Atm reactivation reverses ataxia telangiectasia phenotypes in vivo

Hereditary deficiencies in DNA damage signaling are invariably associated with cancer predisposition, immunodeficiency, radiation sensitivity, gonadal abnormalities, premature aging, and tissue degeneration. ATM kinase has been established as a central player in DNA double-strand break repair and it...

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Bibliographic Details
Published in:Cell death & disease 2018-02, Vol.9 (3), p.314-13, Article 314
Main Authors: Di Siena, Sara, Campolo, Federica, Gimmelli, Roberto, Di Pietro, Chiara, Marazziti, Daniela, Dolci, Susanna, Lenzi, Andrea, Nussenzweig, Andre, Pellegrini, Manuela
Format: Article
Language:English
Subjects:
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14/19
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45/23
45/29
45/77
64/60
Aging
Animal models
Antibodies
Ataxia
Ataxia telangiectasia
Ataxia telangiectasia mutated protein
Biochemistry
Biomedical and Life Sciences
Body weight
Cancer
Cell Biology
Cell Culture
Cerebellum
Degeneration
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Double-strand break repair
Gene therapy
Immunodeficiency
Immunology
Kinases
Life Sciences
Life span
Radioresistance
Recovery of function
Rodents
Spermatogenesis
Tamoxifen
Thymoma
Transgenic animals
Transgenic mice
Transplantation
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Summary:Hereditary deficiencies in DNA damage signaling are invariably associated with cancer predisposition, immunodeficiency, radiation sensitivity, gonadal abnormalities, premature aging, and tissue degeneration. ATM kinase has been established as a central player in DNA double-strand break repair and its deficiency causes ataxia telangiectasia, a rare, multi-system disease with no cure. So ATM represents a highly attractive target for the development of novel types of gene therapy or transplantation strategies. Atm tamoxifen-inducible mouse models were generated to explore whether Atm reconstitution is able to restore Atm function in an Atm-deficient background. Body weight, immunodeficiency, spermatogenesis, and radioresistance were recovered in transgenic mice within 1 month from Atm induction. Notably, life span was doubled after Atm restoration, mice were protected from thymoma and no cerebellar defects were observed. Atm signaling was functional after DNA damage in vivo and in vitro. In summary, we propose a new Atm mouse model to investigate novel therapeutic strategies for ATM activation in ataxia telangiectasia disease.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-018-0357-8