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

Cell Death Dis. 2011 Aug 4;2(8):e187. doi: 10.1038/cddis.2011.70.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Apoptosis*
  • CHO Cells
  • Chromosome Aberrations
  • Cricetinae
  • Cricetulus
  • Cross-Linking Reagents / pharmacology*
  • DNA / chemistry*
  • DNA / drug effects*
  • DNA / metabolism
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins / metabolism
  • Endonucleases / metabolism
  • G2 Phase
  • HeLa Cells
  • Humans
  • Microscopy, Video
  • Nitrogen Mustard Compounds / pharmacology
  • Time-Lapse Imaging
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents, Alkylating
  • Cross-Linking Reagents
  • DNA-Binding Proteins
  • Nitrogen Mustard Compounds
  • Tumor Suppressor Protein p53
  • X-ray repair cross complementing protein 3
  • DNA
  • ERCC1 protein, human
  • Endonucleases