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

Radiosensitive [T.sup.-][B.sup.-] 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 DN...

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Published inThe Journal of clinical investigation Vol. 119; no. 1; pp. 91 - 98
Main 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
Format Journal Article
LanguageEnglish
Published American Society for Clinical Investigation 01.01.2009
Subjects
Care and treatment
Diagnosis
Gene mutations
Genetic aspects
Genetic recombination
Health aspects
Severe combined immunodeficiency
Poland
Netherlands
Turkey
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Summary:Radiosensitive [T.sup.-][B.sup.-] 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.
ISSN:0021-9738