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

Riballo, E, Critchlow, S E, Teo, S-H, Doherty, A J, Priestley, A, Broughton, B, Kysela, B, Beamish, H, Plowman, N, Arlett, C F, Lehmann, A R, Jackson, S P and Jeggo, P A (1999) Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Current Biology, 9 (13). 699 - 702. ISSN 0960-9822

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: Aidan Doherty
Date Deposited: 06 Feb 2012 18:44
Last Modified: 17 Sep 2012 10:50
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