UNC-45A Is Highly Expressed in the Proliferative Cells of the Mouse Genital Tract and in the Microtubule-Rich Areas of the Mouse Nervous System

Clemente, Valentino; Hoshino, Asumi; Meints, Joyce; Shetty, Mihir; Starr, Timothy K.; Lee, Michael K.; Bazzaro, Martina

doi:10.3390/cells10071604

Cited by 2 publications

(3 citation statements)

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“…UNC-45A is a newly characterized MAP with ATP-independent MT severing properties [13, 20, 42]. UNC-45A-mediated MT severing is preceded by the presence of kinks and bent regions in the MTs [13].…”

Section: Discussionmentioning

confidence: 99%

“…In mammalian cells UNC-45A exhibits a dual role that is not mutually exclusive, functioning as a regulator of both myosin and MT activities. With regards to the latter, UNC-45A is a centrosome-[17] [18] and mitotic-spindle associated protein in cancer cells [19] [17], and is enriched in MT dense areas of nervous system and ciliated epithelium [20]. UNC-45A exhibits upregulated expression in cancer cells, wherein it antagonizes the MT-stabilizing properties of Paclitaxel, enabling cells to undergo division via multipolar spindles despite the presence of the drug.…”

Section: Introductionmentioning

confidence: 99%

“…and is enriched in MT dense areas of nervous system and ciliated epithelium [20]. UNC-45A exhibits upregulated expression in cancer cells, wherein it antagonizes the MT-stabilizing properties of Paclitaxel, enabling cells to undergo division via multipolar spindles despite the presence of the drug.…”

Section: Introductionmentioning

confidence: 99%

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The Microtubule Severing Protein UNC-45A Counteracts the Microtubule Straightening Effects of Taxol

Hoshino,

Clemente,

Shetty

et al. 2023

Preprint

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UNC-45A is the only known ATP-independent microtubule (MT) severing protein. Thus, it severs MTs via a novel mechanism.In vitroand 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. Usingin vitrobiophysical 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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