I active site contributes to kinase activity. Nucleic Acids Res 26:2963- 2970, 1998.

    Article  PubMed  CAS  Google Scholar 

  17. Juan CC, Hwang J, Liu AA et al: Human DNA topoisomerase I is encoded by a single-copy gene that maps to chromosome region 20q12-13.2. Proc Natl Acad Sci USA 85:8910–8913, 1988.

    Article  PubMed  CAS  Google Scholar 

  18. Kunze N, Yang G, Dolberg M, et al: Structure of the human type I DNA topoisomerase gene. J Biol Chem 266:9610–9616, 1991.

    PubMed  CAS  Google Scholar 

  19. Kunze N, Klein M, Richter A, et al: Structural characterization of the human DNA topoisomerase I gene promoter. Eur J Biochem 194:323–330, 1990.

    Article  PubMed  CAS  Google Scholar 

  20. Heiland S, Knippers R, Kunze N: The promoter region of the human type-I DNA-topoisomerase gene. Protein-binding sites and sequences involved in transcriptional regulation. Eur J Bio- chem 21:813–822, 1993.

    Google Scholar 

  21. Hwong CL, Chen CY, Shang HF, et al: Increased synthesis and degradation of DNA topoisomerase I during the initial phase of human T lymphocyte proliferation. J Biol Chem 268:18982- 18986, 1993.

    PubMed  CAS  Google Scholar 

  22. Kaufmann SH, Charron M, Burke PJ, et al: Changes in topoi- somerase I levels and localization during myeloid maturationin vitro andin vivo. Cancer Res 55:1255–1260, 1995.

    PubMed  CAS  Google Scholar 

  23. Romig H, Richter A: Expression of the topoisomerase I gene in serum stimulated human fibroblasts.Biochim Biophys Acta 1048:274–280, 1990.

    PubMed  CAS  Google Scholar 

  24. Desai SD, Liu LF, Vazquez-Abad D, et al: Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. J Biol Chem 272:24159–24164, 1997.

    Article  PubMed  CAS  Google Scholar 

  25. Heck MM, Hittelman WN, Earnshaw WC: Differential expres- sion of DNA topoisomerases I and II during the eukaryotic cell cycle. Proc Natl Acad Sci USA 85:1086–1090, 1988.

    Article  PubMed  CAS  Google Scholar 

  26. Baker SD, Wadkins RM, Stewart CF, et al: Cell cycle analysis of amount and distribution of nuclear DNA topoisomerase I as determined by fluorescence digital imaging microscopy. Cytometry 19:134–145, 1995.

    Article  PubMed  CAS  Google Scholar 

  27. Bronstein IB, Vorobyev S, Timofeev A, et al: Elevations of DNA topoisomerase I catalytic activity and immunoprotein in human malignancies. Oncol Res 8:17–25, 1996.

    PubMed  CAS  Google Scholar 

  28. Muller MT, Pfund WP, Mehta VB, et al: Eukaryotic type I topoi- somerase is enriched in the nucleolus and catalytically active on ribosomal DNA. EMBO J 4:1237–1243, 1985.

    PubMed  CAS  Google Scholar 

  29. Hirano T, Konoha G, Toda T, et al: Essential roles of the RNA polymerase I largest subunit and DNA topoisomerases in the formation of fission yeast nucleolus. J Cell Biol 108:243–253, 1989.

    Article  PubMed  CAS  Google Scholar 

  30. Meyer KN, Kjeldsen E, Straub T, et al: Cell cycle-coupled relocation of types I and II topoisomerases and modulation of catalytic enzyme activities. J Cell Biol 136:775–788, 1997.

    Article  PubMed  CAS  Google Scholar 

  31. 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.

    PubMed  CAS  Google Scholar 

  32. Thrash C, Bankier AT, Barell BG, et al: Cloning, characterization and sequence of the yeast topoisomerase I gene. Proc Natl Acad Sci USA 82:4374–4378, 1985.

    Article  PubMed  CAS  Google Scholar 

  33. Kim RA, Wang JC: Function of DNA topoisomerases as replication swivels inSaccharomyces cerevisiae. J Mol Biol 208:257–267, 1989.

    Article  PubMed  CAS  Google Scholar 

  34. DiMauro EG, Camilloni, EG, Verdone L, et al: DNA topoisomerase I controls the kinetics of promoter activation and DNA topology inSaccharomyces cerevisiae. Mol Cell Biol 13:6702- 6710, 1993.

    CAS  Google Scholar 

  35. Lee MP, Brown SD, Chen A, et al: DNA topoisomerase I is essential inDrosophila melanogaster. Proc Natl Acad Sci USA 90:6656–6660, 1993.

    Article  PubMed  CAS  Google Scholar 

  36. Morham SG, Kluckman KD, Voulomanos N, et al: Targeted dis- ruption of the mouse topoisomerase I gene by camptothecin selection. Mol Cell Biol 16:6804–6809, 1996.

    PubMed  CAS  Google Scholar 

  37. Yang L, Wold MS, Li JJ, et al: Roles of DNA topoisomerases in simian virus 40 DNA replicationin vitro. Proc Natl Acad Sci USA 84:950–954, 1987.

    Article  PubMed  CAS  Google Scholar 

  38. Gilmour DS, Pflugfelder G, Wang JC, et al: Topoisomerase I interacts with transcribed regions in Drosophila cells. Cell 44:401–407, 1986.

    Article  PubMed  CAS  Google Scholar 

  39. Gar g LC, DiAngelo S, Jacob ST: Role of DNA topoisomerase I in the transcription of supercoiled rRNA gene. Proc Natl Acad Sci USA 84:3185–3188, 1987.

    Article  Google Scholar 

  40. Merino A, Madden KR, Lane WS, et al: DNA topoisomerase I is involved in both repression and activation of transcription. Nature 365:227–232, 1993.

    Article  PubMed  CAS  Google Scholar 

  41. Shykind BM, Kim J, Stewart L, et al: Topoisomerase I enhances TFIID-TFIIA complex assembly during activaton of transcription. Genes Dev 11:397–407, 1997.

    Article  PubMed  CAS  Google Scholar 

  42. Kretzschmar M, Meisternst M, Roeder RG: 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.

    Article  PubMed  CAS  Google Scholar 

  43. Bullock P, Champoux JJ, Botchan M: Association of crossover points with topoisomerase I cleavage sites: a model for nonhomologous recombination. Science 230:954–958, 1985.

    Article  PubMed  CAS  Google Scholar 

  44. Cheng C, Kussie P, Pavletich N, et al: Conservation of structure and mechanism between eukaryotic topoisomerase I and site- specific recombinases. Cell 92:841–850, 1998.

    Article  PubMed  CAS  Google Scholar 

  45. Zhu J, Schiestl RH: Topoisomerase I involvement in illegitimate recombination inSaccharomyces cerevisiae. Mol Cell Biol 16:1805–1812, 1996.

    PubMed  CAS  Google Scholar 

  46. Bullock P, Forrester W, Botchan M: DNA sequence studies of simian virus 40 chromosomal excision and integration in rat cells. J Mol Biol 174:55–84, 1984.

    Article  PubMed  CAS  Google Scholar 

  47. Hino O, Ohtake K, Rogler, CE: Features of two hepatitis B virus (HBV) DNA integrations suggest mechanisms of HBV integration. J Virol 63:2638–2643, 1989.

    PubMed  CAS  Google Scholar 

  48. Wang HP, Rogler CE: Topoisomerase I-mediated integration of hepadnavirus DNAin vitro. J Virol 65:2381–2392, 1991.

    PubMed  CAS  Google Scholar 

  49. Anderson RD, Berger NA: International Commission for Protection Against Environmental Mutagens and Carcinogens. Mutagenicity and carcinogenicity of topoisomerase-interactive agents. Mutat Res 309:109–142, 1994.

    PubMed  CAS  Google Scholar 

  50. Lanza A, Tornaletti S, Rodolfo C, et al: Human DNA topoisomerase I-mediated cleavages stimulated by ultraviolet light-induced DNA damage. J Biol Chem 271:6978–6986, 1996.

    Article  PubMed  CAS  Google Scholar 

  51. Pourquier P, Pilon AA, Kohlhagen G, et al: Trapping of mammalian topoisomerase I and recombinations induced by damaged DNA containing nicks or gaps. Importance of DNA end phosphorylation and camptothecin effects. J Biol Chem 272:26441–26447, 1997.

    Article  PubMed  CAS  Google Scholar 

  52. Rosenstein BS, Subramanian D, Muller MT: The involvement of topoisomerase I in the induction of DNA-protein crosslinks and DNA single-strand breaks in cells of ultraviolet-irradiated human and frog cell lines. Radiat Res 148:575–579, 1997.

    Article  PubMed  CAS  Google Scholar 

  53. Subramanian D, Rosenstein BS, Muller MT: Ultraviolet-induced DNA damage stimulates topoisomerase I-DNA complex formation in vivo: possible relationship with DNA repair. Cancer Res 58:976–984, 1998.

    PubMed  CAS  Google Scholar 

  54. Vichi P, Coin F, Renaud JP, et al: Cisplatin and UV-damaged DNA lure the basal transcription factor TFIID/TBP. EMBO J 16:7444–7456, 1997.

    Article  PubMed  CAS  Google Scholar 

  55. Castano IB, Brzoska PM, SadoffBU, et al: Mitotic chromosome condensation in the rDNA requires TRF4 and DNA topoisomerase I inSaccharomyces cerevisiae. Genes Dev 10:2564–2576, 1996.

    Article  PubMed  CAS  Google Scholar 

  56. Kimura K, Hirano T: ATP-dependent positive supercoiling of DNA by 13S condensin: a biochemical implication for chromosome condensation. Cell90:625–634, 1997.

    Article  PubMed  CAS  Google Scholar 

  57. Durban E, Goodenough M, Mills J, et al: Topoisomerase I phosphorylationin vitro and in rapidly growing Novikoff hepatoma cells. EMBO J 4:2921–2926, 1985.

    PubMed  CAS  Google Scholar 

  58. Kaiserman HB, Ingebritsen TS, Benbow RM: Regulation ofXenopus laevis DNA topoisomerase I activity by phosphorylation in vitro. Biochemistry 27:3216–3222, 1988.

    Article  PubMed  CAS  Google Scholar 

  59. Samuels DS, Shimizu Y, Shimizu N: Protein kinase C phosphorylates DNA topoisomerase I. FEBS Lett 259:57–60, 1989.

    Article  PubMed  CAS  Google Scholar 

  60. Pommier Y, Kerrigan D, Hartman KD, et al: Phosphorylation of mammalian DNA topoisomerase I and activation by protein kinase C. J Biol Chem 265:9418–9422, 1990.

    PubMed  CAS  Google Scholar 

  61. Tournier MF, Sobczak J, de Nechaud B, et al: Comparison of biochemical properties of DNA-topoisomerase I from normal and regenerating liver. Eur J Biochem 210:359–364, 1992.

    Article  PubMed  CAS  Google Scholar 

  62. D’arpa P, Liu LF: Cell cycle-specific and transcription-related phosphorylation of mammalian topoisomerase I. Exp Cell Res 217:125–131, 1995.

    Article  PubMed  Google Scholar 

  63. Krupitza G, Cerutti P: ADP-ribosylation of ADPR-transferase and topoisomerase I in intact mouse epidermal cells JB6. Biochemistry 28:2034–2040, 1989.

    Article  PubMed  CAS  Google Scholar 

  64. Boothman DA, Fukunaga N, Wang M: Down-regulation of topoisomerase I in mammalian cells following ionizing radiation. Cancer Res 54:4618–4626, 1994.

    PubMed  CAS  Google Scholar 

  65. Ferro AM, Higgins NP, Olivera BM: Poly(ADP-ribosylation) of a DNA topoisomerase. J Biol Chem 258:6000–6003, 1983.

    PubMed  CAS  Google Scholar 

  66. Jongstra-Bilen J, Ittel ME, Niedergang C, et al: DNA topoisomerase I from calf thymus is inhibitedin vitro by poly(ADP- ribosylation). Eur J Biochem 136:391–396, 1983.

    Article  PubMed  CAS  Google Scholar 

  67. Kasid UN, Halligan B, Liu LF,et al: Poly(ADP-ribose)-mediated post-translational modification of chromatin-associated human topoisomerase I. Inhibitory effects on catalytic activity. J Biol Chem 264:18687–18692, 1989.

    PubMed  CAS  Google Scholar 

  68. Adamietz P: Poly(ADP-ribose) synthase is the major endogenous nonhistone acceptor for poly(ADP-ribose) in alkylated rat hepatoma cells. Eur J Biochem 169:365–372, 1987.

    Article  PubMed  Google Scholar 

  69. Ferro AM, Olivera BM: Poly(ADP-ribosylation) of DNA topoisomerase I from calf thymus. J Biol Chem 259:547–554, 1984.

    PubMed  CAS  Google Scholar 

  70. Javaherian K, Liu LF: Association of eukaryotic DNA topoisomerase I with nucleosomes and chromosomal proteins. Nucleic Acids Res 11:461–472, 1983.

    Article  PubMed  CAS  Google Scholar 

  71. Rose KM, Szopa J, Han FS et al: Association of DNA topoisomerase I and RNA polymerase I: a possible role for topoisomerase I in ribosomal gene transcription. Chromosoma 96:411- 416, 1988.

    Article  PubMed  CAS  Google Scholar 

  72. Bharti AK, Olson MO, Kufe DW,et al: Identification of a nucleolin binding site in human topoisomerase I. J Biol Chem 271:1993–1997, 1996.

    Article  PubMed  CAS  Google Scholar 

  73. Kordiyak GJ, Jakes S, Ingebritsen TS et al: Casein kinase II stimulatesXenopus laevis DNA topoisomerase I by physical association. Biochemistry 33:13484–13491, 1994.

    Article  PubMed  CAS  Google Scholar 

  74. Gobert C, Bracco L, Rossi F, et al: Modulation of DNA topoisomerase I activity by p53. Biochemistry 35:5778–5786, 1996.

    Article  PubMed  CAS  Google Scholar 

  75. Albor A, Kaku S, Kulesz-Martin M: Wild-type and mutant forms of p53 activate human topoisomerase I: a possible mechanism for gain of function in mutants. Cancer Res 58:2091–2094, 1998.

    PubMed  CAS  Google Scholar 

  76. Larsen AK, Gobert C, Gilbert C, et al: DNA topoisomerases as repair enzymes: Mechanism(s) of action and regulation by p53. Acta Biochim Pol 45:535–544, 1998.

    PubMed  CAS  Google Scholar 

  77. Gobert C, Skaldanowski A, Larsen AK: The interaction between p53 and DNA topoisomerase I is regulated differently in cells with wild-type and mutant p53. Proc Natl Acad Sci USA, in press, 1999.

  78. McLeod HL, Douglas F, Oates M et al: Topoisomerase I and II activity in human breast, cervix, lung and colon cancer. Int J Cancer 59:607–611, 1994.

    Article  PubMed  CAS  Google Scholar 

  79. Vassal G, Pondarré C, Cappelli C, et al: DNA topoisomerase I, a new target for the treatment of neuroblastoma. Eur J Cancer 33:2011–2015, 1997.

    Article  PubMed  CAS  Google Scholar 

  80. Husain I, Mohler JL, Seigler H, et al: Elevation of topoisomerase I messenger RNA, protein, and catalytic activity in human tumors: demonstration of tumor-type specificity and implications for cancer chemotherapy. Cancer Res 54:539–546, 1994.

    PubMed  CAS  Google Scholar 

  81. Giovanella BC, Steblin JS, Wall ME, et al: DNA topoisomerase I targeted chemotherapy of human colon cancer in xenografs. Science 246:1046–1048, 1989.

    Article  PubMed  CAS  Google Scholar 

  82. Lynch BJ, Komaromy-Hiller G, Bronstein IB et al: Expression of DNA topoisomerase I, DNA topoisomerase II-alpha, and p53 in metastatic malignant melanoma. Hum Pathol 29:1240- 1245, 1998.

    Article  PubMed  CAS  Google Scholar 

  83. McLeod HL, Keith WN: Variation in topoisomerase I gene copy number as a mechanism for intrinsic drug sensitivity. Br J Cancer 74:508–512, 1996.

    PubMed  CAS  Google Scholar 

  84. Liu LF, Desai SD, Wu JX, et al: The roles of ubiquitin-dependent proteolysis in determining the sensitivity/resistance of tumor cells to topoisomerase inhibitors. Proc Am Ass Cancer Res 40:775, 1999.

    Google Scholar 

  85. Larsen AK, Skladanowski A: Cellular resistance to topoisomerase-targeted drugs: from drug uptake to cell death. Biochem Biophys Acta, 1400:257–274, 1998.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Biology and Pharmacology of DNA Topoisomerases, CNRS UMR 8532, Institut Gustave-Roussy, Villejuif, France

    Annette K Larsen & Céline Gobert

Authors
  1. Annette K Larsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Céline Gobert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Annette K Larsen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Larsen, A.K., Gobert, C. DNA topoisomerase I in oncology: Dr Jekyll or Mr Hyde?. Pathol. Oncol. Res. 5, 171–178 (1999). https://doi.org/10.1053/paor.1999.0209

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1053/paor.1999.0209

Keywords

Search

Navigation