Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Current biology, 1999-07, Vol.9 (13), p.699,S1-702,S2

Ort / Verlag

England: Elsevier Inc

Erscheinungsjahr

1999

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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.