TY - JOUR
T1 - DNA repair is limiting for haematopoietic stem cells during ageing
AU - Nijnik, Anastasia
AU - Woodbine, Lisa
AU - Marchetti, Caterina
AU - Dawson, Sara
AU - Lambe, Teresa
AU - Liu, Cong
AU - Rodrigues, Neil P.
AU - Crockford, Tanya L.
AU - Cabuy, Erik
AU - Vindigni, Alessandro
AU - Enver, Tariq
AU - Bell, John I.
AU - Slijepcevic, Predrag
AU - Goodnow, Christopher C.
AU - Jeggo, Penelope A.
AU - Cornall, Richard J.
N1 - Funding Information:
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thank I. Weissman, D. Rossi, P. Papathanasiou, F. Alt, C. Yan, A. Gennery and A. Enders for comments and for exchanging unpublished findings.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.
PY - 2007/6/7
Y1 - 2007/6/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34250001450&partnerID=8YFLogxK
U2 - 10.1038/nature05875
DO - 10.1038/nature05875
M3 - Article
C2 - 17554302
AN - SCOPUS:34250001450
SN - 0028-0836
VL - 447
SP - 686
EP - 690
JO - Nature
JF - Nature
IS - 7145
ER -