Abstract
Sister chromatid cohesion plays a key role in ensuring precise chromosome segregation during mitosis, which is mediated by the multisubunit cohesin complex. However, the molecular regulation of cohesin subunits stability remains unclear. Here, we show that NudCL2 (NudC-like protein 2) is essential for the stability of cohesin subunits by regulating Hsp90 ATPase activity in mammalian cells. Depletion of NudCL2 induces mitotic defects and premature sister chromatid separation and destabilizes cohesin subunits that interact with NudCL2. Similar defects are also observed upon inhibition of Hsp90 ATPase activity. Interestingly, ectopic expression of Hsp90 efficiently rescues the protein instability and functional deficiency of cohesin induced by NudCL2 depletion, but not vice versa. Moreover, NudCL2 not only binds to Hsp90, but also significantly modulates Hsp90 ATPase activity and promotes the chaperone function of Hsp90. Taken together, these data suggest that NudCL2 is a previously undescribed Hsp90 cochaperone to modulate sister chromatid cohesion by stabilizing cohesin subunits, providing a hitherto unrecognized mechanism that is crucial for faithful chromosome segregation during mitosis.
Highlights
During mitosis, the proper segregation of duplicated chromosomes into daughter cells is required for maintaining genome integrity
After ectopic expression of siRNA-resistant NudCL2, approximately 20% of mitotic cells showed misaligned chromosomes compared to less than 10% in the control, and the mitotic index decreased to about 10% compared to approximately 5% in the control (Supplementary Fig. 2), indicating that the mitotic defects in cells depleted of NudCL2 were partially rescued by ectopic expression of siRNA-resistant NudCL2
Since NudCL2 regulates the stability of cohesin subunits and LIS1, and contains a conserved p23 domain, the core structure of p23 required for its cochaperone function of Heat shock protein 90 (Hsp90) [19, 35], we explored whether NudCL2 functions as an Hsp90 cochaperone to stabilize client proteins
Summary
The proper segregation of duplicated chromosomes into daughter cells is required for maintaining genome integrity. Sister chromatid cohesion, which is mediated by the highly conserved protein complex cohesin, plays an essential role in chromosome segregation [1]. The cohesin complex involved in mitosis is composed of four highly conserved subunits. Two structural maintenance of chromosomes proteins (Smc1α and Smc3) form a heterodimer by interacting their hinge regions. One α-kleisin subunit protein (Rad21) interacts with the head domains of Smc1α and Smc and effectively closes the ring. One stromal antigen (SA1 or SA2) directly interacts with Rad via its C-terminal region to stabilize the cohesin ring structure [1, 2]
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