Article abstract
Nature Genetics 41, 891 - 898 (2009)
Published online: 20 July 2009 | doi:10.1038/ng.420
A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging
Matilde Murga1, Samuel Bunting2, Maria F Montaña1, Rebeca Soria1, Francisca Mulero3, Marta Cañamero4, Youngsoo Lee5, Peter J McKinnon5, Andre Nussenzweig2 & Oscar Fernandez-Capetillo1
Abstract
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.
- Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
- Molecular Imaging Unit, CNIO, Madrid, Spain.
- Comparative Pathology Unit, CNIO, Madrid, Spain.
- Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Correspondence to: Matilde Murga1 e-mail: mmurga@cnio.es
Correspondence to: Oscar Fernandez-Capetillo1 e-mail: ofernandez@cnio.es