Research ArticlePosttranslational Modifications

SUMO deconjugation is required for arsenic-triggered ubiquitylation of PML

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Sci. Signal.  09 Jun 2015:
Vol. 8, Issue 380, pp. ra56
DOI: 10.1126/scisignal.aaa3929

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SUMO switching for degradation

Promyelocytic leukemia protein (PML) organizes various proteins into structures called PML nuclear bodies. Acute promyelocytic leukemia is caused by a fusion protein consisting of PML and the transcription factor RARα. Degradation of this oncoprotein can be induced by arsenic trioxide chemotherapy through modification of PML by SUMO1, SUMO2, and ubiquitin. Fasci et al. found that in untreated cells, SUMO2 was constantly added to Lys65 in PML and constantly removed from this residue by the deconjugating enzyme SENP1. In cells exposed to arsenic trioxide, SUMO1, rather than SUMO2, was conjugated to Lys65, which led to the formation of SUMO2 chains on a different residue, Lys160, that in turn triggered the ubiquitylation of PML, as well as reorganization of PML nuclear bodies. These results further define how arsenic trioxide induces the degradation of the RARα-PML oncoprotein, by promoting an exchange of SUMO paralogs on a “switch” residue that stimulates SUMO modification on a “chain” residue.


Acute promyelocytic leukemia is characterized by a chromosomal translocation that produces an oncogenic fusion protein of the retinoic acid receptor α (RARα) and promyelocytic leukemia protein (PML). Arsenic trioxide chemotherapy of this cancer induces the PML moiety to organize nuclear bodies, where the oncoprotein is degraded. This process requires the participation of two SUMO paralogs (SUMO1 and SUMO2) to promote PML ubiquitylation mediated by the ubiquitin E3 ligase RNF4 and reorganization of PML nuclear bodies. We demonstrated that the ubiquitylation of PML required the SUMO deconjugation machinery, primarily the deconjugating enzyme SENP1, and was suppressed by expression of non-deconjugatable SUMO2. We hypothesized that constitutive SUMO2 conjugation and deconjugation occurred basally and that arsenic trioxide treatment caused the exchange of SUMO2 for SUMO1 on a fraction of Lys65 in PML. On the basis of data obtained with mutational analysis and quantitative proteomics, we propose that the SUMO switch at Lys65 of PML enhanced nuclear body formation, subsequent SUMO2 conjugation to Lys160, and consequent RNF4-dependent ubiquitylation of PML. Our work provides insights into how the SUMO system achieves selective SUMO paralog modification and highlights the crucial role of SENPs in defining the specificity of SUMO signaling.

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