TY - JOUR
T1 - A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining
AU - Van Der Burg, Mirjam
AU - IJspeert, Hanna
AU - Verkaik, Nicole S.
AU - Turul, Tuba
AU - Wiegant, Wouter W.
AU - Morotomi-Yano, Keiko
AU - Mari, Pierre Olivier
AU - Tezcan, Ilhan
AU - Chen, David J.
AU - Zdzienicka, Malgorzata Z.
AU - Van Dongen, Jacques J M
AU - Van Gent, Dik C.
PY - 2009/1/5
Y1 - 2009/1/5
N2 - 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.
AB - 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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U2 - 10.1172/JCI37141
DO - 10.1172/JCI37141
M3 - Article
C2 - 19075392
AN - SCOPUS:61749104245
SN - 0021-9738
VL - 119
SP - 91
EP - 98
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -