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Molecular and Cellular Biology, June 2001, p. 4046-4054, Vol. 21, No. 12
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.12.4046-4054.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Wei-Min Tong,1 M. Prakash Hande,2,dagger Peter M. Lansdorp,2,3 and Zhao-Qi Wang1,*

International Agency for Research on Cancer (IARC), F-69008 Lyon, France,1 and Terry Fox Laboratory, British Columbia Cancer Research Center,2 and Department of Medicine, University of British Columbia,3 Vancouver, British Columbia V5Z1L3, Canada

Received 13 November 2000/Returned for modification 9 January 2001/Accepted 15 March 2001

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.

* Corresponding author. Mailing address: International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, F-69008 Lyon, France. Phone: 33-4-72 73 85 10. Fax: 33-4-72 73 83 29. E-mail: zqwang{at}iarc.fr.

dagger Present address: Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York NY 10032.

Molecular and Cellular Biology, June 2001, p. 4046-4054, Vol. 21, No. 12
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.12.4046-4054.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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