Multiple determinants and consequences of cohesion fatigue in mammalian cells

Molecular Biology of the Cell
Hem SapkotaGary J Gorbsky

Abstract

Cells delayed in metaphase with intact mitotic spindles undergo cohesion fatigue, where sister chromatids separate asynchronously, while cells remain in mitosis. Cohesion fatigue requires release of sister chromatid cohesion. However, the pathways that breach sister chromatid cohesion during cohesion fatigue remain unknown. Using moderate-salt buffers to remove loosely bound chromatin cohesin, we show that "cohesive" cohesin is not released during chromatid separation during cohesion fatigue. Using a regulated protein heterodimerization system to lock different cohesin ring interfaces at specific times in mitosis, we show that the Wapl-mediated pathway of cohesin release is not required for cohesion fatigue. By manipulating microtubule stability and cohesin complex integrity in cell lines with varying sensitivity to cohesion fatigue, we show that rates of cohesion fatigue reflect a dynamic balance between spindle pulling forces and resistance to separation by interchromatid cohesion. Finally, while massive separation of chromatids in cohesion fatigue likely produces inviable cell progeny, we find that short metaphase delays, leading to partial chromatid separation, predispose cells to chromosome missegregation. Thus, complete s...Continue Reading

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Citations

May 27, 2020·Essays in Biochemistry·Qian Zhang, Hong Liu
Dec 12, 2018·Nature Reviews. Cancer·Susanne M A Lens, René H Medema
Apr 17, 2020·Journal of Cell Science·Hem SapkotaGary J Gorbsky
Sep 19, 2019·Nature Communications·V Pragathi MasamsettiAnthony J Cesare
Mar 25, 2021·Seminars in Cell & Developmental Biology·Marina Rodriguez-MuñozAnna Genescà
Apr 29, 2021·Molecular Biology of the Cell·Lu YangHong Liu

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Methods Mentioned

BETA
pull apart
light sheet
immunoprecipitation

Software Mentioned

Metamorph

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