Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs.
Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs.
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DOI：
10.1083/jcb.200407178
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发表时间：
2004-11-22
影响因子：
7.8
通讯作者：
Blasco, Maria A
中科院分区：
文献类型：
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作者：
Espejel, Silvia;Klatt, Peter;Menissier-de Murcia, Josiane;Martin-Caballero, Juan;Flores, Juana M;Taccioli, Guillermo;de Murcia, Gilbert;Blasco, Maria A
DNA修复蛋白聚(ADP-核糖)聚合酶-1(PARP-1)、Ku86和DNA-PK催化亚单位(DNA-PKcs)参与了端粒代谢。为了从基因上剖析这些活动对端粒功能以及有机体癌症和衰老的影响，我们培育了端粒酶和上述任何DNA修复蛋白PARP-1、Ku86或DNA-PKcs双重缺陷的小鼠。首先，我们证明，与单一的端粒酶缺乏的对照相比，在没有端粒酶的情况下取消PARP-1不会影响端粒缩短、端粒封顶或生物体的存活率。因此，PARP-1在端粒代谢中不起主要作用，甚至在端粒酶缺乏的情况下也不起作用。相反，与单一端粒酶缺陷的小鼠相比，端粒酶和Ku86或DNA-PKcs双重缺陷的小鼠表现出更快的组织活力丧失。有趣的是，这种生物体生存能力的丧失与增殖性缺陷和年龄相关的病理相关，但与癌症发病率的增加无关。这些结果支持这样一种观点，即端粒酶和短端粒的缺失与DNA修复缺陷相结合，加速了衰老过程，而不会影响肿瘤的发生。
The DNA repair proteins poly(ADP-ribose) polymerase-1 (PARP-1), Ku86, and catalytic subunit of DNA-PK (DNA-PKcs) have been involved in telomere metabolism. To genetically dissect the impact of these activities on telomere function, as well as organismal cancer and aging, we have generated mice doubly deficient for both telomerase and any of the mentioned DNA repair proteins, PARP-1, Ku86, or DNA-PKcs. First, we show that abrogation of PARP-1 in the absence of telomerase does not affect the rate of telomere shortening, telomere capping, or organismal viability compared with single telomerase-deficient controls. Thus, PARP-1 does not have a major role in telomere metabolism, not even in the context of telomerase deficiency. In contrast, mice doubly deficient for telomerase and either Ku86 or DNA-PKcs manifest accelerated loss of organismal viability compared with single telomerase-deficient mice. Interestingly, this loss of organismal viability correlates with proliferative defects and age-related pathologies, but not with increased incidence of cancer. These results support the notion that absence of telomerase and short telomeres in combination with DNA repair deficiencies accelerate the aging process without impacting on tumorigenesis.