Multiple Determinants and Consequences of Cohesion Fatigue in Mammalian Cells

Abstract

Cells delayed in metaphase with intact mitotic spindles undergo cohesion fatigue, where sister chromatids separate asynchronously, while cells remain in M phase. Cohesion fatigue requires release of sister chromatid cohesion. However, the pathways necessary to breach sister chromatid cohesion during cohesion fatigue remain unknown. By manipulating microtubule stability and Cohesin complex integrity in cell lines with varying sensitivity to cohesion fatigue, we show rates of cohesion fatigue reflect a dynamic balance between spindle pulling forces and resistance to separation by interchromatid cohesion. Cohesion fatigue that results in complete chromatid separation may be an unrecognized but common source of chromosome instability.Here, we extend the significance of cohesion fatigue by showing that even limited delays at metaphase lead to partial centromere separation and predispose cells to chromosome missegregation.