UNC-45A Is a Novel Microtubule-Associated Protein and Regulator of Paclitaxel Sensitivity in Ovarian Cancer Cells
Abstract
UNC-45A, a highly conserved member of the UCS (UNC45A/CRO1/SHE4P) protein family of cochaperones, plays an important role in regulating cytoskeletal-associated functions in invertebrates and mammalian cells, including cytokinesis, exocytosis, cell motility, and neuronal development. Here, for the first time, UNC-45A is demonstrated to function as a mitotic spindle-associated protein that destabilizes microtubules (MT) activity. Using in vitro biophysical reconstitution and total internal reflection fluorescence microscopy analysis, we reveal that UNC-45A directly binds to taxol-stabilized MTs in the absence of any additional cellular cofactors or other MT-associated proteins and acts as an ATP-independent MT destabilizer. In cells, UNC-45A binds to and destabilizes mitotic spindles, and its depletion causes severe defects in chromosome congression and segregation. UNC-45A is overexpressed in human clinical specimens from chemoresistant ovarian cancer and that UNC-45A–overexpressing cells resist chromosome missegregation and aneuploidy when treated with clinically relevant concentrations of paclitaxel. Lastly, UNC-45A depletion exacerbates paclitaxel-mediated stabilizing effects on mitotic spindles and restores sensitivity to paclitaxel.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2019
- Source ID
- 10.1158/1541-7786.mcr-18-0670
Entities
People
- Ashley Mooneyham
- Courtney E Coombes
- Edith Emmings
- Joyce Meints
- Liqiang Chen
- Mark Mcclellan
- Martina Bazzaro
- Melissa Gardner
- Michael K Lee
- Mihir Shetty
- Qing Yang
- Teng Ai
- Vijayalakshmi Shridhar
- Yoshie Iizuka
Organizations
- Mayo Medical School
- National Institutes of Health
- United States Department of Defense
- University of Minnesota