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Drug discrimination by prokaryotic and eukaryotic topoisomerases is vital to therapeutic utility, but is poorly understood. We developed a next-generation sequencing (NGS) approach to identify drug-resistance mutations in eukaryotic topoisomerases. We show that alterations conferring resistance to poisons of human and yeast topoisomerase II derive from a rich mutational \u2018landscape\u2019 of amino acid substitutions broadly distributed throughout the entire enzyme. Both general and discriminatory drug-resistant behaviors are found to arise from different point mutations found at the same amino acid position and to occur far outside known drug-binding sites. Studies of selected resistant enzymes confirm the NGS data and further show that the anti-cancer quinolone vosaroxin acts solely as an intercalating poison, and that the antibacterial ciprofloxacin can poison yeast topoisomerase II. The innate drug-sensitivity of the DNA binding and cleavage region of human and yeast topoisomerases (particularly hTOP2\u03b2) is additionally revealed to be significantly regulated by the enzymes\u2019 adenosine triphosphatase regions. Collectively, these studies highlight the utility of using NGS-based methods to rapidly map drug resistance landscapes and reveal that the nucleotide turnover elements of type II topoisomerases impact drug specificity.<\/jats:p>","DOI":"10.1093\/nar\/gkz579","type":"journal-article","created":{"date-parts":[[2019,7,3]],"date-time":"2019-07-03T19:09:53Z","timestamp":1562180993000},"page":"8163-8179","source":"Crossref","is-referenced-by-count":20,"title":["A complex suite of loci and elements in eukaryotic type II topoisomerases determine selective sensitivity to distinct poisoning agents"],"prefix":"10.1093","volume":"47","author":[{"given":"Tim R","family":"Blower","sequence":"first","affiliation":[{"name":"Johns Hopkins University School of Medicine, Department of Biophysics and Biophysical Chemistry, Baltimore, MD\u00a021205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afif","family":"Bandak","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine, Department of Biophysics and Biophysical Chemistry, Baltimore, MD\u00a021205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy S Y","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA\u00a094720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline A","family":"Austin","sequence":"additional","affiliation":[{"name":"Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John L","family":"Nitiss","sequence":"additional","affiliation":[{"name":"Biopharmaceutical Sciences Department, University of Illinois College of Pharmacy, 1601 Parkview Avenue, N310, Rockford, IL\u00a061107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M","family":"Berger","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine, Department of Biophysics and Biophysical Chemistry, Baltimore, MD\u00a021205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,7,9]]},"reference":[{"key":"2019091012305085800_B1","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/nrm3228","article-title":"All tangled up: How cells direct, manage and exploit topoisomerase function","volume":"12","author":"Vos","year":"2011","journal-title":"Nat. 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