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

Authors
  • 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
Type
Published Article
Journal
The Journal of clinical investigation
Publication Date
Jan 01, 2009
Volume
119
Issue
1
Pages
91–98
Identifiers
DOI: 10.1172/JCI37141
PMID: 19075392
Source
Medline
License
Unknown

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.

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