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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.

Original publication

DOI

10.1038/nature05875

Type

Journal article

Journal

Nature

Publication Date

07/06/2007

Volume

447

Pages

686 - 690

Keywords

Aging, Animals, Cell Proliferation, Cellular Senescence, DNA Breaks, Double-Stranded, DNA Damage, DNA Ligase ATP, DNA Ligases, DNA Repair, Hematopoietic Stem Cells, Humans, Mice, Mice, Inbred C57BL, Mutation, Missense, Syndrome