Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction

Item Type:	Article
Title:	Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction
Creators Name:	Orth, J.D. and Loewer, A. and Lahav, G. and Mitchison, T.J.
Abstract:	Mitotic arrest induced by anti-mitotic drugs can cause apoptosis or p53-dependent cell cycle arrest. It can also cause DNA damage, but the relationship between these events has been unclear. Live, single cell imaging in human cancer cells responding to an anti-mitotic Kinesin-5 inhibitor (K5I), and additional anti-mitotic drugs, revealed strong induction of p53 after cells slipped from prolonged mitotic arrest into G1. We investigated the cause of this induction. We detected DNA damage late in mitotic arrest and also after slippage. This damage was inhibited by treatment with caspase inhibitors, and by stable expression of mutant, non-cleavable ICAD, which prevents activation of the apoptosis-associated nuclease CAD. These treatments also inhibited induction of p53 after slippage from prolonged arrest. DNA damage was not due to full apoptosis, since most cytochrome C was still sequestered in mitochondria when damage occurred. We conclude that prolonged mitotic arrest partially activates the apoptosis pathway. This partly activates CAD, causing limited DNA damage and p53 induction after slippage. Increased DNA damage via caspases and CAD may be an important aspect of anti-mitotic drug action. More speculatively, partial activation of CAD may explain the DNA damaging effects of diverse cellular stresses that do not immediately trigger apoptosis.
Keywords:	Antimitotic Agents, Apoptosis, Cell Cycle Checkpoints, Deoxyribonucleases, DNA Damage, Kinesin, Mitosis, Quinolines, Tumor Cell Line, Tumor Suppressor Protein p53
Source:	Molecular Biology of the Cell
ISSN:	1059-1524
Publisher:	American Society for Cell Biology
Volume:	23
Number:	4
Page Range:	567-576
Date:	15 February 2012
Official Publication:	https://doi.org/10.1091/mbc.E11-09-0781
PubMed:	View item in PubMed

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