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

By E Riballo, S E Critchlow, S-H Teo, A J Doherty, A Priestley, B Broughton, B Kysela, H Beamish, N Plowman, C F Arlett, A R Lehmann, S P Jackson and P A Jeggo


The major mechanism for the repair of DNA double-strand breaks (DSBs) in mammalian cells is non-homologous end-joining (NHEJ), a process that involves the DNA-dependent protein kinase [1] and [2], XRCC4 and DNA ligase IV [3], [3], [4] and [6]. Rodent cells and mice defective in these components are radiation-sensitive and defective in V(D)J-recombination, showing that NHEJ also functions to rejoin DSBs introduced during lymphocyte development [7] and [8]. 180BR is a radiosensitive cell line defective in DSB repair, which was derived from a leukaemia patient who was highly sensitive to radiotherapy [9], [10] and [11]. We have identified a mutation within a highly conserved motif encompassing the active site in DNA ligase IV from 180BR cells. The mutated protein is severely compromised in its ability to form a stable enzyme–adenylate complex, although residual activity can be detected at high ATP concentrations. Our results characterize the first patient with a defect in an NHEJ component and suggest that a significant defect in NHEJ that leads to pronounced radiosensitivity is compatible with normal human viability and does not cause any major immune dysfunction. The defect, however, may confer a predisposition to leukaemia

Publisher: Elsevier
Year: 1999
DOI identifier: 10.1016/s0960-9822(99)80311-x
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