Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity.

Riballo, Enriqueta, Doherty, Aidan J, Dai, Yan, Stiff, Thomas, Oettinger, Marjorie A, Jeggo, Penny A and Kysela, Boris (2001) Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity. Journal of Biological Chemistry, 276. pp. 31124-31132. ISSN 0021-9258

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Abstract

DNA ligase IV functions in DNA non-homologous end-joining, in V(D)J recombination, and during brain development. We previously reported a homozygous mutation (R278H) in DNA ligase IV in a developmentally normal leukemia patient who overresponded to radiotherapy. The impact of this hypomorphic mutation has been evaluated using cellular, biochemical, and structural approaches. Structural modeling 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 modeling. At the cellular level, the mutation confers a unique V(D)J recombination phenotype affecting the fidelity of signal joint formation with little effect on the frequency of the reaction. These findings suggest that hypomorphic mutations in ligase IV may allow normal development but confer marked radiosensitivity.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: Queti Riballo
Date Deposited: 06 Feb 2012 20:24
Last Modified: 02 Apr 2012 09:10
URI: http://srodev.sussex.ac.uk/id/eprint/25747
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