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Chromosomal breaks during mitotic catastrophe trigger gamma H2AX-ATM-p53-mediated apoptosis
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
2011 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 124, no 17, 2951-2963 p.Article in journal (Refereed) Published
Abstract [en]

Although the cause and outcome of mitotic catastrophe (MC) has been thoroughly investigated, precisely how the ensuing lethality is regulated during or following this process and what signals are involved remain unknown. Moreover, the mechanism of the decision of cell death modalities following MC is still not well characterised. We demonstrate here a crucial role of the gamma H2AX-ATM-p53 pathway in the regulation of the apoptotic outcome of MC resulting from cells entering mitosis with damaged DNA. In addition to p53 deficiency, the depletion of ATM (ataxia telangiectasia mutated), but not ATR ( ataxia telangiectasia and Rad3-related protein), protected against apoptosis and shifted cell death towards necrosis. Activation of this pathway is triggered by the augmented chromosomal damage acquired during anaphase in doxorubicin-treated cells lacking 4-3-3 sigma (also known as epithelial cell marker protein-1 or stratifin). Moreover, cells that enter mitosis with damaged DNA encounter segregation problems because of their abnormal chromosomes, leading to defects in mitotic exit, and they therefore accumulate in G1 phase. These multi- or micronucleated cells are prevented from cycling again in a p53- and p21-dependent manner, and subsequently die. Because increased chromosomal damage resulting in extensive H2AX phosphorylation appears to be a direct cause of catastrophic mitosis, our results describe a mechanism that involves generation of additional DNA damage during MC to eliminate chromosomally unstable cells.

Place, publisher, year, edition, pages
2011. Vol. 124, no 17, 2951-2963 p.
Keyword [en]
Apoptosis, Cell death, Checkpoint, Genomic instability, Mitotic catastrophe
National Category
Natural Sciences
URN: urn:nbn:se:su:diva-68021DOI: 10.1242/jcs.081612ISI: 000294419200008OAI: diva2:471893
authorCount :4Available from: 2012-01-03 Created: 2012-01-02 Last updated: 2012-01-03Bibliographically approved

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