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...
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Veröffentlicht in: | Current biology 1999-07, Vol.9 (13), p.699,S1-702,S2 |
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Sprache: | eng |
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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. |
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ISSN: | 0960-9822 1879-0445 |
DOI: | 10.1016/S0960-9822(99)80311-X |