Murga Matilde, Bunting Samuel, Montaña Maria F, Soria Rebeca, Mulero Francisca, Cañamero Marta, Lee Youngsoo, McKinnon Peter J, Nussenzweig Andre, Fernandez-Capetillo Oscar
Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Nat Genet. 2009 Aug;41(8):891-8. doi: 10.1038/ng.420. Epub 2009 Jul 20.
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.
尽管DNA损伤被认为是衰老的驱动力，但内源性产生的损伤的本质仍不清楚。复制应激是内源性DNA损伤的一个来源，主要由ATR激酶来预防。我们构建了一种以ATR严重缺陷为特征的Seckel综合征小鼠模型。Seckel小鼠在胚胎发育期间（此时细胞增殖广泛）表现出高水平的复制应激，但在出生后的生命中这种应激减少到了微量。尽管有这种减少，成年Seckel小鼠仍表现出加速衰老，在缺乏p53的情况下衰老进一步加剧。这些结果共同支持了一个模型，即复制应激，尤其是在子宫内的复制应激，促成了出生后生命中的衰老起始，而这由检查点蛋白ATR和p53的复制应激限制作用来平衡。
