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

Severe combined immunodeficiency (SCID) mice 1 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 cells 2 . 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 repair 3–5 . 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-PKcs 9,10 . Other reports have implied that the SCID phenotype correlates with nonsense mutations at the extreme 3′ end of Prkdc , the DNA-PKcs gene 11–14 . 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).