Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice
Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice
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DOI：
10.1038/sj.embor.7400127
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发表时间：
2004-05-01
期刊：
影响因子：
7.7
通讯作者：
Blasco, MA
中科院分区：
文献类型：
--
作者：
Espejel, S;Martín, M;Blasco, MA
非同源末端连接（NHEJ）是哺乳动物细胞用于科普基因组中连续发生的双链断裂（DSB）的主要修复机制。哺乳动物NHEJ机制的关键组分之一是由Ku 86/70异二聚体和DNA-PK催化亚基（DNA-PKcs）形成的DNA-PK复合物。在这里，我们报告了详细的终身跟踪DNA-PKcs缺陷小鼠。除了在衰老生物体的背景下定义DNA-PKcs在端粒长度维持中的作用外，我们观察到DNA-PKcs缺陷小鼠的寿命较短，并且显示出比相应的野生型同窝仔更早发生衰老相关的病理学。此外，DNA-PKcs消融与T淋巴瘤和感染的发生率显著升高相关。总之，这些数据将DNA-PKcs在DNA修复和端粒长度维持中的双重作用与生物体衰老和癌症联系起来。
Non-homologous end joining (NHEJ) is the principal repair mechanism used by mammalian cells to cope with double-strand breaks (DSBs) that continually occur in the genome. One of the key components of the mammalian NHEJ machinery is the DNA-PK complex, formed by the Ku86/70 heterodimer and the DNA-PK catalytic subunit (DNA-PKcs). Here, we report on the detailed life-long follow-up of DNA-PKcs-defective mice. Apart from defining a role of DNA-PKcs in telomere length maintenance in the context of the ageing organism, we observed that DNA-PKcs-defective mice had a shorter life span and showed an earlier onset of ageing-related pathologies than the corresponding wild-type littermates. In addition, DNA-PKcs ablation was associated with a markedly higher incidence of T lymphomas and infections. In conclusion, these data link the dual role of DNA-PKcs in DNA repair and telomere length maintenance to organismal ageing and cancer.