Abstract

Poly(ADP-ribose) polymerase (PARP-1), which catalyzes poly-ADP-ribosylation of nuclear proteins upon DNA damage, is a multifunctional molecule operative in a range of cellular processes including cell death, DNA repair and recombination, as well as in the maintenance of chromosome stability. Mice lacking PARP-1 are hypersensitive to g-radiation and exhibit telomere shortening, increased sister chromatid exchange and chromosomal aberrations, as well as chromosome gains and losses. Although low tumor incidence was observed in young animals, after multiple generations in a PARP-1 null background, mice were susceptible to malignancy. In addition, PARP-1 deficiency provoked epithelial tumor formation in mice heterozygous for p53 mutation. These tumors associated with dysfunctional telomeres and increased genomic instability, causing an LOH of p53. Interestingly, more than 45% of PARP-1–/– p53–/– mice developed brain tumors at a young age and the characteristics of these tumors are reminiscent of human medulloblastomas. We have also found that haploinsufficiency of Ku80, the DNA binding subunit of DNA-dependent protein kinase (DNA-PK), promotes HCC development in PARP-1 null mice. Molecular and cytogenetic analyses of these tumors will be discussed. Taken together, these data indicate that PARP-1 plays an important role in suppressing chromosome aberrations and tumorigenesis.

Keywords: PARP-1, p53, Ku80, genomic instability, medulloblastomas, hepatocellular carcinoma