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Int J Radiat Oncol Biol Phys. 2014 Jan 1;88(1):175-81. doi: 10.1016/j.ijrobp.2013.09.041. Epub 2013 Nov 13.

Deficiency in homologous recombination renders Mammalian cells more sensitive to proton versus photon irradiation.

Author information

  • 1Laboratory for Molecular Radiobiology, University Hospital Zurich, Zurich, Switzerland.
  • 2Center for Proton Therapy, Paul Scherrer Institute, Villigen, Switzerland.
  • 3Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
  • 4Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
  • 5Laboratory for Molecular Radiobiology, University Hospital Zurich, Zurich, Switzerland. Electronic address: martin.pruschy@usz.ch.

Abstract

PURPOSE:

To investigate the impact of the 2 major DNA repair machineries on cellular survival in response to irradiation with the 2 types of ionizing radiation.

METHODS AND MATERIALS:

The DNA repair and cell survival endpoints in wild-type, homologous recombination (HR)-deficient, and nonhomologous end-joining-deficient cells were analyzed after irradiation with clinically relevant, low-linear energy transfer (LET) protons and 200-keV photons.

RESULTS:

All cell lines were more sensitive to proton irradiation compared with photon irradiation, despite no differences in the induction of DNA breaks. Interestingly, HR-deficient cells and wild-type cells with small interfering RNA-down-regulated Rad51 were markedly hypersensitive to proton irradiation, resulting in an increased relative biological effectiveness in comparison with the relative biological effectiveness determined in wild-type cells. In contrast, lack of nonhomologous end-joining did not result in hypersensitivity toward proton irradiation. Repair kinetics of DNA damage in wild-type cells were equal after both types of irradiation, although proton irradiation resulted in more lethal chromosomal aberrations. Finally, repair kinetics in HR-deficient cells were significantly delayed after proton irradiation, with elevated amounts of residual γH2AX foci after irradiation.

CONCLUSION:

Our data indicate a differential quality of DNA damage by proton versus photon irradiation, with a specific requirement for homologous recombination for DNA repair and enhanced cell survival. This has potential relevance for clinical stratification of patients carrying mutations in the DNA damage response pathways.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24239385
[PubMed - indexed for MEDLINE]
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