Reversible regulation of ORC2 SUMOylation by PIAS4 and SENP2

Abstract

The small ubiquitin-related modifier (SUMO) system is essential for smooth progression of cell cycle at the G2/M phase. Many centromeric proteins are reversibly SUMOylated to ensure proper chromosome segregation at the mitosis. SUMOylation of centromeric Origin Recognition Complex subunit 2 (ORC2) at the G2/M phase is essential in maintaining genome integrity. However, how ORC2 SUMOylation is regulated remains largely unclear. Here we show that ORC2 SUMOylation is reversibly controlled by SUMO E3 ligase PIAS4 and De-SUMOylase SENP2. Either depletion of PIAS4 or overexpression of SENP2 eliminated SUMOylation of ORC2 at the G/M phase and consequently resulted in abnormal centromeric histone H3 lysine 4 methylation. Cells stably expressing SENP2 protein or small interfering RNA for PIAS4 bypassed mitosis and endoreduplicated their genome to become polyploidy. Furthermore, percentage of polyploid cells is reduced after coexpression of ORC2-SUMO2 fusion protein. Thus, the proper regulation of ORC2 SUMOylation at the G2/M phase by PIAS4 and SENP2 is critical for smooth progression of the mitotic cycle of cells.

Nonreplicative functions of the origin recognition complex

“…It has been shown that ORC2 localizes to the centromeres during the cell cycle G2/M phase [43,54,55] (Figure 1a). Post-translational modification of ORC2 with the SUMO2 attachment is important for the maintenance of centromeric histone H3 methylation status, and the prevention of heterochromatin re-replication via the recruitment of demethylase KDM5A [8] (Figure 1b). Moreover, the regulation of ORC2 SUMOylation at the G2/M phase is critical for smooth progression of the mitotic cycle of cells.…”

“…In contrast, in metazoa, ORC has a more dynamic interaction with DNA. For example, the complex is not bound to the chromatin during the S and M phases in Xenopus [7] and human cells [8]. Interestingly, in Drosophila and human cells, the ORC1 subunit appears to be a key regulator of ORC replicative function.…”

“…This subunit is degraded at the end of the M phase by the anaphase-promoting complex in Drosophila [9], while in human, it undergoes an ubiquitin-mediated proteolysis at the end of the G1/S transition [10]. However, in both organisms, ORC1 re-binding to chromatin is essential for the pre-RC assembly during G1 phase [7,8]. Moreover, in mammals the BAH (bromo-adjacent homology) domain of ORC1 recognizes the H4K20me2 modification [11], which is associated with replication.…”

<p>Desumoylation of aggrecan and collagen II facilitates degradation via aggrecanases in IL-1β-mediated osteoarthritis</p>

“…Among them, SENP1 and SENP2 are closely connected and are involved in both SUMO maturation and deconjugation 11. Wang et al showed that SENP2 is a desumoylation protease that has a significant role in the modulation of transforming growth factor-β signaling 12. Based on these previous studies, we decided to investigate the relationship between the highly homologous SUMO family members and the progressive loss of aggrecan during OA progression, and whether SENPs are involved in OA.…”