Abstract
A delay in the completion of metaphase induces a stress response that inhibits further cell proliferation or induces apoptosis. This response is thought to protect against genomic instability and is important for the effects of anti-mitotic cancer drugs. Here, we show that mitotic arrest induces a caspase-dependent DNA damage response (DDR) at telomeres in non-apoptotic cells. This pathway is under the control of Mcl-1 and other Bcl-2 family proteins and requires caspase-9, caspase-3/7 and the endonuclease CAD/DFF40. The gradual caspase-dependent loss of the shelterin complex protein TRF2 from telomeres promotes a DDR that involves DNA-dependent protein kinase (DNA-PK). Suppression of mitotic telomere damage by enhanced expression of TRF2, or the inhibition of either caspase-3/7 or DNA-PK during mitotic arrest, promotes subsequent cell survival. Thus, we demonstrate that mitotic stress is characterised by the sub-apoptotic activation of a classical caspase pathway, which promotes telomere deprotection, activates DNA damage signalling, and determines cell fate in response to a prolonged delay in mitosis.
Highlights
A delay in the completion of metaphase induces a stress response that inhibits further cell proliferation or induces apoptosis
Slow degradation of cyclin B1 even though the checkpoint is active can lead eventually to cells slipping from mitotic arrest[7], but such cells can subsequently undergo cell cycle arrest in G1 or apoptosis[8,9]
Other work has indicated that deprotection of telomeres during mitotic arrest initiates a DNA damage response (DDR) that controls subsequent cell cycle progression and cell death[10]
Summary
A delay in the completion of metaphase induces a stress response that inhibits further cell proliferation or induces apoptosis. Results and Discussion Mitotic DNA damage at telomeres in non-apoptotic cells requires caspase activity and is under the control of Bcl-2 family proteins. Cells arrested in mitosis for 2 or 6 h showed a time-dependent increase in the mean number of γH2AX foci formed at telomeres compared to normal mitotic cells (Fig. 1B).
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