A novel radiosensitive SCID patient with a pronounced G2/M sensitivity |
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Authors: | Wouter W. Wiegant Matty Meyers Nicole S. Verkaik Mirjam van der Burg Firouz Darroudi Ron Romeijn Ewa Bernatowska Beata Wolska-Kusnierz Bozena Mikoluc Nicolaas G.J. Jaspers Cees Vreeken Hanna Ijspeert Rebecca E.E. Esveldt-van Lange Anna A. Friedl Jean-Pierre de Villartay Leon H.F. Mullenders Jacques J.M. van Dongen Dik C. van Gent Albert Pastink Małgorzata Z. Zdzienicka |
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Affiliation: | 1. Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands;2. Department of Cell Biology and Genetics, Erasmus Medical Center, Rotterdam, The Netherlands;3. Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands;4. Department of Immunology, The Children''s Memorial Health Institute, Warsaw, Poland;5. Department of Pediatrics and Developmental Disorders of Children and Adolescents, Medical University in Bialystok, Poland;6. Radiobiological Institute, Ludwig-Maximilian University of Munich, Munich, Germany;7. INSERM U768, Site Necker Enfants-Malades, Paris, France;8. Department of Molecular Cell Genetics, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland;1. Radiopathology Laboratory, Autoridad Regulatoria Nuclear (ARN), Buenos Aires, Argentina;2. Toxicology Laboratory, Universidad Nacional del Sur (UNS), Bahía Blanca, Argentina;3. Commissariat a l’Energie Atomique et aux Energies Alternatives (CEA), Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Paris, France;4. University Paris Diderot, Sorbonne Paris Cité, UMR E-5 Institut Universitaire d’Hematologie, Saint-Louis Hospital, Paris, France;1. University of Pavia, Physics Department, via Bassi 6, I-27100, Pavia, Italy;2. INFN (Italian Institute of Nuclear Physics)-Section of Pavia, via Bassi 6, I-27100, Pavia, Italy;3. Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, Campinas, SP, Brazil;1. Molecular Pathology Laboratory, Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India;2. Department of Radiotherapy and Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India;3. Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India;4. Scientist Fellow, Microbial Type Culture Collection and Gene Bank, Institute of Microbial Technology, Chandigarh, India;5. Department of Obstetrics and Gynecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India;1. Department of Neurobiology, Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel 69978;2. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel 69978 |
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Abstract: | V(D)J rearrangement in lymphoid cells involves repair of double-strand breaks (DSBs) through non-homologous end joining (NHEJ). Defects in this process lead to increased radiosensitivity and severe combined immunodeficiency (RS-SCID). Here, a SCID patient, M3, is described with a T?B+NK+ phenotype but without causative mutations in CD3δ, ?, ζ or IL7Rα, genes specifically involved in T cell development. Clonogenic survival of M3 fibroblasts showed an increased sensitivity to the DSB-inducing agents ionizing radiation and bleomycin, as well as the crosslinking compound, mitomycin C. We did not observe inactivating mutations in known NHEJ genes and results of various DSB-repair assays in G1 M3 cells were indistinguishable from those obtained with normal cells. However, we found increased chromosomal radiosensitivity at the G2 phase of the cell cycle. Checkpoint analysis indicated functional G1/S and intra-S checkpoints after irradiation but impaired activation of the “early” G2/M checkpoint. Together these results indicate a novel class of RS-SCID patients characterized by the specific absence of T lymphocytes and associated with defects in G2-specific DSB repair. The pronounced G2/M radiosensitivity of the RS-SCID patient described here, suggests a defect in a putative novel and uncharacterized factor involved in cellular DNA damage responses and T cell development. |
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