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Targeted Disruption of the Artemis Murine Counterpart Results in SCID and Defective V(D)J Recombination That Is Partially Corrected with Bone Marrow Transplantation¹

Lanying Li^2,*, Eduardo Salido^2,*, Yungui Zhou^*, Swati Bhattacharyya^*, Steven M. Yannone, Elizabeth Dunn^*, Juanito Meneses, Ann J. Feeney and Morton J. Cowan^3,*

Departments of ^* Pediatrics and Obstetrics/Gynecology and Reproductive Science, University of California, San Francisco, CA 94143; Department of Immunology, The Scripps Research Institutes, La Jolla, CA 92037; and Department of Molecular Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720

Artemis is a mammalian protein, the absence of which results in SCID in Athabascan-speaking Native Americans (SCIDA). This novel protein has been implicated in DNA double-strand break repair and V(D)J recombination. We have cloned the Artemis murine counterpart, mArt, and generated a mouse with a targeted disruption of mArt. Artemis-deficient mice show a similar T^–B^– NK⁺ immunodeficiency phenotype, and carry a profound impairment in coding joint rearrangement, while retaining intact signal ends and close to normal signal joint formation. mArt^–/– embryonic fibroblasts show increased sensitivity to ionizing radiation. Hemopoietic stem cell (HSC) transplantation using 500-5000 enriched congenic, but not allogeneic mismatched HSC corrected the T cell and partially corrected the B cell defect. Large numbers (40,000) of allogeneic mismatched HSC or pretreatment with 300 cGy of radiation overcame graft resistance, resulting in limited B cell engraftment. Our results suggest that the V(D)J and DNA repair defects seen in this mArt^–/– mouse model are comparable to those in humans with Artemis deficiency, and that the recovery of immunity following HSC transplantation favors T rather than B cell reconstitution, consistent with what is seen in children with this form of SCID.

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				S. M. Yannone, I. S. Khan, R.-Z. Zhou, T. Zhou, K. Valerie, and L. F. Povirk Coordinate 5' and 3' endonucleolytic trimming of terminally blocked blunt DNA double-strand break ends by Artemis nuclease and DNA-dependent protein kinase Nucleic Acids Res., June 1, 2008; 36(10): 3354 - 3365. [Abstract] [Full Text] [PDF]

				G. Mostoslavsky, A. J. Fabian, S. Rooney, F. W. Alt, and R. C. Mulligan Complete correction of murine Artemis immunodeficiency by lentiviral vector-mediated gene transfer PNAS, October 31, 2006; 103(44): 16406 - 16411. [Abstract] [Full Text] [PDF]