Some mutations in the xeroderma pigmentosum D gene may lead to moderate but significant radiosensitivity associated with a delayed radiation-induced ATM nuclear localization

Int J Radiat Biol. 2020 Mar;96(3):394-410. doi: 10.1080/09553002.2020.1694189. Epub 2019 Nov 26.


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.

Keywords: ATM; DSB repair; XPD; radiosensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus*
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • Cell Line
  • Cell Survival
  • Chromatin / metabolism
  • DNA Breaks, Double-Stranded
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • MRE11 Homologue Protein / metabolism
  • Micronucleus Tests
  • Mutation*
  • Radiation Tolerance
  • Radiation, Ionizing
  • Ultraviolet Rays
  • X-Rays
  • Xeroderma Pigmentosum / genetics*
  • Xeroderma Pigmentosum Group D Protein / genetics*


  • Chromatin
  • MRE11 protein, human
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • MRE11 Homologue Protein
  • Xeroderma Pigmentosum Group D Protein
  • ERCC2 protein, human

Supplementary concepts

  • Xeroderma Pigmentosum, Complementation Group D