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 Akyüz, N.
Right arrow Articles by Wiesmüller, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Akyüz, N.
Right arrow Articles by Wiesmüller, L.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2002, p. 6306-6317, Vol. 22, No. 17
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.17.6306-6317.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

DNA Substrate Dependence of p53-Mediated Regulation of Double-Strand Break Repair

Nuray Akyüz,1,2 Gisa S. Boehden,1,2 Silke Süsse,1,2 Andreas Rimek,2 Ute Preuss,3 Karl-Heinz Scheidtmann,3 and Lisa Wiesmüller1,2*

Universitätsfrauenklinik, D-89075 Ulm,1 Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, D-20251 Hamburg,2 Abteilung Molekulargenetik, Institut für Genetik, Universität Bonn, D-53117 Bonn, Germany3

Received 24 January 2002/ Returned for modification 27 February 2002/ Accepted 4 June 2002

DNA double-strand breaks (DSBs) arise spontaneously after the conversion of DNA adducts or single-strand breaks by DNA repair or replication and can be introduced experimentally by expression of specific endonucleases. Correct repair of DSBs is central to the maintenance of genomic integrity in mammalian cells, since errors give rise to translocations, deletions, duplications, and expansions, which accelerate the multistep process of tumor progression. For p53 direct regulatory roles in homologous recombination (HR) and in non-homologous end joining (NHEJ) were postulated. To systematically analyze the involvement of p53 in DSB repair, we generated a fluorescence-based assay system with a series of episomal and chromosomally integrated substrates for I-SceI meganuclease-triggered repair. Our data indicate that human wild-type p53, produced either stably or transiently in a p53-negative background, inhibits HR between substrates for conservative HR (cHR) and for gene deletions. NHEJ via microhomologies flanking the I-SceI cleavage site was also downregulated after p53 expression. Interestingly, the p53-dependent downregulation of homology-directed repair was maximal during cHR between sequences with short homologies. Inhibition was minimal during recombination between substrates that support reporter gene reconstitution by HR and NHEJ. p53 with a hotspot mutation at codon 281, 273, 248, 175, or 143 was severely defective in regulating DSB repair (frequencies elevated up to 26-fold). For the transcriptional transactivation-inactive variant p53(138V) a defect became apparent with short homologies only. These results suggest that p53 plays a role in restraining DNA exchange between imperfectly homologous sequences and thereby in suppressing tumorigenic genome rearrangements.

* Corresponding author. Mailing address: Universitätsfrauenklinik, Prittwitzstrasse 43, 89075 Ulm, Germany. Phone: 49-731-50027640. Fax: 49-731-50026674. E-mail: Lisa.Wiesmueller{at}medizin.uni-ulm.de.

Molecular and Cellular Biology, September 2002, p. 6306-6317, Vol. 22, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.17.6306-6317.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Zhang, X.-P., Liu, F., Cheng, Z., Wang, W. (2009). Cell fate decision mediated by p53 pulses. Proc. Natl. Acad. Sci. USA 106: 12245-12250 [Abstract] [Full Text]  
  • Keimling, M., Wiesmuller, L. (2009). DNA double-strand break repair activities in mammary epithelial cells--influence of endogenous p53 variants. Carcinogenesis 30: 1260-1268 [Abstract] [Full Text]  
  • Restle, A., Farber, M., Baumann, C., Bohringer, M., Scheidtmann, K. H., Muller-Tidow, C., Wiesmuller, L. (2008). Dissecting the role of p53 phosphorylation in homologous recombination provides new clues for gain-of-function mutants. Nucleic Acids Res 36: 5362-5375 [Abstract] [Full Text]  
  • Plo, I., Nakatake, M., Malivert, L., de Villartay, J.-P., Giraudier, S., Villeval, J.-L., Wiesmuller, L., Vainchenker, W. (2008). JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders. Blood 112: 1402-1412 [Abstract] [Full Text]  
  • Gatz, S. A., Keimling, M., Baumann, C., Dork, T., Debatin, K.-M., Fulda, S., Wiesmuller, L. (2008). Resveratrol modulates DNA double-strand break repair pathways in an ATM/ATR-p53- and -Nbs1-dependent manner. Carcinogenesis 29: 519-527 [Abstract] [Full Text]  
  • Schmidt, K. H., Wu, J., Kolodner, R. D. (2006). Control of Translocations between Highly Diverged Genes by Sgs1, the Saccharomyces cerevisiae Homolog of the Bloom's Syndrome Protein.. Mol. Cell. Biol. 26: 5406-5420 [Abstract] [Full Text]  
  • Baumann, C., Boehden, G. S., Burkle, A., Wiesmuller, L. (2006). Poly(ADP-RIBOSE) polymerase-1 (Parp-1) antagonizes topoisomerase I-dependent recombination stimulation by P53. Nucleic Acids Res 34: 1036-1049 [Abstract] [Full Text]  
  • Schildkraut, E., Miller, C. A., Nickoloff, J. A. (2005). Gene conversion and deletion frequencies during double-strand break repair in human cells are controlled by the distance between direct repeats. Nucleic Acids Res 33: 1574-1580 [Abstract] [Full Text]  
  • Muller-Tidow, C., Ji, P., Diederichs, S., Potratz, J., Baumer, N., Kohler, G., Cauvet, T., Choudary, C., van der Meer, T., Chan, W.-Y. I., Nieduszynski, C., Colledge, W. H., Carrington, M., Koeffler, H. P., Restle, A., Wiesmuller, L., Sobczak-Thepot, J., Berdel, W. E., Serve, H. (2004). The Cyclin A1-CDK2 Complex Regulates DNA Double-Strand Break Repair. Mol. Cell. Biol. 24: 8917-8928 [Abstract] [Full Text]  
  • Del Carratore, R., Petrucci, A., Simili, M., Fronza, G., Galli, A. (2004). Involvement of human p53 in induced intrachromosomal recombination in Saccharomyces cerevisiae. Mutagenesis 19: 333-339 [Abstract] [Full Text]  
  • Blackburn, A. C., McLary, S. C., Naeem, R., Luszcz, J., Stockton, D. W., Donehower, L. A., Mohammed, M., Mailhes, J. B., Soferr, T., Naber, S. P., Otis, C. N., Jerry, D. J. (2004). Loss of Heterozygosity Occurs via Mitotic Recombination in Trp53+/- Mice and Associates with Mammary Tumor Susceptibility of the BALB/c Strain. Cancer Res. 64: 5140-5147 [Abstract] [Full Text]  
  • Boehden, G. S., Restle, A., Marschalek, R., Stocking, C., Wiesmuller, L. (2004). Recombination at chromosomal sequences involved in leukaemogenic rearrangements is differentially regulated by p53. Carcinogenesis 25: 1305-1313 [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]  
  • Sah, N. K., Munshi, A., Nishikawa, T., Mukhopadhyay, T., Roth, J. A., Meyn, R. E. (2003). Adenovirus-mediated wild-type p53 radiosensitizes human tumor cells by suppressing DNA repair capacity. Molecular Cancer Therapeutics 2: 1223-1231 [Abstract] [Full Text]  
  • Overholtzer, M., Rao, P. H., Favis, R., Lu, X.-Y., Elowitz, M. B., Barany, F., Ladanyi, M., Gorlick, R., Levine, A. J. (2003). The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability. Proc. Natl. Acad. Sci. USA 100: 11547-11552 [Abstract] [Full Text]  
  • Larsen, E., Gran, C., Saether, B. E., Seeberg, E., Klungland, A. (2003). Proliferation Failure and Gamma Radiation Sensitivity of Fen1 Null Mutant Mice at the Blastocyst Stage. Mol. Cell. Biol. 23: 5346-5353 [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»