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Death receptor-induced apoptosis reveals a novel interplay between the chromosomal passenger complex and CENP-C

Alison J Faragher1, Xiao-Ming Sun, Michael Butterworth

  • 1MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom.

Molecular Biology of the Cell
|February 9, 2007
PubMed

Insights

Caspase activation during apoptosis disrupts centromeres by cleaving key proteins, leading to the displacement of the chromosomal passenger complex. This study reveals a novel link between caspase activity and centromere structure maintenance.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Apoptosis Research

Background:

  • The chromosomal passenger complex (CPC) regulates mitosis but its centromere targeting and functional link to kinetochore structure remain unclear.
  • Caspase activation initiates apoptosis but its role in centromere integrity is not well understood.

Purpose of the Study:

  • To investigate the functional link between caspase activation and centromere structure.
  • To elucidate the mechanism by which the chromosomal passenger complex interacts with centromeric proteins during apoptosis.

Main Methods:

  • Studied caspase-8 activation in MCF-7 cells during death receptor-induced apoptosis.
  • Analyzed the translocation of cleaved caspase-8 to the nucleus.
  • Assessed the impact on centromere protein C (CENP-C) and Inner Centromere Protein (INCENP) levels and localization.
  • Investigated the localization of Aurora B kinase.
  • Utilized site-directed mutagenesis to identify caspase cleavage sites in INCENP and CENP-C.

Main Results:

  • Cleaved caspase-8 translocates to the nucleus, correlating with CENP-C loss and centromere disruption.
  • Caspase-8 activates caspase-7, which cleaves CENP-C and INCENP.
  • Cleavage of CENP-C and INCENP leads to mislocalization of the chromosomal passenger complex and Aurora B kinase.
  • Mutating caspase cleavage sites prevents passenger complex mislocalization, confirming caspase-mediated disruption.

Conclusions:

  • Caspase activation during apoptosis causes centromere disruption through cleavage of CENP-C and INCENP.
  • This cleavage event leads to the displacement of the chromosomal passenger complex from centromeres.
  • The study establishes a functional interplay between the passenger complex and CENP-C, mediated by caspases.

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