PARP IS IMPORTANT FOR GENOMIC STABILITY BUT DISPENSABLE IN APOPTOSIS

Mice lacking the gene encoding poly(ADP-ribosyl) transferase (PARP or ADPRT) display no phenotypic abnormalities, although aged mice are sus ceptible to epidermal hyperplasia and obesity in a mixed genetic backg round. Whereas embryonic fibroblasts lacking PARP exhibit normal DNA e xcision repair, they grow more slowly in vitro. Here we investigated t he putative roles of PARP in cell proliferation, cell death, radiosens itivity, and DNA recombination, as well as chromosomal stability. We s how that the proliferation deficiency in vitro and in vive is most lik ely caused by a hypersensitive response to environmental stress. Altho ugh PARP is specifically cleaved during apoptosis, cells Backing this molecule apoptosed normally in response to treatment with anti-Fas, tu mor neurosis factor alpha, gamma-irradiation, and dexamethasone, indic ating that PARP is dispensable in apoptosis and that PARP-/-thymocytes are not hypersensitive to ionizing radiation. Furthermore, the capaci ty of mutant cells to carry out immunoglobulin class switching and V(D )J recombination is normal. Finally, primary PARP mutant fibroblasts a nd splenocytes exhibited an elevated frequency of spontaneous sister c hromatid exchanges and elevated micronuclei formation after treatment with genotoxic agents, establishing an important role for PARP in the maintenance of genomic integrity.