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

Nature genetics | Aug 29, 2009

http://www.ncbi.nlm.nih.gov/pubmed/19620979

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.

Pubmed ID: 19620979 RIS Download

Mesh terms: Abnormalities, Multiple | Aging | Alleles | Animals | Apoptosis | Ataxia Telangiectasia Mutated Proteins | Brain | Cell Cycle Proteins | DNA Damage | DNA Repair | DNA Replication | DNA-Activated Protein Kinase | DNA-Binding Proteins | Disease Models, Animal | Embryo, Mammalian | Fibroblasts | Humans | Mice | Nuclear Proteins | Phenotype | Progeria | Protein Kinase Inhibitors | Protein-Serine-Threonine Kinases | Stress, Physiological | Syndrome | Tumor Suppressor Protein p53

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Associated grants

  • Agency: European Research Council, Id: 210520
  • Agency: NINDS NIH HHS, Id: R01 NS037956
  • Agency: NINDS NIH HHS, Id: R01 NS037956-11

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