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

TY - JOUR

T1 - Mutant mice lacking the p53 C-terminal domain model telomere syndromes

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.

PY - 2013/6/27

Y1 - 2013/6/27

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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84879794532

U2 - 10.1016/j.celrep.2013.05.028

DO - 10.1016/j.celrep.2013.05.028

M3 - Article

C2 - 23770245

AN - SCOPUS:84879794532

VL - 3

SP - 2046

EP - 2058

JO - Cell Reports

JF - Cell Reports

IS - 6

ER -