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SUMO-1 conjugation to intact DNA topoisomerase I amplifies cleavable complex formation induced by camptothecin

Oncogene volume 21, pages 7913–7922 (2002)Cite this article

Abstract

DNA topoisomerase I (Topo1) manages the topological state of DNA. Cleavable complexes, the covalent Topo1–DNA intermediates, become DNA damaged when the catalytic cycles are inhibited by the anti-tumor drug camptothecin (CPT). Intriguingly, Topo1 is modified rapidly and extensively with SUMO-1, a ubiquitin-like protein, in response to CPT. This study shows that the sumoylation enhances the cleavable complex formation and apoptosis induced by CPT. Indeed, substitutions of Lys117 and Lys153, identified as Topo1 sumoylation sites, reduced the CPT-induced cleavable complexes without influencing its in vitro catalytic activity. Consistent with this observation, CPT-induced cleavable complexes of wild-type Topo1 increased in a sumoylation-dependent manner. We also found that Topo1 sumoylation occurred independently of CPT when Topo1 was inactivated by mutation of the catalytic Tyr723. These findings suggested that Topo1 inactivation by CPT treatment can trigger Topo1 sumoylation, leading to enhanced cleavable complex formation.

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Acknowledgements

We thank Drs Mikihiko Naito and Naoya Fujita for helpful discussions. This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas Cancer from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by the Nishi Cancer Research Fund.

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Authors and Affiliations

  1. Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, o113-0032, Tokyo, Japan

    Koji Horie, Akihiro Tomida & Takashi Tsuruo

  2. Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan

    Koji Horie, Toshiharu Yasugi & Yuji Taketani

  3. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Toshima-ku, 170-8455, Tokyo, Japan

    Yoshikazu Sugimoto & Takashi Tsuruo

  4. Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennohdai, Tsukuba, 305-8575, Ibaraki, Japan

    Hiroyuki Yoshikawa

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  1. Koji Horie
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Correspondence to Takashi Tsuruo.

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Horie, K., Tomida, A., Sugimoto, Y. et al. SUMO-1 conjugation to intact DNA topoisomerase I amplifies cleavable complex formation induced by camptothecin. Oncogene 21, 7913–7922 (2002). https://doi.org/10.1038/sj.onc.1205917

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