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

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 α (RARα), 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 agglomeration of PML-NBs. Most PML-NBs were toroidal and granular dot-like in GFPPML-transduced CHO-K1 and HEK293 cells, respectively. Exposure to As3+ and antimony (Sb3+) greatly reduced the solubility of PML and enhanced SUMOylation within 2 h in the absence of changes in the number and size of PML-NBs. However, the prolonged exposure to As3+ and Sb3+ resulted in agglomeration of PML-NBs. 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. These results warrant the importance of As3+- or Sb3+-induced solubility shift of PML for the regulation intranuclear dynamics of PML-NBs.

 

Comments:

The passage you provided discusses the role of promyelocytic leukemia (PML) proteins in acute promyelocytic leukemia (APL) and the effects of trivalent arsenic (As3+) on PML and PML nuclear bodies (NBs). Here's a breakdown of the key points:

1. Acute promyelocytic leukemia (APL): APL is a type of leukemia characterized by a specific genetic translocation, t(15;17), which results in the fusion of the PML gene on chromosome 15 with the retinoic acid receptor α (RARα) gene on chromosome 17. This fusion protein, PML-RARα, plays a crucial role in the development of APL.

2. Trivalent arsenic (As3+) treatment: As3+ has been shown to effectively cure APL. It binds to cysteine residues of PML and enhances the degradation of PML-RARα. Additionally, As3+ helps restore the structure and function of PML nuclear bodies (PML-NBs), which are subnuclear structures involved in various cellular processes.

3. Size, number, and shape of PML-NBs: PML-NBs can vary in size, number, and shape among different cell types and during cell division. The specific characteristics of PML-NBs in relation to As3+ treatment have not been extensively studied.

4. As3+-induced solubility shift and SUMOylation: The researchers report that exposure to As3+ induces a solubility shift in PML, leading to the formation of insoluble protein aggregates. This solubility shift is accompanied by rapid SUMOylation of PML. SUMOylation is the process of attaching small ubiquitin-like modifier (SUMO) proteins to target proteins, which can affect their function and localization.

5. Late agglomeration of PML-NBs: Prolonged exposure to As3+ leads to the agglomeration of PML-NBs, indicating changes in the structure and organization of these subnuclear bodies.

6. Effects of antimony (Sb3+) and bismuth (Bi3+): Similar to As3+, exposure to antimony (Sb3+) enhances SUMOylation and reduces PML solubility, ultimately leading to agglomeration of PML-NBs. However, bismuth (Bi3+), another Group 15 element, does not induce these changes.

7. ML792 and PML-NBs: ML792, a SUMO activation inhibitor, reduces the number of PML-NBs and increases their size but has a limited effect on the solubility change of PML induced by As3+.

In summary, the study suggests that As3+ and Sb3+ induce a solubility shift in PML, leading to rapid SUMOylation and late agglomeration of PML-NBs. These findings highlight the importance of the As3+-induced solubility change of PML in regulating the intranuclear dynamics of PML-NBs.
 

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S8697 ML792 ML-792 is a potent and selective inhibitor of SUMO (small ubiquitin-like modifier)-activating enzyme (SAE). ML-792 inhibits SAE/SUMO1 and SAE/SUMO2 in ATP–inorganic pyrophosphate (PPi) exchange assays with IC50 of 3 nM and 11 nM, respectively.

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E1 Activating