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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
13
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pubmed:dateCreated |
1999-9-17
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pubmed:abstractText |
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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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
0960-9822
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pubmed:author |
pubmed-author:ArlettC FCF,
pubmed-author:BeamishHH,
pubmed-author:BroughtonBB,
pubmed-author:CritchlowS ESE,
pubmed-author:DohertyA JAJ,
pubmed-author:JacksonS PSP,
pubmed-author:JeggoP APA,
pubmed-author:KyselaBB,
pubmed-author:LehmannA RAR,
pubmed-author:PlowmanNN,
pubmed-author:PriestleyAA,
pubmed-author:RiballoEE,
pubmed-author:TeoS HSH
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
9
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
699-702
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:10395545-Animals,
pubmed-meshheading:10395545-Blotting, Western,
pubmed-meshheading:10395545-Cell Line, Transformed,
pubmed-meshheading:10395545-DNA Ligases,
pubmed-meshheading:10395545-DNA Repair,
pubmed-meshheading:10395545-DNA-Activated Protein Kinase,
pubmed-meshheading:10395545-DNA-Binding Proteins,
pubmed-meshheading:10395545-Fibroblasts,
pubmed-meshheading:10395545-Humans,
pubmed-meshheading:10395545-Mutation,
pubmed-meshheading:10395545-Nuclear Proteins,
pubmed-meshheading:10395545-Precursor Cell Lymphoblastic Leukemia-Lymphoma,
pubmed-meshheading:10395545-Protein-Serine-Threonine Kinases,
pubmed-meshheading:10395545-Rabbits,
pubmed-meshheading:10395545-Radiation, Ionizing,
pubmed-meshheading:10395545-Radiation Tolerance,
pubmed-meshheading:10395545-Sequence Analysis, DNA
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pubmed:year |
1999
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pubmed:articleTitle |
Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient.
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pubmed:affiliation |
MRC Cell Mutation Unit, University of Sussex, Brighton, BN1 9RR, UK.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, Non-U.S. Gov't
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