García-Cao Isabel, García-Cao Marta, Tomás-Loba Antonia, Martín-Caballero Juan, Flores Juana M, Klatt Peter, Blasco María A, Serrano Manuel
Tumor Suppression Group, Spanish National Cancer Center, Madrid.
EMBO Rep. 2006 May;7(5):546-52. doi: 10.1038/sj.embor.7400667. Epub 2006 Mar 31.
There is a great interest in determining the impact of p53 on ageing and, for this, it is important to discriminate among the known causes of ageing. Telomere loss is a well-established source of age-associated damage, which by itself can recapitulate ageing in mouse models. Here, we have used a genetic approach to interrogate whether p53 contributes to the elimination of telomere-damaged cells and its impact on telomere-driven ageing. We have generated compound mice carrying three functional copies of the p53 gene (super-p53) in a telomerase-deficient background and we have measured the presence of chromosomal abnormalities and DNA damage in several tissues. We have found that the in vivo load of telomere-derived chromosomal damage is significantly decreased in super-p53/telomerase-null mice compared with normal-p53/telomerase-null mice. Interestingly, the presence of extra p53 activity neither accelerates nor delays telomere-driven ageing. From these observations, we conclude that p53 has an active role in eliminating telomere-damaged cells, and we exclude the possibility of an age-promoting effect of p53 on telomere-driven ageing.
人们对确定p53对衰老的影响有着浓厚兴趣，为此，区分已知的衰老原因很重要。端粒损耗是与年龄相关损伤的一个公认来源，其本身就能在小鼠模型中重现衰老过程。在此，我们采用遗传学方法来探究p53是否有助于清除端粒受损细胞及其对端粒驱动衰老的影响。我们构建了在端粒酶缺陷背景下携带三个p53基因功能拷贝（超级p53）的复合小鼠，并检测了多个组织中染色体异常和DNA损伤的情况。我们发现，与正常p53/端粒酶缺失小鼠相比，超级p53/端粒酶缺失小鼠中端粒衍生的染色体损伤的体内负荷显著降低。有趣的是，额外的p53活性既不加速也不延迟端粒驱动的衰老。基于这些观察结果，我们得出结论，p53在清除端粒受损细胞中发挥着积极作用，并且我们排除了p53对端粒驱动衰老具有促进衰老作用的可能性。
