Loss of poly(ADP-ribose) polymerase-1 causes increased tumour latency in p53-deficient mice

PARP-1-deficient mice display a severe defect in the base excision repair p athway leading to radiosensitivity and genomic instability. They are protec ted against necrosis induced by massive oxidative stress in various inflamm atory processes. Mice lacking p53 are highly predisposed to malignancy resu lting from defective cell cycle checkpoints, resistance to DNA damage-induc ed apoptosis as well as from upregulation of the iNOS gene resulting in chr onic oxidative stress. Here, we report the generation of doubly null mutant mice. We found that tumour-free survival of parp-1(-/-)p53(-/-)mice increa sed by 50% compared with that of parp-1(+/+)p53(-/-) mice. Tumour formation in nude mice injected with oncogenic parp-1(-/-)p53(-/-) fibroblasts was s ignificantly delayed compared with parp-1(+/+)p53(-/-) cells. Upon gamma -i rradiation, a partial restoration of S-phase radiosensitivity was found in parp-1(-/-)p53(-/-) primary fibroblasts compared with parp-1(+/+)p53(-/-) c ells. In addition, iNOS expression and nitrite release were dramatically re duced in the parp-1(-/-)p53(-/-) mice compared with parp-1(+/+)p53(-/-) mic e. The abrogation of the oxydated status of p53(-/-) cells, due to the abse nce of parp-1, may be the cause of the delay in the onset of tumorigenesis in parp-1(-/-)p53(-/-) mice.