Issue 48, 2023

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

Abstract

The use of copper-based artificial nucleases as potential anticancer agents has been hampered by their poor selectivity in the oxidative DNA cleavage process. An alternative strategy to solve this problem is to design systems capable of selectively damaging noncanonical DNA structures that play crucial roles in the cell cycle. We designed an oligocationic CuII peptide helicate that selectively binds and cleaves DNA three-way junctions (3WJs) and induces oxidative DNA damage via a ROS-mediated pathway both in vitro and in cellulo, specifically at DNA replication foci of the cell nucleus, where this DNA structure is transiently generated. To our knowledge, this is the first example of a targeted chemical nuclease that can discriminate with high selectivity 3WJs from other forms of DNA both in vitro and in mammalian cells. Since the DNA replication process is deregulated in cancer cells, this approach may pave the way for the development of a new class of anticancer agents based on copper-based artificial nucleases.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
29 jun. 2023
Accepted
25 oct. 2023
First published
27 oct. 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2023,14, 14082-14091

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

A. Alcalde-Ordóñez, N. Barreiro-Piñeiro, B. McGorman, J. Gómez-González, D. Bouzada, F. Rivadulla, M. E. Vázquez, A. Kellett, J. Martínez-Costas and M. V. López, Chem. Sci., 2023, 14, 14082 DOI: 10.1039/D3SC03303A

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