title: A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging.
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.
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. mmurga@cnio.es
authors.forename: Matilde
authors.initials: M
authors.lastname: Murga
authors.forename: Samuel
authors.initials: S
authors.lastname: Bunting
authors.forename: Maria F
authors.initials: MF
authors.lastname: Montaña
authors.forename: Rebeca
authors.initials: R
authors.lastname: Soria
authors.forename: Francisca
authors.initials: F
authors.lastname: Mulero
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Lee
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
authors.forename: Andre
authors.initials: A
authors.lastname: Nussenzweig
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D000375:Aging / Q000187:drug effects / Q000235:genetics* / Q000473:pathology*; D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins; D001921:Brain / Q000201:enzymology / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D011371:Progeria / Q000196:embryology* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects; D013577:Syndrome; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D017346:Protein Serine-Threonine Kinases