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Abstract
Deubiquitinating enzymes play key roles in the precise modulation of Aurora B—an essential cell cycle regulator. The expression of Aurora B increases before the onset of mitosis and decreases during mitotic exit; an imbalance in these levels has a severe impact on the fate of the cell cycle. Dysregulation of Aurora B can lead to aberrant chromosomal segregation and accumulation of errors during mitosis, eventually resulting in cytokinesis failure. Thus, it is essential to identify the precise regulatory mechanisms that modulate Aurora B levels during the cell division cycle. Using a deubiquitinase knockout strategy, we identified USP48 as an important candidate that can regulate Aurora B protein levels during the normal cell cycle. Here, we report that USP48 interacts with and stabilizes the Aurora B protein. Furthermore, we showed that the deubiquitinating activity of USP48 helps to maintain the steady-state levels of Aurora B protein by regulating its half-life. Finally, USP48 knockout resulted in delayed progression of cell cycle due to accumulation of mitotic defects and ultimately cytokinesis failure, suggesting the role of USP48 in cell cycle regulation.
Highlights
The proper progression of the cell cycle is orchestrated by a highly coordinated series of molecular events to ensure faithful DNA replication and equal chromosomal segregation into two daughter cells [1]
We used our recently developed Deubiquitinating enzymes (DUBs) knockout single-guide RNAs (sgRNAs) kit consisting of sgRNAs targeting USP sub-family proteins [37]
We investigated significant changes in the protein levels of ectopically expressed Myc-Aurora B by individually transfecting sgRNAs targeting DUBs in HEK293 cells
Summary
The proper progression of the cell cycle is orchestrated by a highly coordinated series of molecular events to ensure faithful DNA replication and equal chromosomal segregation into two daughter cells [1]. Aurora B (AURKB) belongs to the family of serine/threonine protein kinases that play key roles in regulating the mammalian cell division cycle [2]. This family includes Aurora A which functions in the centrosome [3] and Aurora C that regulates meiosis and mitotic events during early embryogenesis [4,5]. Aurora B plays a role in regulating almost every stage of mitosis including the condensation, bi-orientation, and segregation of chromosomes, formation of the spindle checkpoints, and cytokinesis [2,7]. Our data suggest that USP48 plays a critical role in maintaining the steady-state levels of Aurora B by its deubiquitinating activity, thereby ensuring faithful mitotic progression
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