Human Molecular Genetics Advance Access originally published online on March 15, 2006
Human Molecular Genetics 2006 15(8):1303-1311; doi:10.1093/hmg/ddl050
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Radiation-induced delayed cell death in a hypomorphic Artemis cell line
1Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK, 2Genome Damage and Stability Centre, University of Sussex, East Sussex BN1 9RQ, UK and 3Department of Pediatric Immunology, Newcastle General Hospital, Westgate Road, Newcastle-upon-Tyne NE4 6BE, UK
* To whom correspondence should be addressed. Tel: +44 2079052266; Fax: +44 2078138100; Email: m.hubank{at}ich.ucl.ac.uk
Received January 13, 2006; Accepted March 3, 2006
Null mutations in Artemis confer a condition described as RS-SCID, in which patients display radiosensitivity combined with severe combined immunodeficiency. Here, we characterize the defect in Artemis in a patient who displayed progressive combined immunodeficiency (CID) and elevated lymphocyte apoptosis. The patient is a compound heterozygote with novel mutations in both alleles, resulting in Artemis proteins with either L70 deletion or G126D substitution. Both mutational changes impact upon Artemis function and a fibroblast cell line derived from the patient (F96-224) has greatly reduced Artemis protein. In contrast to Artemis null cell lines, which fail to repair a subset of DNA double strand breaks (DSBs) induced by ionizing radiation, F96-224 cells show slow but residual DSB rejoining. Despite showing intermediate cellular and clinical features, F96-224 cells are as radiosensitive as Artemis null cell lines. We developed a FACS-based assay to examine cell division and cellular characteristics for 10 days following exposure to ionizing radiation (2 and 4 Gy). This analysis demonstrated that F96-224 cells show delayed cell death when compared with rapid growth arrest of an Artemis null cell line, and the emergence of a cycling population shown by a control line. F96-224 cells also display elevated chromosome aberrations when compared with control cells. F96-224 therefore represents a novel phenotype for a hypomorphic cell line. We suggest that delayed cell death contributes to the progressive CID phenotype of the Artemis patient.
The authors wish it to be known that both groups contributed equally to this work.
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