DNA strand break-sensing molecule poly(ADP-ribose) polymerase cooperates with p53 in telomere function, chromosome stability, and tumor suppression

Genomic instability is often caused by mutations in genes that are involved in DNA repair and/or cell cycle checkpoints, and it plays an important rol e in tumorigenesis. Poly(ADP-ribose) polymerase (PARP) is a DNA strand brea k-sensing molecule that is involved in the response to DNA damage and the m aintenance of telomere function and genomic stability. We report here that, compared to single-mutant cells, PARP and p53 double-mutant cells exhibit many severe chromosome aberrations, including a high degree of aneuploidy, fragmentations, and end-to-end fusions, which may be attributable to telome re dysfunction, While PARP(-/-) cells showed telomere shortening and p53(-/ -) cells showed normal telomere length, inactivation of PARP in p53(-/-) ce lls surprisingly resulted in very long and heterogeneous telomeres, suggest ing a functional interplay between PARP and p53 at the telomeres, Strikingl y, PARP deficiency widens the tumor spectrum in mice deficient in p53, resu lting in a high frequency of carcinomas in the mammary gland, lung, prostat e, and skin, as well as brain tumors, reminiscent of Li-Fraumeni syndrome i n humans. The enhanced tumorigenesis is likely to be caused by PARP deficie ncy, which facilitates the loss of function of tumor suppressor genes as de monstrated by a high rate of loss of heterozygosity at the p53 locus in the se tumors. These results indicate that PARP and p53 interact to maintain ge nome integrity and identify PARP as a cofactor for suppressing tumorigenesi s.