Arsenic trioxide stimulates SUMO-2/3 modification leading to RNF4-dependent proteolytic targeting of PML

• Published in: FEBS letters Vol. 582; no. 21; pp. 3174 - 3178
• Main Authors: Weisshaar, Stefan R., Keusekotten, Kirstin, Krause, Anke, Horst, Christiane, Springer, Helen M., Göttsche, Kerstin, Dohmen, R. Jürgen, Praefcke, Gerrit J.K.
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 22.09.2008
• Subjects: 6×His tag; Antineoplastic Agents - pharmacology; arsenic trioxide; Arsenicals - pharmacology; ATO; Cell Line, Tumor; Down-Regulation; glutathione; glutathione S-transferase; GSH; GST; His6; Humans; Leukemia, Promyelocytic, Acute - metabolism; Ni-NTA; nickel-nitrilo triacetic acid; nuclear body; Nuclear Proteins - metabolism; Oxides - pharmacology; PML; Promyelocytic leukemia; Proteasome Endopeptidase Complex - metabolism; Protein degradation; relatively interesting new gene; Relatively interesting new gene finger; RING; RING finger protein 4; RNF4; SAE; SIM; Small ubiquitin-like modifier; small ubiquitin-related modifier; Small Ubiquitin-Related Modifier Proteins - metabolism; SUMO; SUMO activating enzyme; SUMO conjugating enzyme; SUMO interaction motif; Transcription Factors - metabolism; UBC9; Ubiquitin; ubiquitin ligase for SUMO conjugates; Ubiquitination - drug effects; Ubiquitins - metabolism; ULS; His 6; Ubiquitin; Promyelocytic leukemia; Protein degradation; SUMO; UBC9; GST; RNF4; Relatively interesting new gene finger; PML; NB; Small ubiquitin-like modifier; RING; SAE; SIM; ATO; GSH; ULS; Ni-NTA
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2008.08.008

We have recently reported that poly-SUMO-2/3 conjugates are subject to a ubiquitin-dependent proteolytic control in human cells. Here we show that arsenic trioxide (ATO) increases SUMO-2/3 modification of promyelocytic leukemia (PML) leading to its subsequent ubiquitylation in vivo. The SUMO-binding ubiquitin ligase RNF4 mediates this modification and causes disruption of PML nuclear bodies upon treatment with ATO. Reconstitution of SUMO-dependent ubiquitylation of PML by RNF4 in vitro and in a yeast trans vivo system revealed a preference of RNF4 for chain forming SUMOs. Polysumoylation of PML in response to ATO thus leads to its recognition and ubiquitylation by RNF4.