Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient.
Curr Biol
; 9(13): 699-702, 1999 Jul 01.
Article
in En
| MEDLINE
| ID: mdl-10395545
ABSTRACT
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] [4] [5] [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] [10] [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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Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA Ligases
/
Radiation Tolerance
/
DNA-Binding Proteins
/
DNA Repair
/
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Type of study:
Diagnostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Curr Biol
Journal subject:
BIOLOGIA
Year:
1999
Document type:
Article
Affiliation country: