Arsenic is a clinically effective treatment for acute promyelocytic leukaemia 
(APL) in which the promyelocytic leukaemia (PML) protein is fused to retinoic 
receptor alpha (RARα). PML-RARα is degraded by the proteasome by a 
SUMO-dependent, ubiquitin-mediated pathway in response to arsenic treatment, 
curing the disease. Six major PML isoforms are expressed as a result of 
alternative splicing, each of which encodes a unique C-terminal region. Using a 
system in which only a single EYFP-linked PML isoform is expressed, we 
demonstrate that PMLI, PMLII and PMLVI accumulate in the cytoplasm following 
arsenic treatment, whereas PMLIII, PMLIV and PMLV do not. 3D structured 
illumination was used to obtain super-resolution images of PML bodies, revealing 
spherical shells of PML along with associated SUMO. Arsenic treatment results in 
dramatic isoform-specific changes to PML body ultrastructure. After extended 
arsenic treatment most PML isoforms are degraded, leaving SUMO at the core of 
the nuclear bodies. A high-content imaging assay identifies PMLV as the isoform 
most readily degraded following arsenic treatment, and PMLIV as relatively 
resistant to degradation. Immunoprecipitation analysis demonstrates that all PML 
isoforms are modified by SUMO and ubiquitin after arsenic treatment, and by 
using siRNA, we demonstrate that arsenic-induced degradation of all PML isoforms 
is dependent on the ubiquitin E3 ligase RNF4. Intriguingly, depletion of RNF4 
results in marked accumulation of PMLV, suggesting that this isoform is an 
optimal substrate for RNF4. Thus the variable C-terminal domain influences the 
rate and location of degradation of PML isoforms following arsenic treatment.