We reported previously that the genetic SCID disease observed in Arabian foals is explained by a defect in V (D) J recombination that profoundly affects both coding and signal end joining. As in CB-17 SCID mice, the molecular defect in SCID foals is in the catalytic subunit of the DNA-dependent protein kinase (DNA-PK CS); however, in SCID mice, signal end resolution remains relatively intact. Moreover, recent reports indicate that mice that completely lack DNA-PK CS also generate signal joints at levels that are indistinguishable from those observed in CB-17 SCID mice, eliminating the possibility that a partially active version of DNA-PK CS facilitates signal end resolution in SCID mice. We have analyzed TCR B rearrangements and find that signal joints are reduced by∼ 4 logs in equine SCID thymocytes as compared with normal horse thymocytes. A potential explanation for the differences between SCID mice and foals is that the mutant DNA-PK CS allele in SCID foals inhibits signal end resolution. We tested this hypothesis using DNA-PK CS expression vectors; in sum, we find no evidence of a dominant-negative effect by the mutant protein. These and other recent data are consistent with an emerging consensus: that in normal cells, DNA-PK CS participates in both coding and signal end resolution, but in the absence of DNA-PK CS an undefined end joining pathway (which is variably expressed in different species and cell types) can facilitate imperfect signal and coding end joining.