A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging

• Published in: Nature genetics Vol. 41; no. 8; pp. 891 - 898
• Main Authors: Murga, Matilde, Fernandez-Capetillo, Oscar, Bunting, Samuel, Montaña, Maria F, Soria, Rebeca, Mulero, Francisca, Cañamero, Marta, Lee, Youngsoo, McKinnon, Peter J, Nussenzweig, Andre
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing Group 01.08.2009
• Subjects: Abnormalities, Multiple - enzymology; Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Aging - drug effects; Aging - genetics; Aging - pathology; Alleles; Animal models in research; Animals; Apoptosis - drug effects; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Brain - enzymology; Brain - pathology; Cancer; Causes of; Cell cycle; Cell Cycle Proteins - metabolism; Control; Disease Models, Animal; DNA Damage; DNA Repair - drug effects; DNA Replication - drug effects; DNA-Activated Protein Kinase - metabolism; DNA-Binding Proteins - metabolism; Dwarfism; Embryo, Mammalian - drug effects; Embryo, Mammalian - enzymology; Embryo, Mammalian - metabolism; Embryo, Mammalian - pathology; Embryonic development; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - pathology; Fundamental and applied biological sciences. Psychology; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Humans; Kinases; Mice; Molecular biology; Nuclear Proteins - metabolism; Phenotype; Physiological aspects; Progeria - embryology; Progeria - enzymology; Progeria - pathology; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - metabolism; Proteins; Stress, Physiological - drug effects; Studies; Syndrome; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - metabolism; United States; Spain; Animal model; Vertebrata; Mammalia; Mouse; Ageing; Rodentia; Stress
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.420

Although DNA damage is considered a driving force for aging, the nature of the damage that arises endogenously remains unclear. Replicative stress, a source of endogenous DNA damage, is prevented primarily by the ATR kinase. We have developed a mouse model of Seckel syndrome characterized by a severe deficiency in ATR. Seckel mice show high levels of replicative stress during embryogenesis, when proliferation is widespread, but this is reduced to marginal amounts in postnatal life. In spite of this decrease, adult Seckel mice show accelerated aging, which is further aggravated in the absence of p53. Together, these results support a model whereby replicative stress, particularly in utero, contributes to the onset of aging in postnatal life, and this is balanced by the replicative stress-limiting role of the checkpoint proteins ATR and p53.