The response of Parp knockout mice against DNA damaging agents

Gene-disruption studies involving poly(ADP-ribose) polymerase (Parp) have i dentified the various roles of Parp in cellular responses to DNA damage. Th e partial rescue of V[D]J recombination process in SCID/Parp(-/-) double mu tant mice indicates the participation of Parp in the repair of DNA strand b reak. Parp(-/-) mice are more sensitive to the lethal effects of alkylating agents. Parp is also thought to be involved in base-excision repair after DNA damage caused by alkylating agents, On the other hand, resistance of Pa rp(-/-) mice to DNA damage induced by reactive oxygen species implicates th e contribution of Parp to cell death through NAD depletion. Parp(-/-) mice with two different genetic backgrounds also show enhanced sensitivity to th e lethal effects of gamma-irradiation. Parp(-/-) mice show more severe vill ous atrophy of the small intestine compared to the wild-type counterpart in a genetic background of 129Sv/C57BL6. Other forms of enhanced tissue damag e have been identified in Parp(-/-) mice with a genetic background of 129Sv /ICR. For example, Parp(-/-) mice exhibit extensive hemorrhage in the gland ular stomach and other tissues, such as the testes, after gamma-irradiation . Severe myelosuppression is also observed in both Parp(+/+) and Parp(-/-) mice, but Parp(+/+) mice show extensive extramedullary hematopoiesis in the spleen during the recovery phase of post-irradiation, whereas the spleen o f Parp(-/-) mice exhibits severe atrophy with no extramedullary hematopoies is. The absence of extramedullary hematopoiesis in the spleen is probably t he underlying mechanism of hemorrhagic tendency in various tissues of Parp( -/-) mice. These findings suggest that lass of Parp activity could contribu te to post-irradiation tissue hemorrhage. (C) 2000 Elsevier Science B.V. Al l rights resented.