DNA repair is limiting for haematopoietic stem cells during ageing


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 Lig4Y288C mutation. The Lig4Y288C 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 Lig4Y288C 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.

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Figure 1: Identification of an ENU-induced missense substitution in LigIV in the tiny mouse strain.
Figure 2: Impact of the Y288C mutation.
Figure 3: Double-strand breaks accumulate in Lig4 Y288C embryonic fibroblasts independently of replication and confer impaired proliferation.
Figure 4: Lig4 Y288C impairs the maintenance of adult haematopoietic stem cells.
Figure 5: Lig4 Y288C impairs the intrinsic function of adult haematopoietic stem cells.


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We thank I. Weissman, D. Rossi, P. Papathanasiou, F. Alt, C. Yan, A. Gennery and A. Enders for comments and for exchanging unpublished findings. This work was supported by the Wellcome Trust, the Medical Research Council, the Human Frontiers Science Programme and EU grants. R.J.C. is a Wellcome Trust Senior Clinical Fellow.

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Correspondence to Penelope A. Jeggo or Richard J. Cornall.

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Nijnik, A., Woodbine, L., Marchetti, C. et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature 447, 686–690 (2007). https://doi.org/10.1038/nature05875

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