Genetic interaction between PARP and DNA-PK in V(D)J recombination and tumorigenesis

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Abstract
Poly(ADP-ribose) polymerase (PARP) and DMA-dependent protein kinase (DNA-PK) are DMA break-activated molecules1,2. Although mice that lack PARP display no gross phenotype and normal DNA excision repair3, they exhibit high levels of sister chromatid exchange4, indicative of elevated recombination rates. Mutation of the gene for DNA-PK catalytic subunit (Prkdc) causes defective antigen receptor V(D)J recombination and arrests B- and T-lymphocyte development in severe combined immune-deficiency (SCID) mice5,6. SOD V(D)J recombination can be partly rescued in T-lymphocytes by either DNA-damaging agents (gamma-irradiation and bleomycin)7,8 or a null mutation of the p53 gene9,10, possibly because of transiently elevated DNA repair activity in response to DNA damage or to delayed apoptosis in the absence of p53. To determine whether the increased chromosomal recombination observed in PARP-deficient cells affects SCID V(D)J recombination, we generated mice lacking both PARP and DNA-PK. Here, we show that thymocytes of SCID mice express both CD4 and CDS co-receptors, bypassing the SCID block. Double-mutant T-cells in the periphery express TCRβ, which is attributable to productive TCRβ joints. Double-mutant mice develop a high frequency of T-cell lymphoma. These results demonstrate that increased recombination activity after the loss of PARP anti-recombinogenic function can rescue V(D)J recombination in SCID mice and indicate that PARP and DNA-PK cooperate to minimize genomic damage caused by DNA strand breaks.
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