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.

Atm reactivation reverses ataxia telangiectasia phenotypes in vivo / Di Siena, S.; Campolo, F.; Gimmelli, R.; Di Pietro, C.; Marazziti, D.; Dolci, S.; Lenzi, A.; Nussenzweig, A.; Pellegrini, M.. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 9:3(2018), pp. 1-14. [10.1038/s41419-018-0357-8]

Atm reactivation reverses ataxia telangiectasia phenotypes in vivo

Di Siena S.;Campolo F.;Gimmelli R.;Dolci S.;Lenzi A.;
2018

Abstract

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.
2018
animals; ataxia telangiectasia; ataxia telangiectasia mutated proteins; DNA damage; enzyme activation; female; humans; male; mice; transgenic; phenotype; signal transduction; disease model; animal
01 Pubblicazione su rivista::01a Articolo in rivista
Atm reactivation reverses ataxia telangiectasia phenotypes in vivo / Di Siena, S.; Campolo, F.; Gimmelli, R.; Di Pietro, C.; Marazziti, D.; Dolci, S.; Lenzi, A.; Nussenzweig, A.; Pellegrini, M.. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 9:3(2018), pp. 1-14. [10.1038/s41419-018-0357-8]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1411512
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