Human Molecular Genetics Advance Access published online on August 27, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh278
© 2004 by Oxford University Press
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1 Institut für Humangenetik, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany; Molecular Genetics Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101
* To whom correspondence should be addressed. E-mail: martin.digweed{at}charite.de.
The human genetic disorder, Nijmegen Breakage Syndrome, is characterised by radiosensitivity, immunodeficiency, chromosomal instability and an increased risk for cancer of the lymphatic system. The NBS1 gene codes for a protein, nibrin, involved in the processing/repair of DNA double strand breaks and in cell cycle checkpoints. Most patients are homozygous for a founder mutation, a 5bp deletion, which might not be a null mutation since functionally relevant truncated nibrin proteins are observed, at least in vitro. In agreement with this hypothesis, null mutation of the homologous gene, Nbn, in mice is lethal. Here we have used Cre recombinase/LoxP technology to generate an inducible Nbn null mutation allowing the examination of DNA-repair and cell cycle-checkpoints in the complete absence of nibrin. Induction of Nbn null mutation leads to loss of the G2/M checkpoint, increased chromosome damage, radiomimetic-sensitivity and cell death. In vivo, this particularly affects the lymphatic tissues, bone marrow, thymus and spleen whilst liver, kidney and muscle are hardly affected. In vitro, null mutant murine fibroblasts can be rescued from cell death by transfer of human nibrin cDNA and, more significantly, by a cDNA carrying the 5bp deletion. This demonstrates, for the first time, that the common human mutation is hypomorphic and that the expression of a truncated protein is sufficient to restore nibrin's vital cellular functions.
Article
An inducible null mutant murine model of Nijmegen Breakage Syndrome proves the essential function of NBS1 in chromosomal stability and cell viability
2 International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France
3 Institut für Humangenetik, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
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