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Brettrager et al. Cancer Drug Resist 2019;2:1153-63 Cancer
DOI: 10.20517/cdr.2019.91 Drug Resistance

Review Open Access

Targeting Tyrosyl-DNA phosphodiesterase I to
enhance toxicity of phosphodiester linked DNA-
adducts

Evan J. Brettrager, Robert C.A.M. van Waardenburg
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.

Correspondence to: Dr. Robert C.A.M. van Waardenburg, Department of Pharmacology and Toxicology, University of Alabama
at Birmingham, 155 Volker Hall, 1670 University Boulevard, Birmingham, AL 35294-0019, USA.
E-mail: rvanwaar@uab.edu
How to cite this article: Brettrager EJ, van Waardenburg RCAM. Targeting Tyrosyl-DNA phosphodiesterase I to enhance
toxicity of phosphodiester linked DNA-adducts. Cancer Drug Resist 2019;2:1153-63. http://dx.doi.org/10.20517/cdr.2019.91
Received: 5 Oct 2019 First Decision: 19 Nov 2019 Revised: 19 Nov 2019 Accepted: 29 Nov 2019 Published: 19 Dec 2019

Science Editor: Frits Peters Copy Editor: Jing-Wen Zhang Production Editor: Tian Zhang

Abstract
Our genomic DNA is under constant assault from endogenous and exogenous sources, which needs to be resolved to
maintain cellular homeostasis. The eukaryotic DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1) catalyzes
the hydrolysis of phosphodiester bonds that covalently link adducts to DNA-ends. Tdp1 utilizes two catalytic histidines
to resolve a growing list of DNA-adducts. These DNA-adducts can be divided into two groups: small adducts, including
oxidized nucleotides, RNA, and non-canonical nucleoside analogs, and large adducts, such as (drug-stabilized)
topoisomerase- DNA covalent complexes or failed Schiff base reactions as occur between PARP1 and DNA. Many Tdp1
substrates are generated by chemotherapeutics linking Tdp1 to cancer drug resistance, making a compelling argument
to develop small molecules that target Tdp1 as potential novel therapeutic agents. Tdp1’s unique catalytic cycle, which
is centered on the formation of Tdp1-DNA covalent reaction intermediate, allows for two principally different targeting
strategies: (1) catalytic inhibition of Tdp1 catalysis to prevent Tdp1-mediated repair of DNA-adducts that enhances
the effectivity of chemotherapeutics; and (2) poisoning of Tdp1 by stabilization of the Tdp1- DNA covalent reaction
intermediate, which would increase the half-life of a potentially toxic DNA-adduct by preventing its resolution, analogous
to topoisomerase targeted poisons such as topotecan or etoposide. The catalytic Tdp1 mutant that forms the molecular
basis of the autosomal recessive neurodegenerative disease spinocerebellar ataxia with axonal neuropathy best
illustrates this concept; however, no small molecules have been reported for this strategy. Herein, we concisely discuss
the development of Tdp1 catalytic inhibitors and their results.

Keywords: Tdp1, small molecules, DNA topoisomerases, Camptothecins, oxidative DNA damage, DNA adducts,
Etoposide, chain terminating nucleotides/nucleoside analogs, DNA metabolism, drug development

© The Author(s) 2019. 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,
and indicate if changes were made.

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