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Science 328 (5975): 240-243

Copyright © 2010 by the American Association for the Advancement of Science

Arsenic Trioxide Controls the Fate of the PML-RAR{alpha} Oncoprotein by Directly Binding PML

Xiao-Wei Zhang,1,* Xiao-Jing Yan,1,* Zi-Ren Zhou,2 Fei-Fei Yang,3 Zi-Yu Wu,3 Hong-Bin Sun,4 Wen-Xue Liang,1 Ai-Xin Song,2 Valérie Lallemand-Breitenbach,5 Marion Jeanne,5 Qun-Ye Zhang,1 Huai-Yu Yang,6 Qiu-Hua Huang,1 Guang-Biao Zhou,7 Jian-Hua Tong,1 Yan Zhang,1 Ji-Hui Wu,4 Hong-Yu Hu,2 Hugues de Thé,5,8 Sai-Juan Chen,1,8,{dagger} Zhu Chen1,8,{dagger}

Abstract: Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide (As2O3) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells, PML-RAR{alpha} (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RAR{alpha} degradation is triggered by their SUMOylation, but the mechanism by which As2O3 induces this posttranslational modification is unclear. Here we show that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RAR{alpha} and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)–conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation. The identification of PML as a direct target of As2O3 provides new insights into the drug’s mechanism of action and its specificity for APL.

1 State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.
2 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS), Shanghai 200031, China.
3 National Synchrotron Radiation Laboratory, University of Science and Technology of China and Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, CAS, Beijing 10004, China.
4 Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China.
5 Université de Paris 7/INSERM/CNRS UMR 944/7151, Equipe Labellisée No. 11 Ligue Nationale Contre le Cancer, Hôpital St. Louis, Avenue C. Vellefaux, 75475 Paris CEDEX 10, France.
6 Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, CAS, Shanghai 201203, China.
7 Laboratory of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, and Key Laboratory of Stem Cell Development, Institute of Zoology, CAS, Beijing, China.
8 The Pôle Sino-Français de génomique et de Sciences du vivant de l’Hôpital Rui-Jin, 197 Rui-Jin Road II, Shanghai, China.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: zchen{at} (Z.C.); sjchen{at} (S.-J.C.)

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