Microtubule poleward flux as a target for modifying chromosome segregation errors

Risteski, Patrik; Martinčić, Jelena; Jagrić, Mihaela; Tintor, Erna; Petelinec, Ana; Tolić, Iva Marija (2024) Microtubule poleward flux as a target for modifying chromosome segregation errors. Proceedings of the National Academy of Sciences, 121 (47). ISSN 0027-8424

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Abstract

Cancer cells often display errors in chromosome segregation, some of which result from improper chromosome alignment at the spindle midplane. Chromosome alignment is facilitated by different rates of microtubule poleward flux between sister kinetochore fibers. However, the role of the poleward flux in supporting mitotic fidelity remains unknown. Here, we introduce the hypothesis that the finely tuned poleward flux safeguards against lagging chromosomes and micronuclei at mitotic exit by promoting chromosome alignment in metaphase. We used human untransformed RPE-1 cells depleted of KIF18A/kinesin-8 as a system with reduced mitotic fidelity, which we rescued by three mechanistically independent treatments, comprising low-dose taxol or codepletion of the spindle proteins HAUS8 or NuMA. The rescue of mitotic errors was due to shortening of the excessively long overlaps of antiparallel microtubules, serving as a platform for motor proteins that drive the flux, which in turn slowed down the overly fast flux and improved chromosome alignment. In contrast to the prevailing view, the rescue was not accompanied by reduction of overall microtubule growth rates. Instead, speckle microscopy revealed that the improved chromosome alignment in the rescue treatments was associated with slower growth and flux of kinetochore microtubules. In a similar manner, a low-dose taxol treatment rescued mitotic errors in a high-grade serous ovarian carcinoma cell line OVKATE. Collectively, our results highlight the potential of targeting microtubule poleward flux to modify chromosome instability and provide insight into the mechanism through which low doses of taxol rescue certain mitotic errors in cancer cells.

Item Type:	Article
Uncontrolled Keywords:	microtubule poleward flux ; chromosome alignment ; chromosome segregation ; mitosis ; chromosome instability
Subjects:	NATURAL SCIENCES > Biology
Divisions:	Division of Molecular Biology
Projects:	Project title Project leader Project code Project type Provedba vrhunskih istraživanja u sklopu Znanstvenog centra izvrsnosti za kvantne i kompleksne sustave te reprezentacije Liejevih algebri-QuantiXLie Hrvoje Buljan; Pavle Pandžić; Vit Tuček; Tomislav Marketin KK.01.1.1.01.0004 EK Inovativni protokoli mikroskopije za interdisciplinarna istraživanja u biomedicini-IPSted Iva Tolić KK.01.1.1.04.0057 EK Kako starost centrosoma utječe na stvaranje, popravak i segregaciju polarnih kromosoma Iva Tolić IPCH-2022-10-9344 HRZZ
Depositing User:	Lorena Palameta
Date Deposited:	18 Apr 2025 07:52
URI:	http://fulir.irb.hr/id/eprint/9715
DOI:	10.1073/pnas.2405015121

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