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

Satoshi Kaito, Kazumasa Aoyama, Motohiko Oshima, Akiho Tsuchiya, Makiko Miyota, Masayuki Yamashita, Shuhei Koide, Yaeko Nakajima-Takagi, Hiroko Kozuka-Hata, Masaaki Oyama, Takao Yogo, Tomohiro Yabushita, Ryoji Ito, Masaya Ueno, Atsushi Hirao, Kaoru Tohyama, Chao Li, Kimihito Cojin Kawabata, Kiyoshi Yamaguchi, Yoichi Furukawa, Hidetaka Kosako, Akihide Yoshimi, Susumu Goyama, Yasuhito Nannya, Seishi Ogawa, Karl Agger, Kristian Helin, Satoshi Yamazaki, Haruhiko Koseki, Noriko Doki, Yuka Harada, Hironori Harada, Atsuya Nishiyama, Makoto Nakanishi and Atsushi Iwama ()
Additional contact information
Satoshi Kaito: The University of Tokyo
Kazumasa Aoyama: The University of Tokyo
Motohiko Oshima: The University of Tokyo
Akiho Tsuchiya: The University of Tokyo
Makiko Miyota: The University of Tokyo
Masayuki Yamashita: The University of Tokyo
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
Karl Agger: BRIC University of Copenhagen
Kristian Helin: BRIC University of Copenhagen
Satoshi Yamazaki: The University of Tokyo
Haruhiko Koseki: RIKEN Center for Integrative Medical Sciences
Noriko Doki: Komagome Hospital
Yuka Harada: Komagome Hospital
Hironori Harada: Komagome Hospital
Atsuya Nishiyama: University of Tokyo
Makoto Nakanishi: University of Tokyo
Atsushi Iwama: The University of Tokyo

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50498-4

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