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

Mutations 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. [Display omitted] •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 Mutations in p53 are well known to cause cancer but have not been implicated in syndromes caused by short telomeres. In this study, Toledo and colleagues show that mutant mice expressing a C-terminal truncation of p53 suffer from aplastic anemia and pulmonary fibrosis, hallmarks of telomere-related syndromes. The mutants exhibit increased p53 activity, have short telomeres, and have a decreased expression of several genes involved in telomere metabolism. These data reveal that p53 plays a major role in telomere regulation.