and mice in which Msh2 and Fancd1 (also known as Brca2) have been knocked out, also experience increased DNA damage and stem-cell decline8. Hyperactivation of the DNA damage response pathway, apparently in the absence of excess DNA damage, can also induce stem-cell attrition, as demonstrated in mice possessing a hypermorphic Rad50 allele; these mice experience bone marrow failure by four weeks of age as a result of increased apoptosis70. A recent study indicates that ionizing-radiation-induced DNA damage leads to melanocyte stem-cell attrition, although in this cell type the basis for depletion relates to accelerated exit from quiescence and enhanced differentiation rather than to apoptosis and senescence71. Furthermore, it is worth noting that some DNA repair proteins, including RAD50, KU70 or KU80, ATM and WRN, are essential for telomere maintenance. One notable protein that is essential for DNA stability and repair is SIRT6, a member of the sirtuin family of proteins that associates with telomeres. The deletion of the gene encoding SIRT6 induces telomere dysfunction with end-to-end chromosomal fusions, resulting in increased cellular senescence, pronounced acceleration of ageing phenotypes and a life expectancy of only three weeks72,73. Together, these engineered mouse models with defective DNA repair machinery provide convincing genetic evidence
