Arsenic trioxide therapy for Acute Promyelocytic Leukaemia (APL) is mediated by SUMO-dependent degradation of Promyelocytic Leukaemia (PML)-Retinoic Acid Receptor α (RARα) oncogenic fusion protein. We demonstrated (Tatham et al., 2008) that ubiquitin mediated proteolysis of PML requires RNF4 E3 ubiquitin ligase. This allows terminal differentiation of tumour cells and cures disease. The primary effect of arsenic is to dramatically increase the SUMO modification of the PML protein, however the mechanistic basis for remarkable observation remains unclear. Our objective is to establish how arsenic interacts with PML to bring about this increased modification. The project will employ a combination of structural biology and cell biology to address this problem.
- RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, Palvimo JJ, Hay RT Nat Cell Biol. 2008 May;10(5):538-46. doi: 10.1038/ncb1716. PMID:18408734 (Read more)