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Repair of and checkpoint response to topoisomerase I-mediated DNA damage

Yves Pommier1, Christophe Redon, V Ashutosh Rao

  • 1Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute/NIH, Building 37, Room 5068, Bethesda, MD 20892-4255, USA. pommier@nih.gov

Mutation Research
|December 4, 2003
PubMed

Insights

Topoisomerase I (Top1) is crucial for DNA relaxation but can cause DNA damage when its functions are disrupted. Understanding Top1 cleavage complexes and their repair is key to cancer therapy selectivity.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry
  • Cancer Research

Background:

  • Topoisomerase I (Top1) is essential for managing DNA supercoiling during transcription and replication.
  • Certain DNA modifications, drugs, and carcinogens can disrupt the coupled cleavage and religation reactions of Top1.
  • This disruption leads to the formation of Top1 cleavage complexes, which pose a threat to genomic integrity.

Purpose of the Study:

  • To elucidate the mechanisms by which Top1 cleavage complexes damage DNA.
  • To investigate the conserved repair pathways for Top1-mediated DNA lesions.
  • To understand the role of DNA repair and checkpoint pathways in cellular responses to Top1 inhibition.

Main Methods:

  • Biochemical analyses of Topoisomerase I activity and DNA cleavage complexes.
  • Genetic studies in yeast and human cell lines with defined genetic defects.
  • Investigation of DNA double-strand break (DSB) formation and transcription stalling.

Main Results:

  • Top1 cleavage complexes induce DNA damage by generating replication-mediated DSBs and stalling transcription.
  • Integrated repair and checkpoint pathways, conserved across species, are involved in resolving Top1-mediated DNA lesions.
  • Defects in these repair/checkpoint pathways contribute to tumor development and influence the efficacy of Top1 inhibitors.

Conclusions:

  • Topoisomerase I inhibition can lead to significant DNA damage and cell death.
  • The cellular response to Top1-mediated DNA damage relies on conserved repair and checkpoint mechanisms.
  • Understanding these pathways is critical for explaining the selective toxicity of Top1 inhibitors, such as camptothecins, in cancer cells.

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