2024年9月2日 / 最終更新日 : 2024年9月2日 ad_y ニュース

2024年 新着論文 45　細胞情報学分野から論文が発表されました

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

Nat Commun. 2024 Aug 28;15(1):7359. doi: 10.1038/s41467-024-50498-4.

Authors

Satoshi Kaito  1   2 , Kazumasa Aoyama  1   3 , Motohiko Oshima  1 , Akiho Tsuchiya  1 , Makiko Miyota  1 , Masayuki Yamashita  1   4 , Shuhei Koide  1 , Yaeko Nakajima-Takagi  1 , Hiroko Kozuka-Hata  5 , Masaaki Oyama  5 , Takao Yogo  6 , Tomohiro Yabushita  7 , Ryoji Ito  8 , Masaya Ueno  9 , Atsushi Hirao  9 , Kaoru Tohyama  10 , Chao Li  11 , Kimihito Cojin Kawabata  12 , Kiyoshi Yamaguchi  13 , Yoichi Furukawa  13 , Hidetaka Kosako  14 , Akihide Yoshimi  2 , Susumu Goyama  15 , Yasuhito Nannya  16 , Seishi Ogawa  17   18 , Karl Agger  19 , Kristian Helin  19   20 , Satoshi Yamazaki  6   21 , Haruhiko Koseki  22   23 , Noriko Doki  24 , Yuka Harada  25 , Hironori Harada  24   26 , Atsuya Nishiyama  27 , Makoto Nakanishi  27 , Atsushi Iwama  28   29

Affiliations

  • 1 Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 2 Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo, Japan.
  • 3 Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan.
  • 4 Division of Experimental Hematology, Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, USA.
  • 5 Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 6 Division of Cell Regulation, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 7 Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 8 Central Institute for Experimental Animals, Yokohama, Kanagawa, Japan.
  • 9 Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
  • 10 Department of Laboratory Medicine, Kawasaki Medical School, Okayama, Japan.
  • 11 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
  • 12 Division of Clinical Precision Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 13 Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 14 Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
  • 15 Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
  • 16 Division of Hematopoietic Disease Control, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 17 Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 18 Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
  • 19 BRIC University of Copenhagen, Copenhagen, Denmark.
  • 20 The Institute of Cancer Research (ICR), London, UK.
  • 21 Division of Cell Engineering, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 22 Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 23 Department of Molecular and Cellular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • 24 Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
  • 25 Clinical Research Support Center, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
  • 26 Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
  • 27 Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  • 28 Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 03aiwama@ims.u-tokyo.ac.jp.
  • 29 Laboratory of Cellular and Molecular Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. 03aiwama@ims.u-tokyo.ac.jp.

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.

© 2024. The Author(s).

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