PARP-2 deficiency affects the survival of CD4+CD8+ double-positive thymocytes

Poly-(ADP-ribose) polymerase-2 (PARP-2) belongs to a large family of enzymes that synthesize and transfer ADPribose polymers to acceptor proteins, modifying their functional properties. PARP-2-deficient (Parp-2(-/-)) cells, similar to Parp-1(-/-) cells, are sensitive to both ionizing radiation and alkylating agents. Here we show that inactivation of mouse Parp-2, but not Parp-1, produced a two-fold reduction in CD4(+)CD8(+) double-positive (DP) thymocytes associated with decreased DP cell survival. Microarray analyses revealed increased expression of the proapoptotic Bcl-2 family member Noxa in Parp-2(-/-) DP thymocytes compared to littermate controls. In addition, DP thymocytes from Parp-2(-/-) have a reduced expression of T-cell receptor (TCR)alpha and a skewed repertoire of TCRa toward the 5' J alpha segments. Our results show that in the absence of PARP-2, the survival of DP thymocytes undergoing TCRa recombination is compromised despite normal amounts of Bcl-x(L). These data suggest a novel role for PARP-2 as an important mediator of T-cell survival during thymopoiesis by preventing the activation of DNA damage-dependent apoptotic response during the multiple rounds of TCRa rearrangements preceding a positively selected TCR.