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Inhibiting translesion DNA synthesis as an approach to combat drug resistance to DNA damaging agents

Jung-Suk Choi1, Seol Kim2, Edward Motea3

  • 1Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA.

Oncotarget
|May 11, 2017
PubMed

Insights

Researchers developed a novel nucleoside analog to visualize and track DNA repair in cancer cells, aiding in the identification of drug-resistant mechanisms and enhancing anti-cancer therapy effectiveness.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Drug Development

Background:

  • Anti-cancer drugs damage DNA, but cancer cells can develop resistance by replicating these lesions.
  • Understanding DNA replication across damaged sites is crucial for overcoming therapeutic resistance.

Purpose of the Study:

  • To develop a tool for visualizing and identifying cells with drug resistance mechanisms involving DNA replication.
  • To investigate the potential of a novel nucleoside analog in cancer diagnostics and therapeutics.

Main Methods:

  • An artificial nucleoside analog with an ethynyl group was synthesized.
  • Click chemistry was used to attach azide-containing fluorophores for visualization.
  • Flow cytometry and microscopy were employed to analyze nucleotide incorporation and cellular response.

Main Results:

  • Nucleotide incorporation into genomic DNA increased upon treatment with DNA damaging agents.
  • The nucleoside analog inhibited translesion DNA synthesis.
  • The analog demonstrated synergy with anti-cancer agents like temozolomide, enhancing therapeutic activity.

Conclusions:

  • The developed nucleoside analog enables visualization of damaged DNA replication, identifying drug-resistant cells.
  • This tool offers combined diagnostic and therapeutic potential for personalized cancer medicine.
Keywords:
DNA damageDNA polymerizationchemotherapyleukemianucleoside analogs

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