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BUB3 that dissociates from BUB1 activates caspase-independent mitotic death (CIMD)

Y Niikura1, H Ogi, K Kikuchi

  • 1Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Cell Death and Differentiation
|January 9, 2010
PubMed

Insights

Caspase-independent mitotic death (CIMD) prevents aneuploidy by eliminating cells with chromosome missegregation. This study reveals BUB1 depletion activates CIMD through BUB3-p73 interaction and c-Abl phosphorylation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Aneuploidy, often caused by spindle checkpoint failure, is linked to cell death.
  • Caspase-independent mitotic death (CIMD) is a newly identified cell death pathway triggered by mitotic errors.
  • Partial BUB1 depletion and kinetochore-microtubule attachment defects induce CIMD.

Purpose of the Study:

  • To elucidate the molecular mechanism underlying BUB1 depletion-induced CIMD.
  • To investigate the fate of cells that survive CIMD.
  • To confirm CIMD's role in preventing aneuploidy.

Main Methods:

  • Investigated cell death pathways in response to BUB1 depletion.
  • Analyzed nuclear morphology in cells that survived CIMD.
  • Examined protein interactions between BUB3, p73, and c-Abl tyrosine kinase.

Main Results:

  • Cells surviving CIMD exhibit abnormal nuclei.
  • BUB3 interacts with p73 in CIMD-occurring cells.
  • Phosphorylation of p73 at Y99 by c-Abl tyrosine kinase, following BUB3 release from BUB1, activates CIMD.

Conclusions:

  • CIMD is a critical cell death mechanism preventing aneuploidy.
  • The BUB3-p73 interaction, modulated by c-Abl, is central to CIMD activation.
  • This pathway eliminates cells with significant chromosome missegregation, maintaining genomic stability.

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