CONJUGATION WITH THE UBIQUITIN-RELATED MODIFIER SUMO-1 REGULATES THE PARTITIONING OF PML WITHIN THE NUCLEUS

The PML protein, identified first as part of the oncogenic PML-RAR alp ha chimera in acute promyelocytic leukemia (APL), concentrates within discrete subnuclear structures, corresponding to some types of nuclear bodies, These structures are disrupted in APL cells, and retinoic aci d (RA) can trigger their reorganization, correlating with its therapeu tic effect in this type of leukemia, Recently, arsenic trioxide (AS(2) O(3)) was identified as a potent antileukemic agent which, similarly t o RA, induces complete remissions in APL patients: Here we show that, in APL cells, As2O3 triggers rapid degradation of PML-RAR alpha and pr ovokes the restoration of intact nuclear bodies, In non-APL cells, the ubiquitin-like protein SUMO-1 is covalently attached to a subset of w ild-type PML in a reversible and phosphorylation-dependent manner. The unmodified form of PML, is found in the soluble nucleoplasmic fractio n, whereas the SUMO-1-polymodified forms of PML are compartmentalized exclusively in the PML nuclear bodies, As2O3 administration strikingly increases the pool of SUMO-1-PML conjugates that, subsequently, accum ulate in enlarged nuclear bodies, In contrast to PML-RAR alpha, the ov erall amount of PML seems to remain unaltered up to 36 h following As2 O3 treatment, These findings indicate that the conjugation of PML with SUMO-1 modulates its intracellular localization and suggest that post -translational modification by SUMO-1 may be more generally involved t han previously suspected in the targeting of proteins to distinct subc ellular structures, They provide additional evidence that the role of 'ubiquitin-like' post-translational modification is not limited to a d egradation signal.