Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 119, Issue 1, Pages 91-98Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI37141
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Funding
- Dutch Organization for Scientific Research [916.56.107]
- Dutch Cancer Society [2002-2734]
- European Community [FIGR-CT-2003-508842]
- DNA repair [LSHG-CT-2005-512113]
- NIH [5-R37-CA050519-16, PO1-CA92584]
- NATIONAL CANCER INSTITUTE [P01CA092584, R37CA050519] Funding Source: NIH RePORTER
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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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