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

I. Kovalszky, József Dudás, Julia Oláh-Nagy, Gábor Pogány, J. Tóvári, J. Tímár, L. Kópper, A. Jeney, Renato V. Iozzo

Research output: Contribution to journalArticle

49 Citations (Scopus)

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 - 1998

Fingerprint

Type I DNA Topoisomerase
Heparitin Sulfate
Fibroblast Growth Factor 2
Modulation
Heparin
Superhelical DNA
A73025
Liver
Enzymes
Cells
U937 Cells
Holoenzymes
Transcription
Cell Nucleus
Catalytic Domain
Binding Sites
Cell Line
DNA
Neoplasms

Keywords

  • Glycosaminoglycans
  • Heparan sulfate
  • Topoisomerase I

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Inhibition of DNA topoisomerase I activity by heparan sulfate and modulation by basic fibroblast growth factor. / Kovalszky, I.; Dudás, József; Oláh-Nagy, Julia; Pogány, Gábor; Tóvári, J.; Tímár, J.; Kópper, L.; Jeney, A.; Iozzo, Renato V.

In: Molecular and Cellular Biochemistry, Vol. 183, No. 1-2, 1998, p. 11-23.

Research output: Contribution to journalArticle

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