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DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus

Nature Genetics volume 17, pages 483–486 (1997)Cite this article

Abstract

Severe combined immunodeficiency (SCID) mice1 are defective in their ability to rearrange their variable (V), diversity (D) and joining (J) genetic elements to generate functional immunoglobulin (Ig) and T-cell receptor (TCR) molecules; as a result, they lack mature B and T cells2. These mice are highly sensitive to ionizing radiation, suggesting that the product of the scid gene plays a critical role in both V(D)J recombination and DMA double-strand break repair3–5. Recent studies suggest that the SCID defect lies in the gene encoding the catalytic subunit of DMA-dependent protein kinase (DNA-PK; refs 6–8), a nuclear protein made up of the Ku 70 and Ku 86 subunits as well as the large catalytic subunit, DNA-PKcs9,10. Other reports have implied that the SCID phenotype correlates with nonsense mutations at the extreme 3′ end of Prkdc, the DNA-PKcs gene11–14. The identity of the gene remains in doubt, however, because the consequences of genetic inactivation of Prkdc have not been determined. This study shows that complete inactivation of Prkdc in a novel insertional mouse mutant recapitulates the SCID phenotype and that Prkdc and scid are allelic. Significantly, DNA-PKcs null mice demonstrate complete penetrance of thymic lymphoblastic lymphomas, strongly suggesting that Prkdc functions in mice as a T-cell tumour suppressor and, by virtue of its association with DNA repair and recombination, belongs to the ‘caretaker’ class of tumour-suppressor genes that includes ATM, BRCA1 and BRCA2(ref.15).

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Authors and Affiliations

  1. Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland, 20892-4255, USA

    Chamelli Jhappan & Glenn Merlino

  2. Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892-0760, USA

    Herbert C. Morse III

  3. Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892-4255, USA

    Robert D. Fleischmann & Michael M. Gottesman

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Jhappan, C., Morse, H., Fleischmann, R. et al. DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus. Nat Genet 17, 483–486 (1997). https://doi.org/10.1038/ng1297-483

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