Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML.
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-RARalpha (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RARalpha 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-RARalpha 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.
Zhang
Xiao-Wei
XW
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.
Yan
Xiao-Jing
XJ
Zhou
Zi-Ren
ZR
Yang
Fei-Fei
FF
Wu
Zi-Yu
ZY
Sun
Hong-Bin
HB
Liang
Wen-Xue
WX
Song
Ai-Xin
AX
Lallemand-Breitenbach
Valérie
V
Jeanne
Marion
M
Zhang
Qun-Ye
QY
Yang
Huai-Yu
HY
Huang
Qiu-Hua
QH
Zhou
Guang-Biao
GB
Tong
Jian-Hua
JH
Zhang
Yan
Y
Wu
Ji-Hui
JH
Hu
Hong-Yu
HY
de Thé
Hugues
H
Chen
Sai-Juan
SJ
Chen
Zhu
Z
D001151:Arsenic / Q000378:metabolism*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism* / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010078:Oxazines / Q000378:metabolism; D010087:Oxides / Q000378:metabolism* / Q000494:pharmacology*; D000071156:Promyelocytic Leukemia Protein; D011487:Protein Conformation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D016335:Zinc Fingers
D001152:Arsenicals; D050505:Mutant Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010078:Oxazines; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; C454115:ReAsH-EDT2 compound; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C530734:p-aminophenylarsine oxide; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human; D001151:Arsenic; D000077237:Arsenic Trioxide