ArticleNucleic acids research2019
A complex suite of loci and elements in eukaryotic type II topoisomerases determine selective sensitivity to distinct poisoning agents.
Article in Nucleic acids research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 18 citations in OpenAlex.
- Yeast Tools for Studying Type II Topoisomerases in Budding Yeast.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Genome Instability Induced by Topoisomerase Misfunction.International journal of molecular sciences · 2024Review
- Structural insights into the assembly of type IIA topoisomerase DNA cleavage-religation center.Nucleic acids research · 2024Article
- Modeling allosteric mechanisms of eukaryotic type II topoisomerases.Biophysical journal · 2024Article
- A unified view on enzyme catalysis by cryo-EM study of a DNA topoisomerase.Communications chemistry · 2024Article
- Naturally mutagenic sequence diversity in a human type II topoisomerase.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Extensive Bioinformatics Analyses Reveal a Phylogenetically Conserved Winged Helix (WH) Domain (Zτ) of Topoisomerase IIα, Elucidating Its Very High Affinity for Left-Handed Z-DNA and Suggesting Novel Putative Functions.International journal of molecular sciences · 2023Article
- Recurrent mutations in topoisomerase IIα cause a previously undescribed mutator phenotype in human cancers.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Article
- The interplay between DNA topoisomerase 2α post-translational modifications and drug resistance.Cancer drug resistance (Alhambra, Calif.) · 2020Review
- Topoisomerases and cancer chemotherapy: recent advances and unanswered questions.F1000Research · 2019Review
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Authors and funding
6 authors at 5 institutions in 2 countries.
Funding
Abstract
Type II topoisomerases catalyze essential DNA transactions and are proven drug targets. 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 'landscape' 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 hTOP2β) is additionally revealed to be significantly regulated by the enzymes' 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.
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