Nijnik Anastasia, Woodbine Lisa, Marchetti Caterina, Dawson Sara, Lambe Teresa, Liu Cong, Rodrigues Neil P, Crockford Tanya L, Cabuy Erik, Vindigni Alessandro, Enver Tariq, Bell John I, Slijepcevic Predrag, Goodnow Christopher C, Jeggo Penelope A, Cornall Richard J
Henry Wellcome Building for Molecular Physiology, Oxford University, Oxford OX3 9DU, UK.
Nature. 2007 Jun 7;447(7145):686-90. doi: 10.1038/nature05875.
Accumulation of DNA damage leading to adult stem cell exhaustion has been proposed to be a principal mechanism of ageing. Here we address this question by taking advantage of the highly specific role of DNA ligase IV in the repair of DNA double-strand breaks by non-homologous end-joining, and by the discovery of a unique mouse strain with a hypomorphic Lig4(Y288C) mutation. The Lig4(Y288C) mouse, identified by means of a mutagenesis screening programme, is a mouse model for human LIG4 syndrome, showing immunodeficiency and growth retardation. Diminished DNA double-strand break repair in the Lig4(Y288C) strain causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during ageing, and severely impairs stem cell function in tissue culture and transplantation. The sensitivity of haematopoietic stem cells to non-homologous end-joining deficiency is therefore a key determinant of their ability to maintain themselves against physiological stress over time and to withstand culture and transplantation.
DNA损伤的积累导致成体干细胞耗竭，这被认为是衰老的主要机制。在此，我们利用DNA连接酶IV在通过非同源末端连接修复DNA双链断裂中的高度特异性作用，以及通过发现一种具有低表达Lig4(Y288C)突变的独特小鼠品系，来解决这个问题。通过诱变筛选程序鉴定出的Lig4(Y288C)小鼠是人类LIG4综合征的小鼠模型，表现出免疫缺陷和生长迟缓。Lig4(Y288C)品系中DNA双链断裂修复能力的下降导致衰老过程中造血干细胞和骨髓细胞数量逐渐减少，并严重损害组织培养和移植中的干细胞功能。因此，造血干细胞对非同源末端连接缺陷的敏感性是其随着时间推移维持自身抵抗生理应激以及耐受培养和移植能力的关键决定因素。
