Journal Article

Radiation-induced delayed cell death in a hypomorphic Artemis cell line

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

in Human Molecular Genetics

Volume 15, issue 8, pages 1303-1311
Published in print April 2006 | ISSN: 0964-6906
Published online March 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl050
Radiation-induced delayed cell death in a hypomorphic Artemis cell line

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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.

Journal Article.  6658 words.  Illustrated.

Subjects: Genetics and Genomics

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