Poly(ADP-ribose) polymerase, a major determinant of early cell response to ionizing radiation

Int J Radiat Biol. 2000 Dec;76(12):1621-9. doi: 10.1080/09553000050201118.

Abstract

Purpose: To determine whether DNA-dependent protein kinase (DNA-PK) and poly(ADP-ribose) polymerase (PARP-1) are involved in eliciting the rapid fluctuations of radiosensitivity that have been observed when cells are exposed to short pulses of ionizing radiation.

Materials and methods: The effect of DNA-PK and PARP-1 inhibitors on the survival of cells to split-dose irradiation was investigated using Chinese hamster V79 fibroblasts and human carcinoma SQ-20B cells. The responses of PARP-1 proficient and PARP-1 knockout mouse 3T3 fibroblasts were compared in a similar split-dose assay.

Results: Inactivation of DNA-PK by wortmannin potentiated radiation-induced cell kill but it did not alter the oscillatory, W-shaped pattern of early radiation response. In contrast, oscillatory radiation response was abolished by 3-aminobenzamide, a reversible inhibitor of enzymes containing a PARP catalytic domain. The oscillatory response was also lacking in PARP-1 knockout mouse 3T3 fibroblasts.

Conclusion: The results show that PARP-1 plays a key role in the earliest steps of cell response to ionizing radiation with clonogenic ability or growth as endpoint. It is hypothesized that rapid poly(ADP-ribosylation) of target proteins, or recruitment of repair proteins by activated PARP-1 at the sites of DNA damage, bring about rapid chromatin remodelling that may affect the incidence of chromosomal damage upon re-irradiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Androstadienes / pharmacology
  • Animals
  • Benzamides / pharmacology
  • Catalytic Domain / radiation effects
  • Cell Line
  • Cell Survival / radiation effects
  • Chromatin / radiation effects
  • Cricetinae
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Dose-Response Relationship, Radiation
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / radiation effects
  • Gamma Rays / adverse effects
  • Humans
  • Mice
  • Nuclear Proteins
  • Poly(ADP-ribose) Polymerases / physiology*
  • Protein-Serine-Threonine Kinases / physiology*
  • Radiation, Ionizing
  • Time Factors
  • Tumor Cells, Cultured
  • Wortmannin

Substances

  • Androstadienes
  • Benzamides
  • Chromatin
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Nuclear Proteins
  • 3-aminobenzamide
  • Poly(ADP-ribose) Polymerases
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein-Serine-Threonine Kinases
  • Wortmannin