Year: 2016
Type: article
Abstract: // Selma M. Cuya 1 , Evan Q. Comeaux 1, 2 , Keith Wanzeck 1, 3 , Karina J. Yoon 1 , Robert C.A.M. van Waardenburg 1 1 Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA 2 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105-3678, USA 3 Department 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 (His nuc ) and a general acid/base histidine (His gab ). A Tdp1His gab 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 His gab -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 Tdp1His nuc Ala and Tdp1His gab Asn 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 Tdp1 mutant 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.
Source: Oncotarget
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
Funder: National Cancer Institute
OpenAlex ID: W2554893984