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

I Simeonova, S Jaber, I Draskovic, B Bardot, M Fang… - Cell reports, 2013 - cell.com
I Simeonova, S Jaber, I Draskovic, B Bardot, M Fang, R Bouarich-Bourimi, V Lejour…
Cell reports, 2013cell.com
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 Δ31, 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 Δ31/Δ31 mice had short telomeres and other phenotypic traits associated with the
telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson …
Summary
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.
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