Abstract

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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Acknowledgements

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thank I. Weissman, D. Rossi, P. Papathanasiou, F. Alt, C. Yan, A. Gennery and A. Enders for comments and for exchanging unpublished findings.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.

Author information

Author notes

    • Christopher C. Goodnow
    • , Penelope A. Jeggo
    •  & Richard J. Cornall

    These authors contributed equally to this work.

Affiliations

  1. Henry Wellcome Building for Molecular Physiology, Oxford University, Oxford OX3 9DU, UK

    • Anastasia Nijnik
    • , Teresa Lambe
    • , Tanya L. Crockford
    • , John I. Bell
    •  & Richard J. Cornall
  2. Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK

    • Lisa Woodbine
    • , Caterina Marchetti
    • , Cong Liu
    •  & Penelope A. Jeggo
  3. International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy

    • Caterina Marchetti
    •  & Alessandro Vindigni
  4. Australian Cancer Research Foundation Genetics Laboratory, John Curtin School of Medical Research, Australian National University, Australia & Australian Phenomics Facility, Canberra, ACT 2601, Australia

    • Sara Dawson
    •  & Christopher C. Goodnow
  5. Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK

    • Neil P. Rodrigues
    •  & Tariq Enver
  6. Brunel Institute of Cancer Genetics and Pharmacogenomics, Brunel University, Uxbridge UB8 3PH, UK

    • Erik Cabuy
    •  & Predrag Slijepcevic

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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

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https://doi.org/10.1038/nature05875

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