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Position- and orientation-specific enhancement of topoisomerase I cleavage complexes by triplex DNA structures

Smitha Antony1, Paola B Arimondo, Jian-Sheng Sun

  • 1Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.

Nucleic Acids Research
|October 8, 2004
PubMed

Insights

Triple helix-forming oligonucleotides (TFOs) modulate Topoisomerase I (Top1) DNA cleavage. TFOs enhance Top1 activity by influencing DNA nicking and religation, with effects dependent on TFO position and orientation.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Genetics

Background:

  • Topoisomerase I (Top1) is crucial for DNA topology regulation.
  • Top1 activity is modulated by DNA modifications and anticancer drugs like camptothecin.

Purpose of the Study:

  • To investigate how triple helix-forming oligonucleotides (TFOs) affect Topoisomerase I (Top1) mediated DNA cleavage.
  • To determine the influence of TFO position and orientation on Top1 nicking and religation activities.

Main Methods:

  • Experimental analysis of Top1 activity in the presence of TFOs.
  • Molecular modeling to understand DNA-TFO-Top1 interactions.

Main Results:

  • TFO binding downstream of the Top1 site enhances DNA cleavage.
  • The specific effect (inhibition of religation vs. enhanced nicking) depends on TFO position and orientation relative to the Top1 site.
  • TFOs can inhibit religation when bound 1 bp downstream or when inverted 4 bp downstream.

Conclusions:

  • TFOs represent a novel class of molecules that can modulate Top1 activity.
  • The position and orientation of TFOs are critical determinants of their effect on Top1-mediated DNA cleavage and religation.
  • Understanding these interactions may inform the development of new therapeutic strategies targeting DNA topology.

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