title: Arsenic trioxide stimulates SUMO-2/3 modification leading to RNF4-dependent proteolytic targeting of PML.
abstract: 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.
authors: Center for Molecular Medicine Cologne (CMMC), Institute for Genetics, Zülpicher Strasse 47, 50674 Köln, Germany.
authors: Stefan R
authors: SR
authors: Weisshaar
authors: Kirstin
authors: K
authors: Keusekotten
authors: Anke
authors: A
authors: Krause
authors: Christiane
authors: C
authors: Horst
authors: Helen M
authors: HM
authors: Springer
authors: Kerstin
authors: K
authors: Göttsche
authors: R Jürgen
authors: RJ
authors: Dohmen
authors: Gerrit J K
authors: GJ
authors: Praefcke
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D009687:Nuclear Proteins; D010087:Oxides; C114070:RNF4 protein, human; C117909:SUMO2 protein, human; C492189:SUMO3 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D014452:Ubiquitins; D046988:Proteasome Endopeptidase Complex; D000077237:Arsenic Trioxide