Usher Syndrome Belongs to the Genetic Diseases Associated with Radiosensitivity: Influence of the ATM Protein Kinase
Usher syndrome (USH) is a rare autosomal recessive disease characterized by the combination of hearing loss, visual impairment due to retinitis pigmentosa, and in some cases vestibular dysfunctions. Studies published in the 1980s reported that USH is associated with cellular radiosensitivity. Howeve...
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MDPI AG
2022-01-01
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| author | Joëlle Al-Choboq Mélanie L. Ferlazzo Laurène Sonzogni Adeline Granzotto Laura El-Nachef Mira Maalouf Elise Berthel Nicolas Foray |
| author_facet | Joëlle Al-Choboq Mélanie L. Ferlazzo Laurène Sonzogni Adeline Granzotto Laura El-Nachef Mira Maalouf Elise Berthel Nicolas Foray |
| author_sort | Joëlle Al-Choboq |
| collection | DOAJ |
| description | Usher syndrome (USH) is a rare autosomal recessive disease characterized by the combination of hearing loss, visual impairment due to retinitis pigmentosa, and in some cases vestibular dysfunctions. Studies published in the 1980s reported that USH is associated with cellular radiosensitivity. However, the molecular basis of this particular phenotype has not yet been documented. The aim of this study was therefore to document the radiosensitivity of USH1—a subset of USH—by examining the radiation-induced nucleo-shuttling of ATM (RIANS), as well as the functionality of the repair and signaling pathways of the DNA double-strand breaks (DSBs) in three skin fibroblasts derived from USH1 patients. The clonogenic cell survival, the micronuclei, the nuclear foci formed by the phosphorylated forms of the X variant of the H2A histone (ɣH2AX), the phosphorylated forms of the ATM protein (pATM), and the meiotic recombination 11 nuclease (MRE11) were used as cellular and molecular endpoints. The interaction between the ATM and USH1 proteins was also examined by proximity ligation assay. The results showed that USH1 fibroblasts were associated with moderate but significant radiosensitivity, high yield of micronuclei, and impaired DSB recognition but normal DSB repair, likely caused by a delayed RIANS, suggesting a possible sequestration of ATM by some USH1 proteins overexpressed in the cytoplasm. To our knowledge, this report is the first radiobiological characterization of cells from USH1 patients at both molecular and cellular scales. |
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| language | English |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5703e6c24d014740a8a400256da829712023-11-23T16:42:43ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-01233157010.3390/ijms23031570Usher Syndrome Belongs to the Genetic Diseases Associated with Radiosensitivity: Influence of the ATM Protein KinaseJoëlle Al-Choboq0Mélanie L. Ferlazzo1Laurène Sonzogni2Adeline Granzotto3Laura El-Nachef4Mira Maalouf5Elise Berthel6Nicolas Foray7Inserm, U1296 Unit, Radiation: Defense, Health and Environment, Centre Léon-Bérard, 28 rue Laennec, 69008 Lyon, FranceInserm, U1296 Unit, Radiation: Defense, Health and Environment, Centre Léon-Bérard, 28 rue Laennec, 69008 Lyon, FranceInserm, U1296 Unit, Radiation: Defense, Health and Environment, Centre Léon-Bérard, 28 rue Laennec, 69008 Lyon, FranceInserm, U1296 Unit, Radiation: Defense, Health and Environment, Centre Léon-Bérard, 28 rue Laennec, 69008 Lyon, FranceInserm, U1296 Unit, Radiation: Defense, Health and Environment, Centre Léon-Bérard, 28 rue Laennec, 69008 Lyon, FranceDepartment of Chemistry and Biochemistry, Faculty of Sciences II, Lebanese University, Fanar 1202, LebanonInserm, U1296 Unit, Radiation: Defense, Health and Environment, Centre Léon-Bérard, 28 rue Laennec, 69008 Lyon, FranceInserm, U1296 Unit, Radiation: Defense, Health and Environment, Centre Léon-Bérard, 28 rue Laennec, 69008 Lyon, FranceUsher syndrome (USH) is a rare autosomal recessive disease characterized by the combination of hearing loss, visual impairment due to retinitis pigmentosa, and in some cases vestibular dysfunctions. Studies published in the 1980s reported that USH is associated with cellular radiosensitivity. However, the molecular basis of this particular phenotype has not yet been documented. The aim of this study was therefore to document the radiosensitivity of USH1—a subset of USH—by examining the radiation-induced nucleo-shuttling of ATM (RIANS), as well as the functionality of the repair and signaling pathways of the DNA double-strand breaks (DSBs) in three skin fibroblasts derived from USH1 patients. The clonogenic cell survival, the micronuclei, the nuclear foci formed by the phosphorylated forms of the X variant of the H2A histone (ɣH2AX), the phosphorylated forms of the ATM protein (pATM), and the meiotic recombination 11 nuclease (MRE11) were used as cellular and molecular endpoints. The interaction between the ATM and USH1 proteins was also examined by proximity ligation assay. The results showed that USH1 fibroblasts were associated with moderate but significant radiosensitivity, high yield of micronuclei, and impaired DSB recognition but normal DSB repair, likely caused by a delayed RIANS, suggesting a possible sequestration of ATM by some USH1 proteins overexpressed in the cytoplasm. To our knowledge, this report is the first radiobiological characterization of cells from USH1 patients at both molecular and cellular scales.https://www.mdpi.com/1422-0067/23/3/1570Usher syndromeradiosensitivityDNA double-strand breaksATMionizing radiation |
| spellingShingle | Joëlle Al-Choboq Mélanie L. Ferlazzo Laurène Sonzogni Adeline Granzotto Laura El-Nachef Mira Maalouf Elise Berthel Nicolas Foray Usher Syndrome Belongs to the Genetic Diseases Associated with Radiosensitivity: Influence of the ATM Protein Kinase International Journal of Molecular Sciences Usher syndrome radiosensitivity DNA double-strand breaks ATM ionizing radiation |
| title | Usher Syndrome Belongs to the Genetic Diseases Associated with Radiosensitivity: Influence of the ATM Protein Kinase |
| title_full | Usher Syndrome Belongs to the Genetic Diseases Associated with Radiosensitivity: Influence of the ATM Protein Kinase |
| title_fullStr | Usher Syndrome Belongs to the Genetic Diseases Associated with Radiosensitivity: Influence of the ATM Protein Kinase |
| title_full_unstemmed | Usher Syndrome Belongs to the Genetic Diseases Associated with Radiosensitivity: Influence of the ATM Protein Kinase |
| title_short | Usher Syndrome Belongs to the Genetic Diseases Associated with Radiosensitivity: Influence of the ATM Protein Kinase |
| title_sort | usher syndrome belongs to the genetic diseases associated with radiosensitivity influence of the atm protein kinase |
| topic | Usher syndrome radiosensitivity DNA double-strand breaks ATM ionizing radiation |
| url | https://www.mdpi.com/1422-0067/23/3/1570 |
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