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Originally published In Press as doi:10.1074/jbc.M103866200 on May 10, 2001

J. Biol. Chem., Vol. 276, Issue 33, 31124-31132, August 17, 2001
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Cellular and Biochemical Impact of a Mutation in DNA Ligase IV Conferring Clinical Radiosensitivity*

Enriqueta RiballoDagger , Aidan J. Doherty§, Yan Dai||, Thomas StiffDagger , Marjorie A. Oettinger||, Penny A. JeggoDagger **, and Boris KyselaDagger **

From the Dagger  Medical Research Council, Cell Mutation Unit, University of Sussex, Brighton BN1 9RR, United Kingdom, the § Cambridge Institute of Medical Research, Wellcome Trust Centre for Molecular Mechanisms in Disease and the Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 2XY, United Kingdom, and the || Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114

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.

* This work was supported by grants from the Human Frontiers Science Program, the Industry-funded United Kingdom Co-ordinating Committee on Cancer Research, the Leukemia Research Fund, and by European Union Grant FIGH CT 1999 00010 (to P. A. J.) and by grants from the Royal Society, Leukemia Research Fund, and Association for International Cancer Research (to A. J. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

A Royal Society University Research Fellow.

** To whom correspondence may be addressed. Tel.: 1273-678482; Fax: 1273-678121; E-mail: p.a.jeggo@sussex.ac.uk (to P. A. J.) or E-mail: b.kysela@sussex.ac.uk (to B. K.).

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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