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Coupling the core of the anticancer drug etoposide to an oligonucleotide induces topoisomerase II-mediated cleavage at specific DNA sequences

Lara, Lorena Infante, Fenner, Sabine, Ratcliffe, Steven, Isidro-Llobet, Albert, Hann, Michael, Bax, Ben and Osheroff, Neil 2018. Coupling the core of the anticancer drug etoposide to an oligonucleotide induces topoisomerase II-mediated cleavage at specific DNA sequences. Nucleic Acids Research 46 (5) , pp. 2218-2233. 10.1093/nar/gky072

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Abstract

Etoposide and other topoisomerase II-targeted drugs are important anticancer therapeutics. Unfortunately, the safe usage of these agents is limited by their indiscriminate induction of topoisomerase II-mediated DNA cleavage throughout the genome and by a lack of specificity toward cancer cells. Therefore, as a first step toward constraining the distribution of etoposide-induced DNA cleavage sites and developing sequence-specific topoisomerase II-targeted anticancer agents, we covalently coupled the core of etoposide to oligonucleotides centered on a topoisomerase II cleavage site in the PML gene. The initial sequence used for this ‘oligonucleotide-linked topoisomerase inhibitor’ (OTI) was identified as part of the translocation breakpoint of a patient with acute promyelocytic leukemia (APL). Subsequent OTI sequences were derived from the observed APL breakpoint between PML and RARA. Results indicate that OTIs can be used to direct the sites of etoposide-induced DNA cleavage mediated by topoisomerase IIα and topoisomerase IIβ. OTIs increased levels of enzyme-mediated cleavage by inhibiting DNA ligation, and cleavage complexes induced by OTIs were as stable as those induced by free etoposide. Finally, OTIs directed against the PML-RARA breakpoint displayed cleavage specificity for oligonucleotides with the translocation sequence over those with sequences matching either parental gene. These studies demonstrate the feasibility of using oligonucleotides to direct topoisomerase II-mediated DNA cleavage to specific sites in the genome.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Additional Information: This article is available under the Creative Commons CC-BY-NC license and permits non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.
Publisher: Oxford University Press
ISSN: 0305-1048
Date of First Compliant Deposit: 8 May 2018
Date of Acceptance: 6 February 2018
Last Modified: 09 Nov 2020 15:45
URI: http://orca.cardiff.ac.uk/id/eprint/111248

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