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

Matilde Murga, Samuel Bunting, Maria F. Montãa, Rebeca Soria, Francisca Mulero, Marta Cãamero, Youngsoo Lee, Peter J. McKinnon, Andre Nussenzweig, Oscar Fernandez-Capetillo

Research output: Contribution to journalArticlepeer-review

253 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)891-898
Number of pages8
JournalNature Genetics
Volume41
Issue number8
DOIs
StatePublished - Aug 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics

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