Mechanism of cell death resulting from DNA interstrand cross-linking in mammalian cells |
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| Authors: | T Osawa D Davies J A Hartley |
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| Institution: | 1Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O''Gorman Building, University College London, London WC1E 6BT, UK;2Laboratory for Systems Biology and Medicine, RCAST, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan;3FACS Laboratory, London Research Institute, Cancer Research UK, 44 Lincolns Inn Fields, London WC2A 3LY, UK |
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| 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 (G2) 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. |
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| Keywords: | DNA interstrand cross-link DNA cross-link repair apoptosis cell-cycle arrest homologous recombination chromosomal abnormality |
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