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Cited by 7Microtubule and mitosis dynamicsCancer Treatment and PharmacologyCellular Mechanics and Interactions

The microtubule-severing protein UNC-45A preferentially binds to curved microtubules and counteracts the microtubule-straightening effects of Taxol

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Hoshino, Asumi, Clemente, Valentino, Shetty, Mihir, Castle, Brian, Odde, David, Bazzaro, Martina·2023·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2023.105355PMC PMC10654038
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Abstract

Abstract UNC-45A is the only known ATP-independent microtubule (MT) severing protein. Thus, it severs MTs via a novel mechanism. In vitro and in cells UNC-45A-mediated MT severing is preceded by the appearance of MT bends. While MTs are stiff biological polymers, in cells, they often curve, and the result of this curving can be breaking off. The contribution of MT severing proteins on MT lattice curvature is largely undefined. Here we show that UNC-45A curves MTs. Using in vitro biophysical reconstitution and TIRF microscopy analysis, we show that UNC-45A is enriched in the areas where MTs are curved versus the areas where MTs are straight. In cells, we show that UNC-45A overexpression increases MT curvature and its depletion has the opposite effect. We also show that this effect occurs is independent of actomyosin contractility. Lastly, we show for the first time that in cells, Paclitaxel straightens MTs, and that UNC-45A can counteracts the MT straightening effects of the drug. Significance: Our findings reveal for the first time that UNC-45A increases MT curvature. This hints that UNC-45A-mediated MT severing could be due to the worsening of MT curvature and provide a mechanistic understanding of how this MT-severing protein may act. UNC-45A is the only MT severing protein expressed in human cancers, including paclitaxel-resistant ovarian cancer. Our finding that UNC-45A counteracts the paclitaxel-straightening effects of MTs in cells suggests an additional mechanism through which cancer cells escape drug treatment.

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Cited by

Sorted by citations

Authors
Hoshino, A., Clemente, V., Shetty, M., Castle, B., Odde, D., & Bazzaro, M.
Affiliations
University of Minnesota (US)
Corresponding author
Bazzaro, Martina
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2023-11
Volume
299
Issue
11
Pages
105355
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2023.105355
PMC
PMC10654038
OpenAlex
W4387709533
Cited by
7
References
0
Citations by year
2026: 1 · 2025: 5 · 2024: 1
FWCI
0.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • US Department of Defense (OC160377)
  • National Institute of General Medical Sciences (R01-GM130800)
  • Alzheimer's Association (AARG-NTF-21-848680)
  • Minnesota Ovarian Cancer Alliance
  • Population Media Center
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
microtubule severing, microtubule curvature, microtubule lattice, paclitaxel, actomyosin contractility, microtubule dynamics, Caenorhabditis elegans

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