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Radiobiological Characterization of Tuberous Sclerosis: a Delay in the Nucleo-Shuttling of ATM May Be Responsible for Radiosensitivity

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Abstract

The tuberous sclerosis complex (TSC) syndrome is associated with numerous cutaneous pathologies (notably on the face), epilepsy, intellectual disability and developmental retardation and, overall, high occurrence of benign tumors in several organs, like angiofibromas, giant cell astrocytomas, renal angiomyolipomas, and pulmonary lymphangioleiomyomatosis. TSC is caused by mutations of either of the hamartin or tuberin proteins that are mainly cytoplasmic. Some studies published in the 1980s reported that TSC is associated with radiosensitivity. However, its molecular basis in TSC cells is not documented enough. Here, we examined the functionality of the repair and signaling of radiation-induced DNA double-strand breaks (DSB) in fibroblasts derived from TSC patients. Quiescent TSC fibroblast cells elicited abnormally low rate of recognized DSB reflected by a low yield of nuclear foci formed by phosphorylated H2AX histones. Irradiated TSC cells also presented a delay in the nucleo-shuttling of the ATM kinase, potentially due to a specific binding of ATM to mutated TSC protein in cytoplasm. Lastly, TSC fibroblasts showed abnormally high MRE11 nuclease activity suggesting genomic instability. A combination of biphosphonates and statins complemented these impairments by facilitating the nucleoshuttling of ATM and increasing the yield of recognized DSB. Our results showed that TSC belongs to the group of syndromes associated with low but significant defect of DSB signaling and delay in the ATM nucleo-shuttling associated with radiosensitivity.

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Acknowledgements

This work was supported by the Plan Cancer/AVIESAN grants, the Commissariat General à l’Investissement (Programmes Investissement d’avenir—projet INDIRA), the Association Pour la Recherche sur l’Ataxie-Telangiectasie (APRAT) and the Association Neurofibromatose et Recklinghausen (ANR).

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  1. Mohamed Kheir Eddine Bach-Tobdji and Amar Djerad contributed equally to this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale, UMR1052, Radiobiology Group, Cancer Research Centre of Lyon, 69008, Lyon, France

    Mélanie L. Ferlazzo, Laurène Sonzogni, Clément Devic, Adeline Granzotto, Larry Bodgi, Jean-Thomas Bachelet & Nicolas Foray

  2. Centre de Recherches Nucléaires d’Alger, 2, Bd Frantz Fanon, Alger, Algeria

    Mohamed Kheir Eddine Bach-Tobdji, Amar Djerad & Assia Djefal-Kerrar

  3. Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris, Paris, France

    Christophe Hennequin

  4. INSERM UMR 1052 - Centre de Recherche en Cancérologie de Lyon, Groupe de Radiobiologie - Bât Cheney A - 28 Rue Laennec, 69008, Lyon, France

    Nicolas Foray

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  1. Mélanie L. Ferlazzo
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  2. Mohamed Kheir Eddine Bach-Tobdji
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Correspondence to Nicolas Foray.

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Ferlazzo, M.L., Bach-Tobdji, M.K.E., Djerad, A. et al. Radiobiological Characterization of Tuberous Sclerosis: a Delay in the Nucleo-Shuttling of ATM May Be Responsible for Radiosensitivity. Mol Neurobiol 55, 4973–4983 (2018). https://doi.org/10.1007/s12035-017-0648-6

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