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Abstract
Purpose: Xeroderma Pigmentosum (XP) is a rare, recessive genetic disease associated with photosensitivity, skin cancer proneness, neurological abnormalities and impaired nucleotide excision repair of the UV-induced DNA damage. Less frequently, XP can be associated with sensitivity to ionizing radiation (IR). Here, a complete radiobiological characterization was performed on a panel of fibroblasts derived from XP-group D patients (XPD).
Materials and methods: Cellular radiosensitivity and the functionality of the recognition and repair of chromosome breaks and DNA double-strand breaks (DSB) was evaluated by different techniques including clonogenic cell survival, micronuclei, premature chromosome condensation, pulsed-field gel electrophoresis, chromatin decondensation and immunofluorescence assays. Quantitative correlations between each endpoint were analyzed systematically.
Results: Among the seven fibroblast cell lines tested, those derived from three non-relative patients holding the p.[Arg683Trp];[Arg616Pro] XPD mutations showed significant cellular radiosensitivity, high yield of residual micronuclei, incomplete DSB recognition, DSB and chromosome repair defects, impaired ATM, MRE11 relocalization, significant chromatin decondensation. Interestingly, XPD transduction and treatment with statins and bisphosphonates known to accelerate the radiation-induced ATM nucleoshuttling led to significant complementation of these impairments.
Conclusions: Our findings suggest that some subsets of XPD patients may be at risk of radiosensitivity reactions and treatment with statins and bisphosphonates may be an interesting approach of radioprotection countermeasure. Different mechanistic models were discussed to better understand the potential specificity of the p.[Arg683Trp];[Arg616Pro] XPD mutations.
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Notes
Acknowledgements
The authors thank C. Beaufrère, F. Puvion-Dutilleul, M. Viau, A. Joubert, Z. Bencokova and C. Massart for their technical assistance.
Disclosure statement
No potential conflict of interest was reported by the authors.
Notes
1 Dose value equivalent to the dose reached for 37% survival if survival S is fitted to S = exp(D/Do).
2 Dose value reached for 10% survival.
Additional information
Funding
Notes on contributors
Mélanie Ferlazzo
Mélanie Ferlazzo is postdoctoral fellow in the UA8 Inserm Unit and focuses on the radiosensitivity syndromes.
Elise Berthel
Elise Berthel is postdoctoral fellow in the UA8 Inserm Unit and focuses on the aging syndromes.
Adeline Granzotto
Adeline Granzotto is an Engineer-assistant in the UA8 Inserm Unit and focuses on the cancer proneness syndromes.
Clément Devic
Clément Devic is a PhD student in the UA8 Inserm Unit and focuses on the low-dose phenomena.
Laurène Sonzogni
Laurène Sonzogni is an Engineer-assistant in the UA8 Inserm Unit and is responsible for the collection of the fibroblast cell lines.
Jean-Thomas Bachelet
Dr. Jean-Thomas Bachelet is a maxillofacial surgeon and PhD student in the UA8 Inserm and focuses on the radiosensitivity syndromes.
Sandrine Pereira
Sandrine Pereira is an Engineer in the UA8 Inserm and expert in aging syndromes.
Michel Bourguignon
Pr. Michel Bourguignon is Professor in Biophysics and Nuclear Medicine and expert in radiation protection.
Alain Sarasin
Alain Sarasin is Director of Research Emeritus in CNRS and expert in Xeroderma Pigmentosum.
Mauro Mezzina
Mauro Mezzina is Director of Research Emeritus in CNRS and expert in Xeroderma Pigmentosum.
Nicolas Foray
Nicolas Foray is Director of Research in INSERM, Director of the UA8 Unit and expert in radiobiology.