Mutant Mice Lacking the p53 C-Terminal Domain Model Telomere Syndromes

• A nonsense mutation encoding a p53 without its C terminus increases p53 activity
• Mice carrying this p53 mutation suffer from aplastic anemia and pulmonary fibrosis
• These mice model dyskeratosis congenita, a syndrome of telomere dysfunction
• p53 downregulates genes involved in telomere metabolism: Dkc1, Rtel1, Terf1, and Tinf2

SummaryMutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53Δ31, 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, p53Δ31/Δ31 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+/Δ31 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 p53Δ31/Δ31 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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