Li Han, Vogel Hannes, Holcomb Valerie B, Gu Yansong, Hasty Paul
Department of Molecular Medicine and Institute of Biotechnology, The University of Texas Health Science Center, San Antonio, Texas 78245, USA.
Mol Cell Biol. 2007 Dec;27(23):8205-14. doi: 10.1128/MCB.00785-07. Epub 2007 Sep 17.
Ku70 forms a heterodimer with Ku80, called Ku, that is critical for repairing DNA double-stand breaks by nonhomologous end joining and for maintaining telomeres. Mice with either gene mutated exhibit similar phenotypes that include increased sensitivity to ionizing radiation and severe combined immunodeficiency. However, there are also differences in the reported phenotypes. For example, only Ku70 mutants are reported to exhibit a high incidence of thymic lymphomas while only Ku80 mutants are reported to exhibit early aging with very low cancer levels. There are two explanations for these differences. First, either Ku70 or Ku80 functions outside the Ku heterodimer such that deletion of one is not identical to deletion of the other. Second, divergent genetic backgrounds or environments influence the phenotype. To distinguish between these possibilities, the Ku70 and Ku80 mutations were crossed together to generate Ku70, Ku80, and double-mutant mice in the same genetic background raised in the same environment. We show that these three cohorts have similar phenotypes that most resemble the previous report for Ku80 mutant mice, i.e., early aging without substantially increased cancer levels. Thus, our observations suggest that the Ku heterodimer is important for longevity assurance in mice since divergent genetic backgrounds and/or environments likely account for these previously reported differences.
Ku70与Ku80形成一种异源二聚体，称为Ku，它对于通过非同源末端连接修复DNA双链断裂以及维持端粒至关重要。任一基因发生突变的小鼠都表现出相似的表型，包括对电离辐射的敏感性增加和严重联合免疫缺陷。然而，报道的表型也存在差异。例如，据报道只有Ku70突变体表现出胸腺淋巴瘤的高发病率，而只有Ku80突变体表现出早期衰老且癌症水平极低。对于这些差异有两种解释。第一，Ku70或Ku80在Ku异源二聚体之外发挥作用，使得缺失一个与缺失另一个不同。第二，不同的遗传背景或环境会影响表型。为了区分这些可能性，将Ku70和Ku80突变体杂交在一起，以在相同环境中饲养的相同遗传背景下产生Ku70、Ku80和双突变小鼠。我们发现这三组小鼠具有相似的表型，最类似于先前关于Ku80突变体小鼠的报道，即早期衰老且癌症水平没有实质性增加。因此，我们的观察结果表明，Ku异源二聚体对于小鼠寿命保障很重要，因为不同的遗传背景和/或环境可能解释了这些先前报道的差异。
