Ku80 is an essential participant, along with Ku70 and DNA-PKcs, in the non-homologous end-joining pathway, one mechanism that mammalian cells use to repair chromosome double-strand breaks (DSBs). Pro-T and pro-B lymphocytes from Ku80−/− mice are very susceptible to apoptosis and proliferate poorly, presumably because of an inability to repair DSBs. In the 31 March issue of Nature, Difilippantonio et al. further investigated Ku80 function by crossing Ku80−/− mice with mice deficient in p53, a protein involved in triggering cell cycle arrest and apoptosis in cells with unrepaired chromosome lesions. Loss of p53 rescued the proliferation defects of Ku80−/− pro-B cells, but not pro-T cells, indicating that p53 is required for the induction of apoptosis in B-cell but not T-cell precursors with chromosome abnormalities induced by loss of Ku80. However, by 12 weeks of age, Ku80−/−p53−/− mice died from disseminated B-cell lymphoma. Chromosome analysis of Ku80−/− cells by spectral karyotyping (picture) showed a specific set of chromosomal translocations and amplifications involving, among others, c-Myc and the IgH locus, translocations that occur in Burkitt's lymphoma. Many other rearrangments of chromosomes, and even aneuploidy, were also seen in these cells. These findings place Ku80 in the company of ATM, BRCA1 and other proteins as genomic ‘caretakers’.