A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging.
A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging.
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DOI：
10.1038/ng.420
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发表时间：
2009-08
期刊：
影响因子：
30.8
通讯作者：
Fernandez-Capetillo, Oscar
中科院分区：
文献类型：
--
作者：
Murga, Matilde;Bunting, Samuel;Montana, Maria F.;Soria, Rebeca;Mulero, Francisca;Canamero, Marta;Lee, Youngsoo;McKinnon, Peter J.;Nussenzweig, Andre;Fernandez-Capetillo, Oscar
DNA损伤的逐渐积累被认为是启动衰老的驱动力之一。然而，内生损害的性质仍不明确。已知的内源性损伤的一个来源是复制应激(Replicative Stress，RS)，它与DNA复制密切相关，主要由ATR激酶来预防。在这里，我们建立了一种人类塞克尔综合征的小鼠模型，其特征是ATR严重不足。Seckel小鼠在胚胎发育期间遭受高水平的RS，当时广泛的增殖，但在出生后生活中下降到边缘水平。尽管有这种下降，成年的Seckel小鼠呈现加速衰老，由于RS的进一步增加，在缺少P53的情况下，这种情况进一步加剧。总之，这些结果支持这样的概念，即内源性RS，特别是在子宫内，有助于出生后生命中衰老的开始，这一点被检查点蛋白ATR和P53的RS限制作用所抵消。
The progressive accumulation of DNA damage is thought to be one of the driving forces that initiates ageing. However, the nature of the damage that arises endogenously is still ill-defined. A known source of endogenous damage is replicative stress (RS), which is intrinsically associated to DNA replication and prevented mainly by the ATR kinase. Here, we have developed a murine model of the human Seckel Syndrome characterized by a severe deficiency in ATR. Seckel mice suffer high levels of RS during embryogenesis when proliferation is widespread, but which decrease to marginal levels in postnatal life. In spite of this decrease, adult Seckel mice present accelerated ageing, which is further aggravated in the absence of p53 due to a further increase of RS. Together, these results support the concept that endogenous RS, particularly in utero, contributes to the onset of ageing in postnatal life and this is counterbalanced by the RS-limiting role of the checkpoint proteins ATR and p53.
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影响因子：
64.5
作者：
Casper, AM;Nghiem, P;Glover, TW
通讯作者：
Glover, TW
DOI：
10.1083/jcb.200704140
发表时间：
2007-09-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Murga M;Jaco I;Fan Y;Soria R;Martinez-Pastor B;Cuadrado M;Yang SM;Blasco MA;Skoultchi AI;Fernandez-Capetillo O
通讯作者：
Fernandez-Capetillo O
影响因子：
1.9
作者：
Arnold, SR;Spicer, D;Gilbert-Barness, E
通讯作者：
Gilbert-Barness, E
影响因子：
64.5
作者：
Barlow, C;Hirotsune, S;WynshawBoris, A
通讯作者：
WynshawBoris, A
DOI：
10.1073/pnas.93.23.13084
发表时间：
1996-11-12
影响因子：
11.1
作者：
Elson, A;Wang, YQ;Leder, P
通讯作者：
Leder, P