Clarissa Dallas

Journal - The Journal of Immunology

Abstract :

We recently described the incidence of a SCID disease in a litter ofJack Russell terriers. In this study, we show that the molecular defectin these animals is faulty V(D)J recombination. Furthermore,we document a complete deficit in DNA-dependent protein kinaseactivity that can be explained by a marked diminution in theexpression of the catalytic subunit DNA-dependent protein kinasecatalytic subunit (DNA-PKcs). We conclude that as is the casein C.B-17 SCID mice and in Arabian SCID foals, the defectivefactor in these SCID puppies is DNA-PKcs. In mice, it has beenclearly established that DNA-PKcs deficiency produces an incompleteblock in V(D)J recombination, resulting in "leaky" coding jointformation and only a modest defect in signal end ligation. Incontrast, DNA-PKcs deficiency in horses profoundly blocks bothcoding and signal end joining. Here, we show that although DNA-PKcsdeficiency in canine lymphocytes results in a block in bothcoding and signal end joining, the deficit in both is intermediatebetween that seen in SCID mice and SCID foals. These data demonstratesignificant species variation in the absolute necessity for DNA-PKcsduring V(D)J recombination. Furthermore, the severity of the V(D)Jrecombination deficits in these three examples of genetic DNA-PKcsdeficiency inversely correlates with the relative DNA-PK enzymaticactivity expressed in normal fibroblasts derived from these threespecies.