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

Mitotic arrest induced by antimitotic 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 antimitotic kinesin-5 inhibitor and additiona...

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Autores principales: Orth, James D., Loewer, Alexander, Lahav, Galit, Mitchison, Timothy J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279386/
https://www.ncbi.nlm.nih.gov/pubmed/22171325
http://dx.doi.org/10.1091/mbc.E11-09-0781
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author Orth, James D.
Loewer, Alexander
Lahav, Galit
Mitchison, Timothy J.
author_facet Orth, James D.
Loewer, Alexander
Lahav, Galit
Mitchison, Timothy J.
author_sort Orth, James D.
collection PubMed
description Mitotic arrest induced by antimitotic 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 antimitotic kinesin-5 inhibitor and additional antimitotic 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, noncleavable inhibitor of caspase-activated DNase, which prevents activation of the apoptosis-associated nuclease caspase-activated DNase (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 apoptotic 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 antimitotic drug action. More speculatively, partial activation of CAD may explain the DNA-damaging effects of diverse cellular stresses that do not immediately trigger apoptosis.
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spelling pubmed-32793862012-04-30 Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction Orth, James D. Loewer, Alexander Lahav, Galit Mitchison, Timothy J. Mol Biol Cell Articles Mitotic arrest induced by antimitotic 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 antimitotic kinesin-5 inhibitor and additional antimitotic 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, noncleavable inhibitor of caspase-activated DNase, which prevents activation of the apoptosis-associated nuclease caspase-activated DNase (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 apoptotic 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 antimitotic drug action. More speculatively, partial activation of CAD may explain the DNA-damaging effects of diverse cellular stresses that do not immediately trigger apoptosis. The American Society for Cell Biology 2012-02-15 /pmc/articles/PMC3279386/ /pubmed/22171325 http://dx.doi.org/10.1091/mbc.E11-09-0781 Text en © 2012 Orth et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Orth, James D.
Loewer, Alexander
Lahav, Galit
Mitchison, Timothy J.
Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction
title Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction
title_full Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction
title_fullStr Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction
title_full_unstemmed Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction
title_short Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction
title_sort prolonged mitotic arrest triggers partial activation of apoptosis, resulting in dna damage and p53 induction
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279386/
https://www.ncbi.nlm.nih.gov/pubmed/22171325
http://dx.doi.org/10.1091/mbc.E11-09-0781
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