title: Mechanism of cell death resulting from DNA interstrand cross-linking in mammalian cells.
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.
authors.affiliation: Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6BT, UK.
authors.forename: T
authors.initials: T
authors.lastname: Osawa
authors.forename: D
authors.initials: D
authors.lastname: Davies
authors.forename: J A
authors.initials: JA
authors.lastname: Hartley
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis; D016466:CHO Cells; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism; D016195:G2 Phase; D006367:HeLa Cells; D006801:Humans; D018715:Microscopy, Video; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology; D059008:Time-Lapse Imaging; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D009588:Nitrogen Mustard Compounds; D016159:Tumor Suppressor Protein p53; C110901:X-ray repair cross complementing protein 3; D004247:DNA; C071447:ERCC1 protein, human; D004720:Endonucleases