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Molecular and Cellular Biology, August 2007, p. 5336-5351, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.01316-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

p53 Mediates Senescence-Like Arrest Induced by Chronic Replicational Stress{triangledown} ,{dagger}

Andriy Marusyk,1 Linda J. Wheeler,2 Christopher K. Mathews,2 and James DeGregori1*

Department of Biochemistry and Molecular Genetics, Program in Molecular Biology, Integrated Department of Immunology, University of Colorado at Denver Health Sciences Center, Aurora, Colorado 80045,1 Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97331-73052

Received 18 July 2006/ Returned for modification 1 September 2006/ Accepted 13 May 2007

Previous studies have shown that exposure of cells to high levels of replicational stress leads to permanent proliferation arrest that does not require p53. We have examined cellular responses to therapeutically relevant low levels of replicational stress that allow limited proliferation. Chronic exposure to low concentrations of hydroxyurea, aphidicolin, or etoposide induced irreversible cell cycle arrest after several population doublings. Inhibition of p53 activity antagonized this arrest and enhanced the long-term proliferation of p53 mutant cells. p21CIP1 was found to be a critical p53 target for arrest induced by hydroxyurea or aphidicolin, but not etoposide, as judged by the ability of p21CIP1 suppression to mimic the effects of p53 disruption. Suppression of Rad51 expression, required for homologous recombination repair, blocked the ability of mutant p53 to antagonize arrest induced by etoposide, but not aphidicolin. Thus, the ability of mutant p53 to prevent arrest induced by replicational stress per se is primarily dependent on preventing p21CIP1 up-regulation. However, when replication stress is associated with DNA strand breaks (such as with etoposide), up-regulation of homologous recombination repair in response to p53 disruption becomes important. Since replicational stress leads to clonal selection of cells with p53 mutations, our results highlight the potential importance of chronic replicational stress in promoting cancer development.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Genetics, Program in Molecular Biology, Integrated Department of Immunology, University of Colorado at Denver Health Sciences Center, Aurora, CO 80045. Phone: (303) 724-3230. Fax: (303) 724-3215. E-mail: james.degregori{at}uchsc.edu

{triangledown} Published ahead of print on 21 May 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2007, p. 5336-5351, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.01316-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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