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Updated: Jul 8, 2025

Visualization of DNA Replication in the Vertebrate Model System DT40 using the DNA Fiber Technique
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Visualization of DNA Replication in the Vertebrate Model System DT40 using the DNA Fiber Technique

Published on: October 27, 2011

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A copper(ii) peptide helicate selectively cleaves DNA replication foci in mammalian cells

Ana Alcalde-Ordóñez1, Natalia Barreiro-Piñeiro2, Bríonna McGorman3

  • 1Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela 15782 Santiago de Compostela Spain.

Chemical Science
|December 15, 2023
PubMed

Insights

Researchers developed a novel copper-based peptide helicate that selectively targets and damages three-way DNA junctions (3WJs). This breakthrough offers a promising new strategy for developing targeted anticancer agents by exploiting cancer cells' deregulated DNA replication processes.

Area of Science:

  • Biochemistry
  • Chemical Biology
  • Molecular Oncology

Background:

  • Copper-based artificial nucleases show anticancer potential but lack selectivity in DNA cleavage.
  • Targeting noncanonical DNA structures, crucial in the cell cycle, offers an alternative strategy for selective cancer therapy.

Purpose of the Study:

  • To design a copper-based artificial nuclease with high selectivity for noncanonical DNA structures.
  • To investigate the targeted DNA cleavage and anticancer potential of the designed nuclease.

Main Methods:

  • Design and synthesis of an oligocationic Cu(II) peptide helicate.
  • In vitro and in cellulo studies to assess DNA binding and cleavage selectivity.
  • Evaluation of ROS-mediated oxidative DNA damage induction at DNA replication foci.

Main Results:

  • The designed helicate selectively binds and cleaves DNA three-way junctions (3WJs) over other DNA forms.
  • Oxidative DNA damage is induced via a ROS-mediated pathway both in vitro and in cellulo.
  • Targeting occurs specifically at DNA replication foci within the cell nucleus.

Conclusions:

  • This study presents the first targeted chemical nuclease with high selectivity for 3WJs in vitro and in mammalian cells.
  • The ability to selectively damage 3WJs, which are transiently generated during DNA replication, offers a novel anticancer strategy.
  • This approach may lead to a new class of copper-based artificial nucleases for cancer therapy.

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