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 journalArticlepeer-review

    44 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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