4.7 Article

Delayed Chromosome Alignment to the Spindle Equator Increases the Rate of Chromosome Missegregation in Cancer Cell Lines

Journal

BIOMOLECULES
Volume 9, Issue 1, Pages -

Publisher

MDPI
DOI: 10.3390/biom9010010

Keywords

chromosome segregation; mitosis; chromosomal instability; molecular motors

Funding

  1. JSPS KAKENHI [24370078, 26640067, 26870054, 15H04368, 16K14604, 18H02434, 16H06635, 18K15234]
  2. MEXT KAKENHI [24114502, 26114702, 18H04896]
  3. Takeda Science Foundation
  4. Princess Takamatsu Cancer Research Fund [10-24210]
  5. Uehara Memorial Foundation
  6. Gonryo Medical Foundation
  7. Kanae Foundation for the Promotion of Medical Science
  8. JSPS Overseas challenge program for young researchers
  9. Grants-in-Aid for Scientific Research [15H04368, 18H02434, 26870054, 16H06635, 24114502, 26640067, 18K15234, 16K14604, 18H04896, 26114702] Funding Source: KAKEN

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For appropriate chromosome segregation, kinetochores on sister chromatids have to attach to microtubules from opposite spindle poles (bi-orientation). Chromosome alignment at the spindle equator, referred to as congression, can occur through the attachment of kinetochores to the lateral surface of spindle microtubules, facilitating bi-orientation establishment. However, the contribution of this phenomenon to mitotic fidelity has not been clarified yet. Here, we addressed whether delayed chromosome alignment to the spindle equator increases the rate of chromosome missegregation. Cancer cell lines depleted of Kid, a chromokinesin involved in chromosome congression, showed chromosome alignment with a slight delay, and increased frequency of lagging chromosomes. Delayed chromosome alignment concomitant with an increased rate of lagging chromosomes was also seen in cells depleted of kinesin family member 4A (KIF4A), another chromokinesin. Cells that underwent chromosome missegregation took relatively longer time to align chromosomes in both control and Kid/KIF4A-depleted cells. Tracking of late-aligning chromosomes showed that they exhibit a higher rate of lagging chromosomes. Intriguingly, the metaphase of cells that underwent chromosome missegregation was shortened, and delaying anaphase onset ameliorated the increased chromosome missegregation. These data suggest that late-aligning chromosomes do not have sufficient time to establish bi-orientation, leading to chromosome missegregation. Our data imply that delayed chromosome alignment is not only a consequence, but also a cause of defective bi-orientation establishment, which can lead to chromosomal instability in cells without severe mitotic defects.

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