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 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.
Tong
W M
WM
International Agency for Research on Cancer (IARC), F-69008 Lyon, France.
Hande
M P
MP
Lansdorp
P M
PM
Wang
Z Q
ZQ
D000818:Animals; D001483:Base Sequence; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000378:metabolism; D004249:DNA Damage; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair; D005260:Female; D016158:Genes, p53; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases