SUMO-specific protease 2 in Mdm2-mediated regulation of p53

Genetic analysis in mice has revealed a key genetic pathway, SUMO-specific protease 2 (SENP2)-Mdm2-p53, essential for trophoblast development. Targeted disruption of SENP2 impairs the G–S transition required for mitotic and endoreduplication cell cycles during the expansion of trophoblast stem cells and their differentiation into polyploidy cells, respectively. The disruption disturbed the subcellular distribution and SUMO modification of Mdm2, leading to interference with p53 degradation. Here, we further explore the mechanism underlying SENP2-mediated regulation of Mdm2 in p53-induced cellular stress. We identify a specific isoform of SENP2 necessary and sufficient to negatively regulate the p53-dependent transcription and its related stress responses. This isoform-specific effect is attributed to the differential compartmentalization of SENP2. SUMO conjugation of Mdm2 induces its co-localization and association with SENP2 in promyelocytic leukemia bodies. Biochemical studies show that SENP2 catalyzes the desumoylation process of Mdm2. SENP2-dependent regulation of Mdm2 is sensitive to its p53-binding activity. Our findings led us to propose a mechanism underlying the SENP2-mediated regulation of Mdm2 that is critical for genome integrity in p53-dependent stress responses.