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. 2022 Jan;59(1):556-573.
doi: 10.1007/s12035-021-02615-3. Epub 2021 Nov 2.

Individual Response to Radiation of Individuals with Neurofibromatosis Type I: Role of the ATM Protein and Influence of Statins and Bisphosphonates

Patrick Combemale #  1   2 , Laurène Sonzogni #  1 , Clément Devic #  1 , Zuzana Bencokova  1 , Mélanie Lydia Ferlazzo  1 , Adeline Granzotto  1 , Steven Franck Burlet  1 , Stéphane Pinson  1   2 , Mona Amini-Adle  1   2 , Joëlle Al-Choboq  1 , Larry Bodgi  1 , Michel Bourguignon  1   3 , Jacques Balosso  4 , Jean-Thomas Bachelet  1 , Nicolas Foray  5
Affiliations

Individual Response to Radiation of Individuals with Neurofibromatosis Type I: Role of the ATM Protein and Influence of Statins and Bisphosphonates

Patrick Combemale et al. Mol Neurobiol. 2022 Jan.

Abstract

Neurofibromatosis type 1 (NF1) is a disease characterized by high occurrence of benign and malignant brain tumours and caused by mutations of the neurofibromin protein. While there is an increasing evidence that NF1 is associated with radiosensitivity and radiosusceptibility, few studies have dealt with the molecular and cellular radiation response of cells from individuals with NF1. Here, we examined the ATM-dependent signalling and repair pathways of the DNA double-strand breaks (DSB), the key-damage induced by ionizing radiation, in skin fibroblast cell lines from 43 individuals with NF1. Ten minutes after X-rays irradiation, quiescent NF1 fibroblasts showed abnormally low rate of recognized DSB reflected by a low yield of nuclear foci formed by phosphorylated H2AX histones. Irradiated NF1 fibroblasts also presented a delayed radiation-induced nucleoshuttling of the ATM kinase (RIANS), potentially due to a specific binding of ATM to the mutated neurofibromin in cytoplasm. Lastly, NF1 fibroblasts showed abnormally high MRE11 nuclease activity suggesting a high genomic instability after irradiation. A combination of bisphosphonates and statins complemented these impairments by accelerating the RIANS, increasing the yield of recognized DSB and reducing genomic instability. Data from NF1 fibroblasts exposed to radiation in radiotherapy and CT scan conditions confirmed that NF1 belongs to the group of syndromes associated with radiosensitivity and radiosusceptibility.

Keywords: DSB repair; DSB repair and signaling in neurofibromatosis type 1; H2AX; MRE11 Indexing phrase; NF1; Neurofibromatosis.

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