DNA repair is limiting for haematopoietic stem cells during ageing

Anastasia Nijnik, Lisa Woodbine, Caterina Marchetti, Sara Dawson, Teresa Lambe, Cong Liu, Neil P. Rodrigues, Tanya L. Crockford, Erik Cabuy, Alessandro Vindigni, Tariq Enver, John I. Bell, Predrag Slijepcevic, Christopher C. Goodnow, Penelope A. Jeggo () and Richard J. Cornall ()
Additional contact information
Anastasia Nijnik: Henry Wellcome Building for Molecular Physiology, Oxford University, Oxford OX3 9DU, UK
Lisa Woodbine: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK
Caterina Marchetti: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK
Sara Dawson: Australian Cancer Research Foundation Genetics Laboratory, John Curtin School of Medical Research, Australian National University, Australia & Australian Phenomics Facility, Canberra, ACT 2601, Australia
Teresa Lambe: Henry Wellcome Building for Molecular Physiology, Oxford University, Oxford OX3 9DU, UK
Cong Liu: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK
Neil P. Rodrigues: Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK
Tanya L. Crockford: Henry Wellcome Building for Molecular Physiology, Oxford University, Oxford OX3 9DU, UK
Erik Cabuy: Brunel Institute of Cancer Genetics and Pharmacogenomics, Brunel University, Uxbridge UB8 3PH, UK
Alessandro Vindigni: International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy
Tariq Enver: Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK
John I. Bell: Henry Wellcome Building for Molecular Physiology, Oxford University, Oxford OX3 9DU, UK
Predrag Slijepcevic: Brunel Institute of Cancer Genetics and Pharmacogenomics, Brunel University, Uxbridge UB8 3PH, UK
Christopher C. Goodnow: Australian Cancer Research Foundation Genetics Laboratory, John Curtin School of Medical Research, Australian National University, Australia & Australian Phenomics Facility, Canberra, ACT 2601, Australia
Penelope A. Jeggo: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK
Richard J. Cornall: Henry Wellcome Building for Molecular Physiology, Oxford University, Oxford OX3 9DU, UK

Nature, 2007, vol. 447, issue 7145, 686-690

Abstract: 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.

Date: 2007
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DOI: 10.1038/nature05875

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