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.
Highlights
Accumulation of genetic and/or epigenetic alterations can cause cell transformation and initiate tumorigenesis
We have shown previously that Origin Recognition Complex subunit 2 (ORC2) is SUMOylated at the G2/M phase of cell cycle and SUMOylation of ORC2 is critical for smooth transition of mitosis [42]; how ORC2 SUMOylation is controlled during cell cycle progression is unknown
To search for the small ubiquitin-related modifier (SUMO) E3 ligase and DeSUMOylase that are responsible for regulation of ORC2 SUMOylation, various SUMO E3 ligases or DeSUMOylases were overexpressed in U2OS cells (Figure 1A, 1B)
Summary
Accumulation of genetic and/or epigenetic alterations can cause cell transformation and initiate tumorigenesis. Genomic instability and its evolution in cancer cells increase tumor heterogeneity and result in an ever more aggressive phenotype [1, 2]. One of the mechanisms for evolution of genomic instability is a transient phase of polyploidization or tetraploidization, which may result from endoreduplication (DNA replication without mitosis), endomitosis (karyokinesis without cytokinesis) or aberrant cell fusion [3,4,5,6]. P53 is critical for initiates senescence or apoptosis induced by formation of tetraploidy that is caused by cell fusion, endoreplication, or endomitosis [9,10,11]. Tetraploidy and/or polyploidy promote the chromosomal rearrangements, translocations or gene amplifications that are major forces for cancer evolution and eventually results in aneuploidy and tumor heterogeneity, which is a hallmark of solid human cancer [5, 19]
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