DNA Strand Break-Sensing Molecule Poly(ADP-Ribose) Polymerase Cooperates with p53 in Telomere Function, Chromosome Stability, and Tumor Suppression

Abstract

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 role in tumorigenesis. Poly(ADP-ribose) polymerase (PARP) is a DNA strand break-sensing molecule that is involved in the response to DNA damage and the maintenance 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 telomere dysfunction. While PARP^−/− cells showed telomere shortening and p53^−/− cells showed normal telomere length, inactivation of PARP in p53^−/− cells surprisingly resulted in very long and heterogeneous telomeres, suggesting a functional interplay between PARP and p53 at the telomeres. Strikingly, PARP deficiency widens the tumor spectrum in mice deficient in p53, resulting in a high frequency of carcinomas in the mammary gland, lung, prostate, and skin, as well as brain tumors, reminiscent of Li-Fraumeni syndrome in humans. The enhanced tumorigenesis is likely to be caused by PARP deficiency, which facilitates the loss of function of tumor suppressor genes as demonstrated by a high rate of loss of heterozygosity at the p53 locus in these tumors. These results indicate that PARP and p53 interact to maintain genome integrity and identify PARP as a cofactor for suppressing tumorigenesis.

ACKNOWLEDGMENTS

We thank D. Galendo for maintenance of the animal colonies and J. Michelon, M. Laval, and N. Lyandrat for technical assistance. We are also grateful to G. Mollon for the preparation of photographs. Further thanks are due to A. Aguzzi, L. Frappart, P. Kleihues, and H. Ohgaki for help in histopathological examination and to A. Baross, A. Grigoriadis, P. Hainaut, and E. F. Wagner for critical reading of the manuscript.

This research, W.-M.T., and Z.-Q.W. are supported by the Association for International Cancer Research, St. Andrews, Scotland, United Kingdom, and by NIH grant RO1CA79493-01. Research in the laboratory of P.M.L. is supported by NIH grants RO1AI29524 and GM56162 and by a grant from the National Cancer Institute of Canada with funds from The Terry Fox Run.