Effects of arsenic on the topology and solubility of promyelocytic leukemia (PML)-nuclear bodies

Abstract

Promyelocytic leukemia (PML) proteins are involved in the pathogenesis of acute promyelocytic leukemia (APL). Trivalent arsenic (As3+) is known to cure APL by binding to cysteine residues of PML and enhance the degradation of PML-retinoic acid receptor (RAR), a t(15;17) gene translocation product in APL cells, and restore PML-nuclear bodies (NBs). The size, number, and shape of PML-NBs vary among cell types and during cell division. However, topological changes of PML-NBs in As3+-exposed cells have not been well-documented. We report that As3+-induced solubility shift underlies rapid SUMOylation of PML and late aggregation of PML-NBs. Most PML-NBs were toroidal and irregular-shaped in GFPPML-transduced CHO-K1 and HEK293 cells, respectively. The annular PML-NBs appeared unstable and dissipated into small PML-NBs in HEK cells. Exposure to As3+ and antimony (Sb3+) greatly reduced the solubility of PML and enhanced SUMOylation within 2 h, and prolonged exposure resulted in PML-NB agglomeration. Exposure to bismuth (Bi3+), another Group 15 element, did not induce any of these changes. ML792, a SUMO activation inhibitor, reduced the number of PML-NBs and increased the size of the NBs, but had little effect on the As3+-induced solubility change of PML. The results show that SUMOylation regulates the dynamics of PML-NBs but does not contribute to the As3+-induced solubility change of PML.