Carcinogenesis Advance Access published online on October 10, 2003
Carcinogenesis, doi:10.1093/carcin/bgg186
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel
* Corresponding author. E-mail: varda.rotter{at}weizmann.ac.il.
Received 28 January 2003
; revised 21 September 2003
; accepted 24 September 2003
The p53 tumor suppressor protein is involved in apoptosis and cell cycle checkpoints. We have recently shown that p53 also facilitates Base Excision Repair (BER). To further examine p53 involvement in the regulation of BER we chose to focus on 3-Methyladenine DNA glycosylase (3-MeAde DNA glycosylase), the first enzyme acting in the BER pathway. 3-MeAde DNA glycosylase activity was found to be modulated by the p53 protein. This modulation was dependent on the type of genotoxic stress used.
p53, 3-Methyladenine DNA glycosylase, DNA repair, Base Excision Repair, Apoptosis
The role of p53 in base excision repair following genotoxic stress
2 Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
-irradiation damage resulted in activation of glycosylase, which was enhanced by p53. Doxorubicin and hydrogen peroxide (H2O2) treatment, although inducing p53 stabilization, did not cause the activation of glycosylase. Nitric oxide (NO) resulted in activation of 3-MeAde DNA glycosylase. Surprisingly this activation was down regulated by wild type p53. The down regulation of 3-MeAde DNA Glycosylase activity was due to trans repression of glycosylase mRNA by p53. Furthermore, we found that AP endonuclease (APE) activity was not altered by NO. Our study provides evidence for a possible anti mutagenic role for p53 following exposure of cells to NO species. In the absence of p53, NO exposure results in elevation of 3-MeAde DNA glycosylase activity that results in elevation in the number of AP sites in DNA. At the same time, APE activity does not rise and removal of the AP sites is not further processed resulting in a mutator phenotype. When p53 is present, it down regulates the transcription of 3-MeAde DNA glycosylase. This provides a new model by which p53 prevents the creation of a mutator phenotype.
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