Mutant mice lacking the p53 C-terminal domain model telomere syndromes

Iva Simeonova, Sara Jaber, Irena Draskovic, Boris Bardot, Ming Fang, Rachida Bouarich-Bourimi, Vincent Lejour, Laure Charbonnier, Claire Soudais, Jean-Christophe Bourdon, Michel Huerre, Arturo Londono-Vallejo, Franck Toledo

    Research output: Contribution to journalArticle

    41 Citations (Scopus)

    Abstract

    Mutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53, a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres. Indeed, p53 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Heterozygous p53 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms. Importantly, several genes involved in telomere metabolism were downregulated in p53 cells, including Dyskerin, Rtel1, and Tinf2, which are mutated in dyskeratosis congenita, and Terf1, which is implicated in aplastic anemia. Together, these data reveal that a truncating mutation can activate p53 and that p53 plays a major role in the regulation of telomere metabolism.
    Original languageEnglish
    Pages (from-to)2046-2058
    Number of pages13
    JournalCell Reports
    Volume3
    Issue number6
    DOIs
    Publication statusPublished - 27 Jun 2013

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    Telomere
    Metabolism
    Dyskeratosis Congenita
    Aplastic Anemia
    Genes
    Mutation
    Pulmonary Fibrosis
    Down-Regulation
    Neoplasms

    Cite this

    Simeonova, I., Jaber, S., Draskovic, I., Bardot, B., Fang, M., Bouarich-Bourimi, R., ... Toledo, F. (2013). Mutant mice lacking the p53 C-terminal domain model telomere syndromes. Cell Reports, 3(6), 2046-2058. https://doi.org/10.1016/j.celrep.2013.05.028
    Simeonova, Iva ; Jaber, Sara ; Draskovic, Irena ; Bardot, Boris ; Fang, Ming ; Bouarich-Bourimi, Rachida ; Lejour, Vincent ; Charbonnier, Laure ; Soudais, Claire ; Bourdon, Jean-Christophe ; Huerre, Michel ; Londono-Vallejo, Arturo ; Toledo, Franck. / Mutant mice lacking the p53 C-terminal domain model telomere syndromes. In: Cell Reports. 2013 ; Vol. 3, No. 6. pp. 2046-2058.
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    Simeonova, I, Jaber, S, Draskovic, I, Bardot, B, Fang, M, Bouarich-Bourimi, R, Lejour, V, Charbonnier, L, Soudais, C, Bourdon, J-C, Huerre, M, Londono-Vallejo, A & Toledo, F 2013, 'Mutant mice lacking the p53 C-terminal domain model telomere syndromes', Cell Reports, vol. 3, no. 6, pp. 2046-2058. https://doi.org/10.1016/j.celrep.2013.05.028

    Mutant mice lacking the p53 C-terminal domain model telomere syndromes. / Simeonova, Iva; Jaber, Sara; Draskovic, Irena; Bardot, Boris; Fang, Ming; Bouarich-Bourimi, Rachida; Lejour, Vincent; Charbonnier, Laure; Soudais, Claire; Bourdon, Jean-Christophe; Huerre, Michel; Londono-Vallejo, Arturo; Toledo, Franck.

    In: Cell Reports, Vol. 3, No. 6, 27.06.2013, p. 2046-2058.

    Research output: Contribution to journalArticle

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    AU - Simeonova, Iva

    AU - Jaber, Sara

    AU - Draskovic, Irena

    AU - Bardot, Boris

    AU - Fang, Ming

    AU - Bouarich-Bourimi, Rachida

    AU - Lejour, Vincent

    AU - Charbonnier, Laure

    AU - Soudais, Claire

    AU - Bourdon, Jean-Christophe

    AU - Huerre, Michel

    AU - Londono-Vallejo, Arturo

    AU - Toledo, Franck

    N1 - Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

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    N2 - Mutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53, a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres. Indeed, p53 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Heterozygous p53 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms. Importantly, several genes involved in telomere metabolism were downregulated in p53 cells, including Dyskerin, Rtel1, and Tinf2, which are mutated in dyskeratosis congenita, and Terf1, which is implicated in aplastic anemia. Together, these data reveal that a truncating mutation can activate p53 and that p53 plays a major role in the regulation of telomere metabolism.

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    Simeonova I, Jaber S, Draskovic I, Bardot B, Fang M, Bouarich-Bourimi R et al. Mutant mice lacking the p53 C-terminal domain model telomere syndromes. Cell Reports. 2013 Jun 27;3(6):2046-2058. https://doi.org/10.1016/j.celrep.2013.05.028