Abstract
During mitosis, tension develops across the centromere as a result of spindle-based forces. Metaphase tension may be critical in preventing mitotic chromosome segregation errors, however, the nature of force transmission at the centromere and the role of centromere mechanics in controlling metaphase tension remains unknown. We combined quantitative, biophysical microscopy with computational analysis to elucidate the mechanics of the centromere in unperturbed, mitotic human cells. We discovered that the mechanical stiffness of the human centromere matures during mitotic progression, which leads to amplified centromere tension specifically at metaphase. Centromere mechanical maturation is disrupted across multiple aneuploid cell lines, leading to a weak metaphase tension signal. Further, increasing deficiencies in centromere mechanical maturation are correlated with rising frequencies of lagging, merotelic chromosomes in anaphase, leading to segregation defects at telophase. Thus, we reveal a centromere maturation process that may be critical to the fidelity of chromosome segregation during mitosis.
Highlights
During mitosis, tension develops across the centromere as a result of spindle-based forces
We report that the mechanical stiffness of the human centromere undergoes a maturation process during mitotic progression that follows a distinct and reproducible pattern, a process that we refer to as “centromere mechanical maturation”
When we reapplied our protocol for evaluating centromere mechanics in this cell line, selecting for the tetraploid cells (Supplementary Fig. 5E), we found that centromere mechanical maturation was impaired in the aneuploid cells
Summary
Tension develops across the centromere as a result of spindle-based forces. Centromere tension has been proposed to act as a mechanical signal to the cell, broadcasting the state of chromosome-spindle attachments, and may take part in regulating the metaphase to anaphase transition[4,5] (Fig. 1b, right). The foundation for this theory was introduced by Nicklas and Koch[6], who used micromanipulation in grasshopper spermocytes to show that inducing tension across a detached chromosome stabilized its microtubule attachments, preventing reorientation. Our results reveal a role for centromere mechanical maturation in regulating metaphase tension during mitosis, which may be critical to the fidelity of chromosome segregation during mitosis
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