Radiosensitive T-B- severe combined immunodeficiency (RS-SCID) is caused by defects in the nonhomologous end-joining (NHEJ) DNA repair pathway, which results in failure of functional V(D)J recombination. Here we have identified the first human RS-SCID patient to our knowledge with a DNA-PKcs missense mutation (L3062R). The causative mutation did not affect the kinase activity or DNA end-binding capacity of DNA-PKcs itself; rather, the presence of long P-nucleotide stretches in the immunoglobulin coding joints indicated that it caused insufficient Artemis activation, something that is dependent on Artemis interaction with autophosphorylated DNA-PKcs. Moreover, overall end-joining activity was hampered, suggesting that Artemis-independent DNA-PKcs functions were also inhibited. This study demonstrates that the presence of DNA-PKcs kinase activity is not sufficient to rule out a defect in this gene during diagnosis and treatment of RS-SCID patients. Further, the data suggest that residual DNA-PKcs activity is indispensable in humans.

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Keywords DCLRE1C protein, DNA binding, DNA dependent protein kinase, DNA repair, PRKDC protein, amino acid sequence, animal, animal cell, artemis gene, article, autophosphorylation, case report, cell line, child, controlled study, cytology, enzyme activity, female, fibroblast, gene, gene activation, gene function, genetic recombination, genetics, genotype, human, human cell, human tissue, immunoglobulin, infant, male, metabolism, missense mutation, molecular genetics, nonhuman, nuclear protein, nucleotide, nucleotide sequence, pedigree, phosphotransferase, physiology, polydeoxyribonucleotide synthase, polydeoxyribonucleotide synthase (atp), preschool child, priority journal, radiation dose, radiation exposure, sequence alignment, severe combined immunodeficiency
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Journal Journal of Clinical Investigation
van der Burg, M, IJspeert, H, Verkaik, N.S, Turul, T, Wiegant, W.W, Morotomi-Yano, K, … van Gent, D.C. (2009). A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. Journal of Clinical Investigation, 119(1), 91–98. doi:10.1172/JCI37141