Chromosomal aberrations in PARP(-/-) mice: Genome stabilization in immortalized cells by reintroduction of poly(ADP-ribose) polymerase cDNA

Depletion of poly(ADP-ribose) polymerase (PARP) increases the frequency of recombination, gene amplification, sister chromatid exchanges, and micronuc lei formation in cells exposed to genotoxic agents, implicating PARP in the maintenance of genomic stability. Flow cytometric analysis now has reveale d an unstable tetraploid population in immortalized fibroblasts derived fro m PARP(-/-) mice. Comparative genomic hybridization detected partial chromo somal gains in 4C5-ter, 5F-ter, and 14A1-C1 in PARP(-/-) mice and immortali zed PARP(-/-) fibroblasts, Neither the chromosomal gains nor the tetraploid population were apparent in PARP(-/-) cells stably transfected with PARP c DNA [PARP(-/-)(+PARP)], indicating negative selection of cells with these g enetic aberrations after reintroduction of PARP cDNA. Although the tumor su ppressor p53 was not detectable in PARP(-/-) cells, p53 expression was part ially restored in PARP(-/-)(+PARP) cells. Loss Of 14D3-ter that encompasses the tumor suppressor gene Rb-1 in PARP(-/-) mice was associated with a red uction in retinoblastoma(Rb) expression; increased expression of the oncoge ne ion was correlated with a gain in 4C5-ter that harbors this oncogene. Th ese results further implicate PARP in the maintenance of genomic stability and suggest that altered expression of p53, Rb, and Jun, as well as undoubt edly many other proteins may be a result of genomic instability associated with PARP deficiency.