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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Research Article

Differential and common DNA repair pathways for topoisomerase I- and II-targeted drugs in a genetic DT40 repair cell screen panel

Yuko Maede, Hiroyasu Shimizu, Toru Fukushima, Toshiaki Kogame, Terukazu Nakamura, Tsuneharu Miki, Shunichi Takeda, Yves Pommier and Junko Murai
Yuko Maede
1Radiation Genetics, Kyoto University, Graduate School of Medicine
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Hiroyasu Shimizu
2Department of Hygiene and Public Health, Osaka Medical College
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Toru Fukushima
3Department of Diabetes and Clinical Nutrition, Kyoto University, Graduate School of Medicine
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Toshiaki Kogame
4Department of Radiation Genetics, Kyoto University Graduate School of Medicine
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Terukazu Nakamura
5Department of Urology, Kyoto Prefectural University
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Tsuneharu Miki
6Urology, Kyoto Prefectural University
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Shunichi Takeda
4Department of Radiation Genetics, Kyoto University Graduate School of Medicine
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Yves Pommier
7Laboratory of Molecular Pharmacology, NIH/NCI
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Junko Murai
1Radiation Genetics, Kyoto University, Graduate School of Medicine
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  • For correspondence: murajun-osk@umin.ac.jp
DOI: 10.1158/1535-7163.MCT-13-0551
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Abstract

Clinical topoisomerase I (Top1) and II (Top2) inhibitors trap topoisomerases on DNA, thereby inducing protein-linked DNA breaks. Cancer cells resist the drugs by removing topoisomerase-DNA complexes, and repairing the drug-induced DNA double-strand breaks (DSBs) by homologous recombination (HR) and non-homologous end-joining (NHEJ). Because numerous enzymes and cofactors are involved in the removal of the topoisomerase-DNA complexes and DSB repair, it has been challenging to comprehensively analyze the relative contribution of multiple genetic pathways in vertebrate cells. Comprehending the relative contribution of individual repair factors would give insights into the lesions induced by the inhibitors and genetic determinants of response. Ultimately, this information would be useful to target specific pathways to augment the therapeutic activity of topoisomerase inhibitors. To this end, we put together 48 isogenic DT40 mutant cells deficient in DNA repair and generated one cell line deficient in autophagy (ATG5). Sensitivity profiles were established for three clinically relevant Top1 inhibitors (camptothecin and the indenoisoquinolines LMP400 and LMP776) and three topoisomerase II inhibitors (etoposide, doxorubicin and ICRF-193). Highly significant correlations were found among Top1 inhibitors as well as Top2 inhibitors, while the profiles of Top1 inhibitors were different from those of Top2 inhibitors. Most distinct repair pathways between Top1 and Top2 inhibitors include NHEJ, TDP1, TDP2, PARP1 and Fanconi Anemia genes whereas HR appears relevant especially for Top1 and to a lesser extent for Top2 inhibitors. We also found and discuss differential pathways among Top1 inhibitors and Top2 inhibitors.

  • Received July 10, 2013.
  • Revision received September 17, 2013.
  • Accepted September 30, 2013.
  • Copyright © 2013, American Association for Cancer Research.
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This OnlineFirst version was published on October 15, 2013
doi: 10.1158/1535-7163.MCT-13-0551

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Differential and common DNA repair pathways for topoisomerase I- and II-targeted drugs in a genetic DT40 repair cell screen panel
Yuko Maede, Hiroyasu Shimizu, Toru Fukushima, Toshiaki Kogame, Terukazu Nakamura, Tsuneharu Miki, Shunichi Takeda, Yves Pommier and Junko Murai
Mol Cancer Ther October 15 2013 DOI: 10.1158/1535-7163.MCT-13-0551

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Differential and common DNA repair pathways for topoisomerase I- and II-targeted drugs in a genetic DT40 repair cell screen panel
Yuko Maede, Hiroyasu Shimizu, Toru Fukushima, Toshiaki Kogame, Terukazu Nakamura, Tsuneharu Miki, Shunichi Takeda, Yves Pommier and Junko Murai
Mol Cancer Ther October 15 2013 DOI: 10.1158/1535-7163.MCT-13-0551
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Molecular Cancer Therapeutics
eISSN: 1538-8514
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