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Cell Death Dis. 2011 Aug 4;2:e187. doi: 10.1038/cddis.2011.70.

Mechanism of cell death resulting from DNA interstrand cross-linking in mammalian cells.

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1
Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6BT, UK.

Abstract

DNA interstrand cross-links (ICLs) are critical cytotoxic lesions produced by cancer chemotherapeutic agents such as the nitrogen mustards and platinum drugs; however, the exact mechanism of ICL-induced cell death is unclear. Here, we show a novel mechanism of p53-independent apoptotic cell death involving prolonged cell-cycle (G(2)) arrest, ICL repair involving HR, transient mitosis, incomplete cytokinesis, and gross chromosomal abnormalities resulting from ICLs in mammalian cells. This characteristic 'giant' cell death, observed by using time-lapse video microscopy, was reduced in ICL repair ERCC1- and XRCC3-deficient cells. Collectively, the results illustrate the coordination of ICL-induced cellular responses, including cell-cycle arrest, DNA damage repair, and cell death.

PMID:
21814285
PMCID:
PMC3181417
DOI:
10.1038/cddis.2011.70
[Indexed for MEDLINE]
Free PMC Article
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