Mutations of the Huntington’s Disease Protein Impact on the ATM-Dependent Signaling and Repair Pathways of the Radiation-Induced DNA Double-Strand Breaks: Corrective Effect of Statins and Bisphosphonates

Abstract

Huntington’s disease (HD) is a neurodegenerative syndrome caused by mutations of the IT15 gene encoding for the huntingtin protein. Some research groups have previously shown that HD is associated with cellular radiosensitivity in quiescent cells. However, there is still no mechanistic model explaining such specific clinical feature. Here, we examined the ATM-dependent signaling and repair pathways of the DNA double-strand breaks (DSB), the key damage induced by ionizing radiation, in human HD skin fibroblasts. Early after irradiation, quiescent HD fibroblasts showed an abnormally low rate of recognized DSB managed by non-homologous end-joining reflected by a low yield of nuclear foci formed by phosphorylated H2AX histones and by 53BP1 protein. Furthermore, HD cells elicited a significant but moderate yield of unrepaired DSB 24 h after irradiation. Irradiated HD cells also presented a delayed nucleo-shuttling of phosphorylated forms of the ATM kinase, potentially due to a specific binding of ATM to mutated huntingtin in the cytoplasm. Our results suggest that HD belongs to the group of syndromes associated with a low but significant defect of DSB signaling and repair defect associated with radiosensitivity. A combination of biphosphonates and statins complements these impairments by facilitating the nucleo-shuttling of ATM, increasing the yield of recognized and repaired DSB.

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Notes

  1. 1.

    The name chorea was historically given by Paracelsius to any disease associated with disordered movements.

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Acknowledgments

We thank Madame Beaufrère for her assistance in editing the English. M.L.F. was supported by the Société Française de Radioprotection (SFRP). We thank the Association Pour la Recherche sur l'Ataxie-Telangiectasie (APRAT), the Electricité de France (Comité de Radioprotection), the Plan Cancer/AVIESAN “Micromegas project, the ANR “Hemi-breaks T” project, the Centre National d’Etudes Spatiales (CNES), and the Commissariat Général à l’Investissement (INDIRA project).

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Correspondence to Nicolas Foray.

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This paper is dedicated to the memory of Edmond-Philippe Malaise, pioneer of the notion of individual radiosensitivity.

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Ferlazzo, M.L., Sonzogni, L., Granzotto, A. et al. Mutations of the Huntington’s Disease Protein Impact on the ATM-Dependent Signaling and Repair Pathways of the Radiation-Induced DNA Double-Strand Breaks: Corrective Effect of Statins and Bisphosphonates. Mol Neurobiol 49, 1200–1211 (2014). https://doi.org/10.1007/s12035-013-8591-7

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Keywords

  • Huntington’s disease
  • Huntingtin
  • DSB repair
  • ATM
  • H2AX
  • MRE11
  • Ionizing radiations