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

Authors: Murga M; Bunting S; Montaña MF; Soria R; Mulero F; Cañamero M; Lee Y; McKinnon PJ; Nussenzweig A; Fernandez-Capetillo O

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.

Keywords: Abnormalities, Multiple/enzymology/genetics/*pathology; Aging/drug effects/*genetics/*pathology; Alleles; Animals; Apoptosis/drug effects; Brain/enzymology/pathology; Cell Cycle Proteins/*metabolism; DNA Damage; DNA Repair/drug effects; *DNA Replication/drug effects; DNA-Activated Protein Kinase/metabolism; DNA-Binding Proteins/metabolism; Disease Models, Animal; Embryo, Mammalian/drug effects/enzymology/metabolism/pathology; Fibroblasts/drug effects/enzymology/pathology; Humans; Mice; Nuclear Proteins/metabolism; Phenotype; Progeria/*embryology/enzymology/pathology; Protein Kinase Inhibitors/pharmacology; Protein-Serine-Threonine Kinases/deficiency/*metabolism; *Stress, Physiological/drug effects; Syndrome; Tumor Suppressor Protein p53/deficiency/metabolism
Journal: Nature genetics
Volume: 41
Issue: 8
Pages: 891-8
Date: July 22, 2009
PMID: 19620979
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Citation:

Murga M, Bunting S, Montaña MF, Soria R, Mulero F, Cañamero M, Lee Y, McKinnon PJ, Nussenzweig A, Fernandez-Capetillo O (2009) A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging. Nature genetics 41: 891-8.


Study Lifespan Factors:
  • Atr Ataxia telangiectasia and Rad3 related


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