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 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. Stem cells and ageing Two groups this week report work on an important hypothesized mechanism of ageing — a diminished capacity to maintain tissue homeostasis due to deficiencies in DNA damage repair. Nijnik et al . show that DNA damage accumulates in stem cells under physiological conditions in vivo as a result of malfunction of DNA repair by the non-homologous end-joining pathway, leading to adult stem cell exhaustion over time. Rossi et al . find age-related diminution of stem cell function in three different genomic maintenance-deficient settings. This study provides direct experimental evidence for an important hypothesized mechanism of ageing, showing that the maintenance of adult haematopoietic stem cell function during ageing and haematopoietic stem cell transplantation is critically dependent on DNA repair by the non-homologous end-joining pathway.