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Papers In Press, published online ahead of print May 10, 2001
MRC CMU, University of Sussex, Brighton BN1 9RR
Corresponding Author: b.kysela{at}sussex.ac.uk
DNA ligase IV functions in DNA non-homologous end-joining, V(D)J recombination and during brain development. We previously reported a homozygous mutation (R278H) in DNA ligase IV in a developmentally normal leukaemia patient who overresponded to radiotherapy. The impact of this hypomorphic mutation has been evaluated using cellular, biochemical and structural approaches. Structural modelling using T7 DNA ligase predicts that the activity and conformational stability of the protein is likely to be impaired. We show that wild type DNA ligase IV/Xrcc4 is an efficient double-stranded ligase with distinct optimal requirements for adenylate complex formation versus rejoining. The mutation impairs the formation of an adenylate complex as well as reducing the rejoining activity. Additionally, it imparts temperature-sensitive activity to the protein consistent with the predictions of the structural modelling. At the cellular level, the mutation confers a unique V(D)J recombination phenotype affecting the fidelity of signal join formation with little effect on the frequency of the reaction. These findings suggest that hypomorphic mutations in ligase IV may allow normal development and but confer marked radiosensitivity.
J. Biol. Chem, 10.1074/jbc.M103866200
Submitted on April 30, 2001
Revised on May 10, 2001
Accepted on May 9, 2001
Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity
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