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Analyses of TCR_B Rearrangements Substantiate a Profound Deficit in Recombination Signal Sequence Joining in SCID Foals: Implications for the Role of DNA-Dependent Protein Kinase in V(D)J Recombination¹

Euy Kyun Shin^*, Tonnie Rijkers, Albert Pastink and Katheryn Meek^2,*

^* Harold C. Simmons Arthritis Research Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75235; and Department of Radiation Genetics and Chemical Mutagenesis, MGC, Leiden University Medical Center, Leiden, The Netherlands

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 C.B-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 C.B-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.

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