Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient

the major mechanism for the repair of DNA double-strand breaks (DSBs) in ma mmalian cells is non-homologous end-joining (NHEJ), a process that involves the DNA dependent protein kinase [1,2], XRCC4 and DNA ligase IV [3-6]: Rod ent cells and mice defective in these components are radiation-sensitive an d defective in V(D)J-recombination, showing that NHEJ also functions to rej oin DSBs introduced during lymphocyte development [7,8], 180BR is a radiose nsitive cell line defective in DSB repair, which was derived from a leukaem ia patient who was highly sensitive to radiotherapy [9-11]. We have identif ied a mutation within a highly conserved motif encompassing the active site in DNA ligase IV from 180BR cells. The mutated protein is severely comprom ised in its ability to form a stable enzyme-adenylate complex, although res idual activity can be detected at high ATP concentrations, Our results char acterize the first patient with a defect in an NHEJ component and suggest t hat a significant defect in NHEJ that leads to pronounced radiosensitivity is compatible with normal human viability and does not cause any major immu ne dysfunction, The defect, however, may confer a predisposition to leukaem ia.