Oncotarget

Research Papers:

Dysregulated human Tyrosyl-DNA phosphodiesterase I acts as cellular toxin

Selma M. Cuya, Evan Q. Comeaux, Keith Wanzeck, Karina J. Yoon and Robert C.A.M. van Waardenburg _

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Oncotarget. 2016; 7:86660-86674. https://doi.org/10.18632/oncotarget.13528

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Abstract

Selma M. Cuya1, Evan Q. Comeaux1,2, Keith Wanzeck1,3, Karina J. Yoon1, Robert C.A.M. van Waardenburg1

1Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA

2Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105-3678, USA

3Department of Medicine, Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294-0001, USA

Correspondence to:

Robert C.A.M. van Waardenburg, email: [email protected]

Keywords: TDP1, DNA-adducts, biochemistry, DNA topoisomerases, DNA repair

Received: July 16, 2016     Accepted: November 09, 2016     Published: November 23, 2016

ABSTRACT

Tyrosyl-DNA phosphodiesterase I (TDP1) hydrolyzes the drug-stabilized 3’phospho-tyrosyl bond formed between DNA topoisomerase I (TOPO1) and DNA. TDP1-mediated hydrolysis uses a nucleophilic histidine (Hisnuc) and a general acid/base histidine (Hisgab). A Tdp1Hisgab to Arg mutant identified in patients with the autosomal recessive neurodegenerative disease SCAN1 causes stabilization of the TDP1-DNA intermediate. Based on our previously reported Hisgab-substitutions inducing yeast toxicity (Gajewski et al. J. Mol. Biol. 415, 741-758, 2012), we propose that converting TDP1 into a cellular poison by stabilizing the covalent enzyme-DNA intermediate is a novel therapeutic strategy for cancer treatment. Here, we analyzed the toxic effects of two TDP1 catalytic mutants in HEK293 cells. Expression of human Tdp1HisnucAla and Tdp1HisgabAsn mutants results in stabilization of the covalent TDP1-DNA intermediate and induces cytotoxicity. Moreover, these mutants display reduced in vitro catalytic activity compared to wild type. Co-treatment of Tdp1mutant with topotecan shows more than additive cytotoxicity. Overall, these results support the hypothesis that stabilization of the TDP1-DNA covalent intermediate is a potential anti-cancer therapeutic strategy.


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