In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 5 ( 2011-05-01), p. 784-794
Abstract:
Genotoxic stress such as ionizing radiation halts entry into mitosis by activation of the G2 DNA damage checkpoint. The CHK1 inhibitor 7-hydroxystaurosporine (UCN-01) can bypass the checkpoint and induce unscheduled mitosis in irradiated cells. Precisely, how cells behave following checkpoint abrogation remains to be defined. In this study, we tracked the fates of individual cells after checkpoint abrogation, focusing in particular on whether they undergo mitotic catastrophe. Surprisingly, while a subset of UCN-01–treated cells were immediately eliminated during the first mitosis after checkpoint abrogation, about half remained viable and progressed into G1. Both the delay of mitotic entry and the level of mitotic catastrophe were dependent on the dose of radiation. Although the level of mitotic catastrophe was specific for different cell lines, it could be promoted by extending the mitosis. In supporting this idea, weakening of the spindle-assembly checkpoint, by either depleting MAD2 or overexpressing the MAD2-binding protein p31comet, suppressed mitotic catastrophe. Conversely, delaying of mitotic exit by depleting either p31comet or CDC20 tipped the balance toward mitotic catastrophe. These results underscore the interplay between the level of DNA damage and the effectiveness of the spindle-assembly checkpoint in determining whether checkpoint-abrogated cells are eliminated during mitosis. Mol Cancer Ther; 10(5); 784–94. ©2011 AACR.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.MCT-10-0809
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2062135-8
SSG:
12
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