An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity |
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| Authors: | Lisa Woodbine Sofia Grigoriadou Aaron A Goodarzi Enriqueta Riballo Christopher Tape Antony W Oliver Menno C van Zelm Matthew S Buckland E Graham Davies Laurence H Pearl Penny A Jeggo |
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| Institution: | 1. Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK;2. Immunology Department, Pathology and Pharmacy Building, Royal London Hospital, London E1 2E, UK;3. CR-UK DNA Repair Enzymes Group, Section of Structural Biology, Institute of Cancer Research, Chester Beatty Labs, London SW3 6JB, UK;4. Erasmus MC, University Medical Center, Department of Immunology, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands;5. Immunology Department, Great Ormond Street Hospital, London WC1N 3JH, UK;6. School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK;1. Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, Essen, Germany;2. Graduate School of Nanobioscience and Advanced Medical Research Center, Yokohama City University, Yokohama, Japan;1. Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany;;2. Unité d''Immuno-Hématologie, Unité d''Immuno-Hématologie, Assistance Publique-Hôpitaux de Paris, Paris, France;;3. Développement Normal et Pathologique du Système Immunitiaire, Unité Institut National de la Santé et de la Recherche Médicale U768, Hôpital Necker Enfants Malades, Paris, France;;4. Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France;;5. Division of Allergy, Immunology and Blood and Marrow Transplant, University of California, San Francisco Benioff Children''s Hospital, San Francisco, CA;;6. Unité d''Epidémiologie des Maladies Emergentes, Institut Pasteur, Paris, France;;7. University Children''s Hospital Munich, Munich, Germany;;8. Institute for Transfusion Medicine, Ulm University, Ulm, Germany;;9. Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg–Hessen, Ulm, Germany;;10. Department of Pediatric Endocrinology, University Medical Center Ulm, Ulm, Germany;;11. Laboratoire de Génétique Humaine des Maladies Infectieuses, Unité Institut National de la Santé et de la Recherche Médicale U980, Faculté Necker, Paris, France;;12. Centre d''Etude des Déficits Immunitaires, Hôpital Necker Enfants Malades, Paris, France;13. Département de Biothérapie, Hôpital Universitaire Necker Ouest, Institut National de la Santé et de la Recherche Médicale, Paris, France;1. Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;2. Molecular Radiation Biology Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;3. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia;5. Royal Children Hospital, Melbourne, VIC, Australia;6. Centre for Genome Damage and Stability, University of Sussex, Brighton BN1 9RQ, UK;1. Laboratory of Inborn Errors of Immunity, Department of Immunology, Microbiology and Transplantation, KU Leuven, Leuven, Belgium;2. Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium;1. Genome Damage and Stability Centre, Life Sciences, University of Sussex, Brighton BN1 9RQ, UK;2. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK;1. Institute of Radio Astronomy of NASU, Chervonopraporna 4, 61002 Kharkov, Ukraine;2. Institute of Physics, Polish Academy of Sciences, Al. Lotników 32/46, 02-668 Warszawa, Poland |
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| Abstract: | Artemis is required for V(D)J recombination and the repair of a subset of radiation-induced DNA double strand breaks (DSBs). Artemis-null patients display radiosensitivity (RS) and severe combined immunodeficiency (SCID), classified as RS-SCID. Strongly impacting hypomorphic Artemis mutations confer marked infant immunodeficiency and a predisposition for EBV-associated lymphomas. Here, we provide evidence that a polymorphic Artemis variant (c.512C > G: p.171P > R), which has a world-wide prevalence of 15%, is functionally impacting. The c.512C > G mutation causes an ～3-fold decrease in Artemis endonuclease activity in vitro. Cells derived from a patient who expressed a single Artemis allele with the polymorphic mutational change, showed radiosensitivity and a DSB repair defect in G2 phase, with Artemis cDNA expression rescuing both phenotypes. The c.512C > G change has an additive impact on Artemis function when combined with a novel C-terminal truncating mutation (p.436C > X), which also partially inactivates Artemis activity. Collectively, our findings provide strong evidence that monoallelic expression of the c.512C > G variant impairs Artemis function causing significant radiosensitivity and a G2 phase DSB repair defect. The patient exhibiting monoallelic c.512C > G-Artemis expression showed immunodeficiency only in adulthood, developed bilateral carcinoma of the nipple and myelodysplasia raising the possibility that modestly decreased Artemis function can impact clinically. |
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