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Enhanced CD95-mediated apoptosis contributes to radiation hypersensitivity of NBS lymphoblasts

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Abstract

The molecular causes for enhanced radiosensitivity of Nijmegen Breakage Syndrome cells are unclear, especially as repair of DNA damage is hardly impeded in these cells. We clearly demonstrate that radiation hypersensitivity is accompanied by enhanced γ-radiation-induced apoptosis in NBS1 deficient lymphoblastoid cell lines. Differences in the apoptotic behavior of NBS1 −/− and NBS1 +/− cells are not due to an altered p53 stabilization or phosphorylation in NBS1 −/− cells. γ-radiation-induced caspase-8 activity is increased and visualization of CD95 clustering by laser scanning microscopy shows a significant higher activation of the death receptor in NBS1 −/− cells. Further investigation of the molecular mechanisms reveals a role for reactive oxygen species-triggered activation of CD95. These results demonstrate that NBS1 suppresses the CD95 death receptor-dependent apoptotic pathway after γ-irradiation and evidence is given that this is achieved by regulation of the PI3-K/AKT survival pathway.

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Acknowledgments

The authors thank M. Digweed for the supply of the lymphoblastoid cell lines used for this study. We thank J. Favor, GSF—Institute of Developmental Genetics, for critically reading the manuscript and highly acknowledge the technical help from K. Winkler and N. Kunz.

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  1. Institute of Radiobiology, GSF–National Research Center for Environment and Health, 85758, Neuherberg, Germany

    Daniel Sagan, Simone Mörtl, Irene Müller, Friederike Eckardt-Schupp & Hedda Eichholtz-Wirth

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  1. Daniel Sagan
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Correspondence to Daniel Sagan.

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Sagan, D., Mörtl, S., Müller, I. et al. Enhanced CD95-mediated apoptosis contributes to radiation hypersensitivity of NBS lymphoblasts. Apoptosis 12, 753–767 (2007). https://doi.org/10.1007/s10495-006-0021-0

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