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Elton et al. Cancer Drug Resist 2020;3:161-70 Cancer
DOI: 10.20517/cdr.2019.117 Drug Resistance

Review Open Access

Effects of DNA topoisomerase IIα splice variants on

acquired drug resistance

Terry S. Elton , Hatice Gulcin Ozer , Jack C. Yalowich 1
1
2
1 Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
2 Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.

Correspondence to: Prof. Jack C. Yalowich, Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State
University, 500 West 12th Avenue, Columbus, OH 43210, USA. E-mail: yalowich.1@osu.edu; Prof. Terry S. Elton, Division of
Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH
43210, USA. E-mail: elton.8@osu.edu
How to cite this article: Elton TS, Ozer HG, Yalowich JC. Effects of DNA topoisomerase IIα splice variants on acquired drug
resistance. Cancer Drug Resist 2020;3:161-70. http://dx.doi.org/10.20517/cdr.2019.117
Received: 23 Dec 2019 First Decision: 21 Jan 2020 Revised: 29 Jan 2020 Accepted: 12 Feb 2020 Available online: 27 Feb 2020

Science Editors: William Henry Gmeiner, Robert C.A.M. van Waardenburg Copy Editor: Jing-Wen Zhang Production Editor: Tian Zhang

Abstract
DNA topoisomerase IIα (170 kDa, TOP2α/170) induces transient DNA double-strand breaks in proliferating cells to
resolve DNA topological entanglements during chromosome condensation, replication, and segregation. Therefore,
TOP2α/170 is a prominent target for anticancer drugs whose clinical efficacy is often compromised due to
chemoresistance. Although many resistance mechanisms have been defined, acquired resistance of human cancer cell
lines to TOP2α interfacial inhibitors/poisons is frequently associated with a reduction of Top2α/170 expression levels.
Recent studies by our laboratory, in conjunction with earlier findings by other investigators, support the hypothesis that
a major mechanism of acquired resistance to TOP2α-targeted drugs is due to alternative RNA processing/splicing.
Specifically, several TOP2α mRNA splice variants have been reported which retain introns and are translated into
truncated TOP2α isoforms lacking nuclear localization sequences and subsequent dysregulated nuclear-cytoplasmic
disposition. In addition, intron retention can lead to truncated isoforms that lack both nuclear localization sequences
and the active site tyrosine (Tyr805) necessary for forming enzyme-DNA covalent complexes and inducing DNA
damage in the presence of TOP2α-targeted drugs. Ultimately, these truncated TOP2α isoforms result in decreased
drug activity against TOP2α in the nucleus and manifest drug resistance. Therefore, the complete characterization
of the mechanism(s) regulating the alternative RNA processing of TOP2α pre-mRNA may result in new strategies to
circumvent acquired drug resistance. Additionally, novel TOP2α splice variants and truncated TOP2α isoforms may be
useful as biomarkers for drug resistance, prognosis, and/or direct future TOP2α-targeted therapies.

Keywords: DNA topoisomerase IIα, chemoresistance, alternative splicing, intron retention, topoisomerase IIα
interfacial inhibitors/poisons

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
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