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Inhibition of TOPORS ubiquitin ligase augments the efficacy of DNA hypomethylating agents through DNMT1 stabilization

Author

Listed:
  • Satoshi Kaito

    (The University of Tokyo
    National Cancer Center Research Institute)

  • Kazumasa Aoyama

    (The University of Tokyo
    Keio University)

  • Motohiko Oshima

    (The University of Tokyo)

  • Akiho Tsuchiya

    (The University of Tokyo)

  • Makiko Miyota

    (The University of Tokyo)

  • Masayuki Yamashita

    (The University of Tokyo
    St. Jude Children’s Research Hospital)

  • Shuhei Koide

    (The University of Tokyo)

  • Yaeko Nakajima-Takagi

    (The University of Tokyo)

  • Hiroko Kozuka-Hata

    (The University of Tokyo)

  • Masaaki Oyama

    (The University of Tokyo)

  • Takao Yogo

    (The University of Tokyo)

  • Tomohiro Yabushita

    (The University of Tokyo)

  • Ryoji Ito

    (Central Institute for Experimental Animals)

  • Masaya Ueno

    (Kanazawa University)

  • Atsushi Hirao

    (Kanazawa University)

  • Kaoru Tohyama

    (Kawasaki Medical School)

  • Chao Li

    (The University of Tokyo)

  • Kimihito Cojin Kawabata

    (The University of Tokyo)

  • Kiyoshi Yamaguchi

    (The University of Tokyo)

  • Yoichi Furukawa

    (The University of Tokyo)

  • Hidetaka Kosako

    (Tokushima University)

  • Akihide Yoshimi

    (National Cancer Center Research Institute)

  • Susumu Goyama

    (The University of Tokyo)

  • Yasuhito Nannya

    (The University of Tokyo)

  • Seishi Ogawa

    (Kyoto University
    Kyoto University)

  • Karl Agger

    (BRIC University of Copenhagen)

  • Kristian Helin

    (BRIC University of Copenhagen
    The Institute of Cancer Research (ICR))

  • Satoshi Yamazaki

    (The University of Tokyo
    The University of Tokyo)

  • Haruhiko Koseki

    (RIKEN Center for Integrative Medical Sciences
    Chiba University)

  • Noriko Doki

    (Komagome Hospital)

  • Yuka Harada

    (Komagome Hospital)

  • Hironori Harada

    (Komagome Hospital
    Tokyo University of Pharmacy and Life Sciences)

  • Atsuya Nishiyama

    (University of Tokyo)

  • Makoto Nakanishi

    (University of Tokyo)

  • Atsushi Iwama

    (The University of Tokyo
    The University of Tokyo)

Abstract

DNA hypomethylating agents (HMAs) are used for the treatment of myeloid malignancies, although their therapeutic effects have been unsatisfactory. Here we show that CRISPR-Cas9 screening reveals that knockout of topoisomerase 1-binding arginine/serine-rich protein (TOPORS), which encodes a ubiquitin/SUMO E3 ligase, augments the efficacy of HMAs on myeloid leukemic cells with little effect on normal hematopoiesis, suggesting that TOPORS is involved in resistance to HMAs. HMAs are incorporated into the DNA and trap DNA methyltransferase-1 (DNMT1) to form DNA-DNMT1 crosslinks, which undergo SUMOylation, followed by proteasomal degradation. Persistent crosslinking is cytotoxic. The TOPORS RING finger domain, which mediates ubiquitination, is responsible for HMA resistance. In TOPORS knockout cells, DNMT1 is stabilized by HMA treatment due to inefficient ubiquitination, resulting in the accumulation of unresolved SUMOylated DNMT1. This indicates that TOPORS ubiquitinates SUMOylated DNMT1, thereby promoting the resolution of DNA-DNMT1 crosslinks. Consistently, the ubiquitination inhibitor, TAK-243, and the SUMOylation inhibitor, TAK-981, show synergistic effects with HMAs through DNMT1 stabilization. Our study provides a novel HMA-based therapeutic strategy that interferes with the resolution of DNA-DNMT1 crosslinks.

Suggested Citation

  • Satoshi Kaito & Kazumasa Aoyama & Motohiko Oshima & Akiho Tsuchiya & Makiko Miyota & Masayuki Yamashita & Shuhei Koide & Yaeko Nakajima-Takagi & Hiroko Kozuka-Hata & Masaaki Oyama & Takao Yogo & Tomoh, 2024. "Inhibition of TOPORS ubiquitin ligase augments the efficacy of DNA hypomethylating agents through DNMT1 stabilization," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50498-4
    DOI: 10.1038/s41467-024-50498-4
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    References listed on IDEAS

    as
    1. Atsuya Nishiyama & Luna Yamaguchi & Jafar Sharif & Yoshikazu Johmura & Takeshi Kawamura & Keiko Nakanishi & Shintaro Shimamura & Kyohei Arita & Tatsuhiko Kodama & Fuyuki Ishikawa & Haruhiko Koseki & M, 2013. "Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication," Nature, Nature, vol. 502(7470), pages 249-253, October.
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