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Human Molecular Genetics Advance Access published online on March 15, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl050
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received January 13, 2006
Revised March 3, 2006
Accepted March 3, 2006

Article

Radiation induced delayed cell death in a hypomorphic Artemis cell line

Paul M. Evans 1, Lisa Woodbine 2, Enriquetta Riballo 2, Andrew R. Gennery 3, Michael Hubank 1 *, and Penny A. Jeggo 2

1 Institute of Child Health, University College London, 30, Guilford Street, London WC1N 1EH, United Kingdom
2 Genome Damage and Stability Centre, University of Sussex, East Sussex, BN1 9RQ, United Kingdom
3 Department of Pediatric Immunology, Newcastle General Hosptial, Westgate Road, Newcastle upon Tyne, NE4 6BE, United Kingdom

* To whom correspondence should be addressed.
Michael Hubank, E-mail: m.hubank{at}ich.ucl.ac.uk


  Abstract

Null mutations in Artemis confer a condition described as RS-SCID, in which patients display radiosensitivity combined with severe combined immunodeficiency. Here, we characterise the defect in Artemis in a patient who displayed progressive combined immunodeficiency 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 ionising 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 ionising radiation (2 and 4 Gy). This analysis demonstrated that F96-224 cells show delayed cell death compared to 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 compared to control cells. F96-224 therefore represents a novel phenotype for a hypomorphic cell line. We suggest that delayed cell death contributes to the progressive combined immunodeficiency phenotype of the Artemis patient.


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