This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Beneke, R.
Right arrow Articles by Möröy, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Beneke, R.
Right arrow Articles by Möröy, T.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2000, p. 6695-6703, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

DNA Excision Repair and DNA Damage-Induced Apoptosis Are Linked to Poly(ADP-Ribosyl)ation but Have Different Requirements for p53

Ralph Beneke,1 Christoph Geisen,1 Branko Zevnik,1 Thomas Bauch,2 Wolfgang-Ulrich Müller,2 Jan-Heiner Küpper,3 and Tarik Möröy1,*

Institut für Zellbiologie (Tumorforschung), IFZ,1 and Institut für Medizinische Strahlenbiologie,2 Universitätsklinikum Essen, D-45122 Essen, and Institut für Pathologie, Universitätsklinikum Tübingen, D-72076 Tübingen,3 Germany

Received 17 April 2000/Returned for modification 1 June 2000/Accepted 9 June 2000

Poly(ADP-ribose) polymerase (PARP) is a DNA binding zinc finger protein that catalyzes the transfer of ADP-ribose residues from NAD+ to itself and different chromatin constituents, forming branched ADP-ribose polymers. The enzymatic activity of PARP is induced upon DNA damage and the PARP protein is cleaved during apoptosis, which suggested a role of PARP in DNA repair and DNA damage-induced cell death. We have generated transgenic mice that lack PARP activity in thymocytes owing to the targeted expression of a dominant negative form of PARP. In the presence of single-strand DNA breaks, the absence of PARP activity correlated with a strongly increased rate of apoptosis compared to cells with intact PARP activity. We found that blockage of PARP activity leads to a drastic increase of p53 expression and activity after DNA damage and correlates with an accelerated onset of Bax expression. DNA repair is almost completely blocked in PARP-deficient thymocytes regardless of p53 status. We found the same increased susceptibility to apoptosis in PARP null mice, a similar inhibition of DNA repair kinetics, and the same upregulation of p53 in response to DNA damage. Thus, based on two different experimental in vivo models, we identify a direct, p53-independent, functional connection between poly(ADP-ribosyl)ation and the DNA excision repair machinery. Furthermore, we propose a p53-dependent link between PARP activity and DNA damage-induced cell death.

* Corresponding author. Mailing address: Institut für Zellbiologie (Tumorforschung), IFZ, Universitätsklinikum Essen, Virchowstrasse 173, D-45122 Essen, Germany. Phone: 49 (201) 723-3380. Fax: 49 (201) 723-5904. E-mail: moeroey{at}uni-essen.de.

Molecular and Cellular Biology, September 2000, p. 6695-6703, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Alvarez-Gonzalez, R. (2007). Genomic Maintenance: The p53 Poly(ADP-ribosyl)ation Connection. Sci Signal 2007: pe68-pe68 [Abstract] [Full Text]  
  • Fisher, A. E. O., Hochegger, H., Takeda, S., Caldecott, K. W. (2007). Poly(ADP-Ribose) Polymerase 1 Accelerates Single-Strand Break Repair in Concert with Poly(ADP-Ribose) Glycohydrolase. Mol. Cell. Biol. 27: 5597-5605 [Abstract] [Full Text]  
  • Susse, S., Scholz, C.-J., Burkle, A., Wiesmuller, L. (2004). Poly(ADP-ribose) polymerase (PARP-1) and p53 independently function in regulating double-strand break repair in primate cells. Nucleic Acids Res 32: 669-680 [Abstract] [Full Text]  
  • Oliver, A. W., Ame, J.-C., Roe, S. M., Good, V., de Murcia, G., Pearl, L. H. (2004). Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2. Nucleic Acids Res 32: 456-464 [Abstract] [Full Text]  
  • Ishizuka, S., Martin, K., Booth, C., Potten, C. S., de Murcia, G., Burkle, A., Kirkwood, T. B. L. (2003). Poly(ADP-ribose) polymerase-1 is a survival factor for radiation-exposed intestinal epithelial stem cells in vivo. Nucleic Acids Res 31: 6198-6205 [Abstract] [Full Text]  
  • Flohr, C., Burkle, A., Radicella, J. P., Epe, B. (2003). Poly(ADP-ribosyl)ation accelerates DNA repair in a pathway dependent on Cockayne syndrome B protein. Nucleic Acids Res 31: 5332-5337 [Abstract] [Full Text]  
  • Wieler, S., Gagne, J.-P., Vaziri, H., Poirier, G. G., Benchimol, S. (2003). Poly(ADP-ribose) Polymerase-1 Is a Positive Regulator of the p53-mediated G1 Arrest Response following Ionizing Radiation. J. Biol. Chem. 278: 18914-18921 [Abstract] [Full Text]  
  • Le Page, F., Schreiber, V., Dherin, C., de Murcia, G., Boiteux, S. (2003). Poly(ADP-ribose) Polymerase-1 (PARP-1) Is Required in Murine Cell Lines for Base Excision Repair of Oxidative DNA Damage in the Absence of DNA Polymerase beta. J. Biol. Chem. 278: 18471-18477 [Abstract] [Full Text]  
  • Schreiber, V., Ame, J.-C., Dolle, P., Schultz, I., Rinaldi, B., Fraulob, V., Menissier-de Murcia, J., de Murcia, G. (2002). Poly(ADP-ribose) Polymerase-2 (PARP-2) Is Required for Efficient Base Excision DNA Repair in Association with PARP-1 and XRCC1. J. Biol. Chem. 277: 23028-23036 [Abstract] [Full Text]  
  • Los, M., Mozoluk, M., Ferrari, D., Stepczynska, A., Stroh, C., Renz, A., Herceg, Z., Wang, Z.-Q., Schulze-Osthoff, K. (2002). Activation and Caspase-mediated Inhibition of PARP: A Molecular Switch between Fibroblast Necrosis and Apoptosis in Death Receptor Signaling. Mol. Biol. Cell 13: 978-988 [Abstract] [Full Text]  
  • Samper, E., Goytisolo, F. A., Murcia, J. M.-d., Gonzalez-Suarez, E., Cigudosa, J. C., de Murcia, G., Blasco, M. A. (2001). Normal telomere length and chromosomal end capping in poly(ADP-ribose) polymerase-deficient mice and primary cells despite increased chromosomal instability. JCB 154: 49-60 [Abstract] [Full Text]  
  • Rieber, M. S., Zangemeister-Wittke, U., Rieber, M. (2001). p53-independent Induction of Apoptosis in Human Melanoma Cells by a bcl-2/bcl-xL Bispecific Antisense Oligonucleotide. Clin. Cancer Res. 7: 1446-1451 [Abstract] [Full Text]  
  • Murcia, J. M.-d., Mark, M., Wendling, O., Wynshaw-Boris, A., de Murcia, G. (2001). Early Embryonic Lethality in PARP-1 Atm Double-Mutant Mice Suggests a Functional Synergy in Cell Proliferation during Development. Mol. Cell. Biol. 21: 1828-1832 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»