PML, the organizer of nuclear bodies (NBs), is expressed in several isoforms 
designated PMLI to VII which differ in their C-terminal region due to 
alternative splicing of a single gene. This variability is important for the 
function of the different PML isoforms. PML NB formation requires the covalent 
linkage of SUMO to PML. Arsenic trioxide (As₂O₃) enhances PML SUMOylation 
leading to an increase in PML NB size and promotes its interaction with RNF4, a 
poly-SUMO-dependent ubiquitin E3 ligase responsible for proteasome-mediated PML 
degradation. Furthermore, the presence of a bona fide SUMO Interacting Motif 
(SIM) within the C-terminal region of PML seems to be required for recruitment 
of other SUMOylated proteins within PML NBs. This motif is present in all PML 
isoforms, except in the nuclear PMLVI and in the cytoplasmic PMLVII. Using a 
bioluminescence resonance energy transfer (BRET) assay in living cells, we found 
that As₂O₃ enhanced the SUMOylation and interaction with RNF4 of nuclear PML 
isoforms (I to VI). In addition, among the nuclear PML isoforms, only the one 
lacking the SIM sequence, PMLVI, was resistant to As₂O₃-induced PML degradation. 
Similarly, mutation of the SIM in PMLIII abrogated its sensitivity to 
As₂O₃-induced degradation. PMLVI and PMLIII-SIM mutant still interacted with 
RNF4. However, their resistance to the degradation process was due to their 
inability to be polyubiquitinated and to recruit efficiently the 20S core and 
the β regulatory subunit of the 11S complex of the proteasome in PML NBs. Such 
resistance of PMLVI to As₂O₃-induced degradation was alleviated by 
overexpression of RNF4. Our results demonstrate that the SIM of PML is 
dispensable for PML SUMOylation and interaction with RNF4 but is required for 
efficient PML ubiquitination, recruitment of proteasome components within NBs 
and proteasome-dependent degradation of PML in response to As₂O₃.