Misregulation of gene expression in primary fibroblasts lacking poly(ADP-ribose) polymerase

Poly(ADP-ribose) polymerase (PARP) is implicated in the maintenance of geno mic integrity, given that inhibition or depletion of this enzyme increases genomic instability in cells exposed to genotoxic agents. We previously sho wed that immortalized fibroblasts derived from PARP(-/-) mice exhibit an un stable tetraploid population, and partial chromosomal gains and losses in P ARP(-/-) mice and immortalized fibroblasts are accompanied by changes in th e expression of p53, Rb, and c-fun, as well as other proteins. A tetraploid population has also now been detected in primary fibroblasts derived from PARP(-/-) mice. Oligonucleotide microarray analysis was applied to characte rize more comprehensively the differences in gene expression between asynch ronously dividing primary fibroblasts derived from PARP(-/-) mice and their wild-type littermates, Of the 11,000 genes monitored, 91 differentially ex pressed genes were identified. The loss of PARP results in down-regulation of the expression of several genes involved in regulation of cell cycle pro gression or mitosis, DNA replication, or chromosomal processing or assembly . PARP deficiency also up-regulates genes that encode extracellular matrix or cytoskeletal proteins that are implicated in cancer initiation or progre ssion or in normal or premature aging. These results provide insight into t he mechanism by which PARP deficiency impairs mitotic function, thereby res ulting in the genomic alterations and chromosomal abnormalities as well as in altered expression of genes that may contribute to genomic instability, cancer, and aging.