A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining

Mirjam Van Der Burg, Hanna IJspeert, Nicole S. Verkaik, Tuba Turul, Wouter W. Wiegant, Keiko Morotomi-Yano, Pierre Olivier Mari, Ilhan Tezcan, David J. Chen, Malgorzata Z. Zdzienicka, Jacques J M Van Dongen, Dik C. Van Gent

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)91-98
Number of pages8
JournalJournal of Clinical Investigation
Volume119
Issue number1
DOIs
StatePublished - Jan 5 2009

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Severe Combined Immunodeficiency
Mutation
DNA
DNA End-Joining Repair
Polynucleotide 5'-Hydroxyl-Kinase
V(D)J Recombination
Missense Mutation
Immunoglobulins
Phosphotransferases
Nucleotides
Joints
Genes
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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. https://doi.org/10.1172/JCI37141

A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. / Van Der Burg, Mirjam; IJspeert, Hanna; Verkaik, Nicole S.; Turul, Tuba; Wiegant, Wouter W.; Morotomi-Yano, Keiko; Mari, Pierre Olivier; Tezcan, Ilhan; Chen, David J.; Zdzienicka, Malgorzata Z.; Van Dongen, Jacques J M; Van Gent, Dik C.

In: Journal of Clinical Investigation, Vol. 119, No. 1, 05.01.2009, p. 91-98.

Research output: Contribution to journalArticle

Van Der Burg, M, IJspeert, H, Verkaik, NS, Turul, T, Wiegant, WW, Morotomi-Yano, K, Mari, PO, Tezcan, I, Chen, DJ, Zdzienicka, MZ, Van Dongen, JJM & Van Gent, DC 2009, 'A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining', Journal of Clinical Investigation, vol. 119, no. 1, pp. 91-98. https://doi.org/10.1172/JCI37141
Van Der Burg, Mirjam ; IJspeert, Hanna ; Verkaik, Nicole S. ; Turul, Tuba ; Wiegant, Wouter W. ; Morotomi-Yano, Keiko ; Mari, Pierre Olivier ; Tezcan, Ilhan ; Chen, David J. ; Zdzienicka, Malgorzata Z. ; Van Dongen, Jacques J M ; Van Gent, Dik C. / A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 1. pp. 91-98.
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