American Association for Cancer Research
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cd-23-0453_supplementary_figure_s2_suppsf2.pdf (24.91 MB)

Supplementary Figure S2 from Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function

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journal contribution
posted on 2023-12-12, 08:20 authored by Pierre Bercier, Qian Qian Wang, Ning Zang, Jie Zhang, Chang Yang, Yasen Maimaitiyiming, Majdouline Abou-Ghali, Caroline Berthier, Chengchen Wu, Michiko Niwa-Kawakita, Thassadite Dirami, Marie-Claude Geoffroy, Omar Ferhi, Samuel Quentin, Shirine Benhenda, Yasumitsu Ogra, Zoher Gueroui, Chun Zhou, Hua Naranmandura, Hugues de Thé, Valérie Lallemand-Breitenbach

Figure S2 shows Crystal structure of MBP-B2 fusion protein, and the similarity between the 3D structure of PML B2 and other TRIM proteins, yet its formation relies on specific amino acids

Funding

Institut National de la Santé et de la Recherche Médicale (Inserm)

Institut des sciences biologiques (INSB)

Collège de France (Le Collège de France)

Alliance Nationale pour les Sciences de la Vie et de la Santé (AVIESAN)

Fondation du Collège de France

European Research Council (ERC)

Sjöbergstiftelsen (Sjöberg Foundation)

National Natural Science Foundation of China (NSFC)

Zhejiang University Student Science and Technology Innovation Activity Plan (浙江省大学生科技创新活动计划)

Fondation ARC pour la Recherche sur le Cancer (ARC)

History

ARTICLE ABSTRACT

PML nuclear bodies (NB) are disrupted in PML-RARA–driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% of patients with APL, driving PML-RARA degradation and NB reformation. In non-APL cells, arsenic binding onto PML also amplifies NB formation. Yet, the actual molecular mechanism(s) involved remain(s) elusive. Here, we establish that PML NBs display some features of liquid–liquid phase separation and that ATO induces a gel-like transition. PML B-box-2 structure reveals an alpha helix driving B2 trimerization and positioning a cysteine trio to form an ideal arsenic-binding pocket. Altering either of the latter impedes ATO-driven NB assembly, PML sumoylation, and PML-RARA degradation, mechanistically explaining clinical ATO resistance. This B2 trimer and the C213 trio create an oxidation-sensitive rheostat that controls PML NB assembly dynamics and downstream signaling in both basal state and during stress response. These findings identify the structural basis for arsenic targeting of PML that could pave the way to novel cancer drugs. Arsenic curative effects in APL rely on PML targeting. We report a PML B-box-2 structure that drives trimer assembly, positioning a cysteine trio to form an arsenic-binding pocket, which is disrupted in resistant patients. Identification of this ROS-sensitive triad controlling PML dynamics and functions could yield novel drugs.See related commentary by Salomoni, p. 2505.This article is featured in Selected Articles from This Issue, p. 2489