Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents

Masayuki Nitta, Osamu Kobayashi, Shinobu Honda, Toru Hirota, Shinji Kuninaka, Tomotoshi Marumoto, Yukitaka Ushio, Hideyuki Saya

Research output: Contribution to journalArticlepeer-review

136 Citations (Scopus)

Abstract

Mitotic catastrophe is an important mechanism for the induction of cell death in cancer cells by antineoplastic agents that damage DNA. This process is facilitated by defects in the G1 and G2 checkpoints of the cell cycle that are apparent in most cancer cells and which allow the cells to enter mitosis with DNA damage. We have now characterized the dynamics of mitotic catastrophe induced by DNA-damaging agents in p53-deficient cancer cells. Cells that entered mitosis with DNA damage transiently arrested at metaphase for more than 10h without segregation of chromosomes and subsequently died directly from metaphase. In those metaphase arrested precatastrophic cells, anaphase-promoting complex appeared to be inactivated and BubR1 was persistently localized at kinetochores, suggesting that spindle checkpoint is activated after the DNA damage. Furthermore, suppression of spindle checkpoint fonction by BnbR1 or Mad2 RNA interference in the DNA damaged cells led to escape from catastrophic death and to subsequent abnormal mitosis. Dysfunction of the spindle checkpoint in p53-deficient cancer cells is thus likely a critical factor in resistance to DNA-damaging therapeutic agents.

Original languageEnglish
Pages (from-to)6548-6558
Number of pages11
JournalOncogene
Volume23
Issue number39
DOIs
Publication statusPublished - 2004 Aug 26

Keywords

  • BubR1
  • DNA damage
  • Mitotic catastrophe
  • Spindle checkpoint
  • Time lapse
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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