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Nucleic Acids Research, 2003, Vol. 31, No. 8 2157-2167
© 2003 Oxford University Press

Impact of DNA ligase IV on the fidelity of end joining in human cells

Julianne Smith, Enriqueta Riballo1, Boris Kysela1, Celine Baldeyron, Kostas Manolis1, Christel Masson, Michael R. Lieber2, Dora Papadopoulo and Penny Jeggo1

UMR 218 CNRS, Institut Curie-Recherche, 26 rue d’Ulm, 75248 Paris, France, 1 Genome Damage and Stability Centre, University of Sussex, East Sussex BN1 9RQ, UK and 2 Norris Comprehensive Cancer Center, University of Southern California, Room 5428, Los Angeles, CA 90089, USA

Correspondence may also be addressed to Dora Papadopoulo. Tel: +33 14234 6704; Fax: +33 14234 6698; Email: dora.papadopoulo{at}curie.fr

A DNA ligase IV (LIG4)-null human pre-B cell line and human cell lines with hypomorphic mutations in LIG4 are significantly impaired in the frequency and fidelity of end joining using an in vivo plasmid assay. Analysis of the null line demonstrates the existence of an error-prone DNA ligase IV-independent rejoining mechanism in mammalian cells. Analysis of lines with hypomorphic mutations demonstrates that residual DNA ligase IV activity, which is sufficient to promote efficient end joining, nevertheless can result in decreased fidelity of rejoining. Thus, DNA ligase IV is an important factor influencing the fidelity of end joining in vivo. The LIG4-defective cell lines also showed impaired end joining in an in vitro assay using cell-free extracts. Elevated degradation of the terminal nucleotide was observed in a LIG4-defective line, and addition of the DNA ligase IV–XRCC4 complex restored end protection. End protection by DNA ligase IV was not dependent upon ligation. Finally, using purified proteins, we demonstrate that DNA ligase IV–XRCC4 is able to protect DNA ends from degradation by T7 exonuclease. Thus, the ability of DNA ligase IV–XRCC4 to protect DNA ends may contribute to the ability of DNA ligase IV to promote accurate rejoining in vivo.


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