PARP-1, PARP-2, and the cellular response to low doses of ionizing radiation

Anthony Chalmers, Peter Johnston, Mick Woodcock, Michael Joiner, Brian Marples

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

Purpose: Poly(ADP-ribose) polymerase-1 (PARP-1) is rapidly and directly activated by single-strand breaks and is required for efficient base excision repair. These properties indicate that inhibition of PARP-1 might enhance the cellular response to low doses of radiation. We tested the effect of chemical inhibition of PARP-1 on low-dose clonogenic survival in a number of cell lines and the low-dose radiation response of a PARP-1 knockout murine cell line. Methods and Materials: Clonogenic cell survival of V79-379A and CHO-K1 hamster fibroblasts, T98G and U373-MG human glioma cells, and 3T3 mouse embryo fibroblast PARP-1 knockout cells was measured using a precise flow cytometry-based plating assay. Chemical inhibitors of PARP enzymes were tested for their effect on clonogenic survival after a range of ionizing radiation doses. Results: Chemical inhibition of PARP activity induced marked radiosensitization of V79, CHO, and exponentially growing T98G cells in the 0.05-0.3-Gy range. This effect was not seen in U373 cells or in confluent T98G populations. Low-dose radiosensitization was not apparent in PARP-1 knockout cells. Conclusion: Low-dose radiosensitization of actively dividing tumor cells by PARP-1 inhibitors suggests that they may have a role in enhancing the efficacy of ultrafractionated or low-dose-rate radiotherapy regimens. We hypothesize that PARP-2 compensates for the absence of PARP-1 in the knockout cell line.

Original languageEnglish (US)
Pages (from-to)410-419
Number of pages10
JournalInternational Journal of Radiation Oncology Biology Physics
Volume58
Issue number2
DOIs
StatePublished - Feb 2004
Externally publishedYes

Keywords

  • DNA repair
  • Low-dose hypersensitivity
  • Low-dose radiation
  • PARP inhibitors
  • Poly(ADP-ribose) polymerase-1
  • Poly(ADP-ribose) polymerase-2

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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