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 mammalian 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]. Rodent cells and mice defective in these components are radiation-sensitive an...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Current biology 1999-07, Vol.9 (13), p.699,S1-702,S2
Hauptverfasser: 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., Jeggo, P.A.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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 [1,2], XRCC4 and DNA ligase IV [3–6]. 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 [7,8]. 180BR is a radiosensitive cell line defective in DSB repair, which was derived from a leukaemia patient who was highly sensitive to radiotherapy [9–11]. 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.
ISSN:0960-9822
1879-0445
DOI:10.1016/S0960-9822(99)80311-X