Inhibition of DNA topoisomerase I activity by heparan sulfate and modulation by basic fibroblast growth factor

Ilona Kovalszky, József Dudás, Julia Oláh-Nagy, Gábor Pogány, József Töváry, József Timár, László Kopper, András Jeney, Renato V. Iozzo

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Abstract

Eukaryotic DNA topoisomerase I catalyzes changes in the superhelical state of duplex DNA by transiently breaking single strands thereby allowing relaxation of both positively and negatively supercoiled DNA. Topoisomerase I is a nuclear enzyme localized at active sites of transcription, and abnormal levels of the enzyme have been observed in a variety of neoplasms. Because the enzyme binds heparin and, given the presence of heparan sulfate within the nuclei of mammalian cells, we sought to investigate the interaction between topoisomerase I and sulfated glycosaminoglycans isolated from normal and neoplastic human liver. The results demonstrated that low concentrations (~ 100 nM) of heparan sulfate from normal liver but not from its malignant counterpart effectively blocked relaxation of supercoiled DNA driven by either purified holoenzyme or topoisomerase I activity present in nuclear extracts of three malignant cell lines. Heparin acted at even lower (~ 10 nM) concentrations. Moreover, we show that basic fibroblast growth factor could interfere with this heparan sulfate/heparin-driven inhibition and that both basic fibroblast growth factor and heparin-binding sites co-localized in the nuclei of U937 leukemic cells. Our results suggest that DNA topoisomerase I activity may be modulated in vivo by specific heparan sulfate moieties present in normal cells but markedly reduced or absent in their transformed counterparts.

Original languageEnglish
Pages (from-to)11-23
Number of pages13
JournalMolecular and Cellular Biochemistry
Volume183
Issue number1-2
DOIs
Publication statusPublished - Jun 20 1998

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Keywords

  • Glycosaminoglycans
  • Heparan sulfate
  • Topoisomerase I

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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