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


van der Burg M., IJspeert H., Verkaik N. S. , Turul T., Wiegant W. W. , Morotomi-Yano K., ...Daha Fazla

JOURNAL OF CLINICAL INVESTIGATION, cilt.119, ss.91-98, 2009 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 119 Konu: 1
  • Basım Tarihi: 2009
  • Doi Numarası: 10.1172/jci37141
  • Dergi Adı: JOURNAL OF CLINICAL INVESTIGATION
  • Sayfa Sayıları: ss.91-98

Özet

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.