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

@article{citeulike:1168103, 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.}, address = {International Agency for Research on Cancer (IARC), F-69008 Lyon, France.}, author = {Tong, W. M. and Hande, M. P. and Lansdorp, P. M. and Wang, Z. Q.}, citeulike-article-id = {1168103}, citeulike-linkout-0 = {http://dx.doi.org/10.1128/MCB.21.12.4046-4054.2001}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/11359911}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=11359911}, doi = {10.1128/MCB.21.12.4046-4054.2001}, issn = {0270-7306}, journal = {Mol Cell Biol}, keywords = {p53, parp, tankyrase, tumorigenesis}, month = {June}, number = {12}, pages = {4046--4054}, posted-at = {2007-03-17 00:21:14}, priority = {2}, title = {DNA strand break-sensing molecule poly(ADP-Ribose) polymerase cooperates with p53 in telomere function, chromosome stability, and tumor suppression.}, url = {http://dx.doi.org/10.1128/MCB.21.12.4046-4054.2001}, volume = {21}, year = {2001} }

TY - JOUR ID - citeulike:1168103 L3 - citeulike-article-id:1168103 N2 - 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. IS - 12 JF - Mol Cell Biol SN - 0270-7306 AD - International Agency for Research on Cancer (IARC), F-69008 Lyon, France. EP - 4054 TI - DNA strand break-sensing molecule poly(ADP-Ribose) polymerase cooperates with p53 in telomere function, chromosome stability, and tumor suppression. VL - 21 SP - 4046 KW - p53 KW - parp KW - tankyrase KW - tumorigenesis AU - Tong, WM AU - Hande, MP AU - Lansdorp, PM AU - Wang, ZQ PY - 2001/06// UR - http://dx.doi.org/10.1128/MCB.21.12.4046-4054.2001 ER -