PARP is important for genomic stability but dispensable in apoptosis

  1. Zhao-Qi Wang1,2,6,
  2. Laura Stingl1,
  3. Ciaran Morrison1,
  4. Michael Jantsch3,
  5. Marek Los4,
  6. Klaus Schulze-Osthoff5, and
  7. Erwin F. Wagner1
  1. 1Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria; 2International Agency for Research on Cancer (IARC), F-69008 Lyon, France; 3Department of Cytology and Genetics, University of Vienna, A-1030 Vienna, Austria; 4Department of Molecular Oncology/ Pediatry, German Cancer Research Center, D-69120 Heidelberg, Germany; 5Medical Clinics, University of Tübingen, D-72076 Tübingen, Germany

Abstract

Mice lacking the gene encoding poly(ADP-ribosyl) transferase (PARP or ADPRT) display no phenotypic abnormalities, although aged mice are susceptible to epidermal hyperplasia and obesity in a mixed genetic background. Whereas embryonic fibroblasts lacking PARP exhibit normal DNA excision repair, they grow more slowly in vitro. Here we investigated the putative roles of PARP in cell proliferation, cell death, radiosensitivity, and DNA recombination, as well as chromosomal stability. We show that the proliferation deficiency in vitro and in vivo is most likely caused by a hypersensitive response to environmental stress. Although PARP is specifically cleaved during apoptosis, cells lacking this molecule apoptosed normally in response to treatment with anti-Fas, tumor neurosis factor α, γ-irradiation, and dexamethasone, indicating that PARP is dispensable in apoptosis and that PARP−/− thymocytes are not hypersensitive to ionizing radiation. Furthermore, the capacity of mutant cells to carry out immunoglobulin class switching and V(D)J recombination is normal. Finally, primary PARP mutant fibroblasts and splenocytes exhibited an elevated frequency of spontaneous sister chromatid exchanges and elevated micronuclei formation after treatment with genotoxic agents, establishing an important role for PARP in the maintenance of genomic integrity.

Keywords

Footnotes

  • 6 Corresponding author.

  • E-MAIL zqwang{at}iarc.fr; FAX +33-4-7273 8329.

    • Received May 29, 1997.
    • Accepted July 14, 1997.
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