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Nucleic Acids Research Advance Access published online on January 21, 2008
Nucleic Acids Research, doi:10.1093/nar/gkm1173
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Regulation of the human AP-endonuclease (APE1/Ref-1) expression by the tumor suppressor p53 in response to DNA damage

Amira Zaky1,2, Carlos Busso3, Tadahide Izumi3, Ranajoy Chattopadhyay1, Ahmad Bassiouny2, Sankar Mitra1 and Kishor K. Bhakat1,*

1Department of Biochemistry and Molecular Biology, Sealy Center for Molecular Medicine, University of Texas Medical Branch, TX-77555, Galveston, USA, 2Department of Biochemistry, Alexandria University, Alexandria, Egypt, 21511 and 3Department of Otolaryngology, Louisiana State University Health Science Center, LA 70112, New Orleans, USA

*To whom correspondence should be addressed. Tel: 409 772 1779; Fax: 409 747 8608; Email: kkbhakat{at}utmb.edu

Received October 31, 2007. Revised December 19, 2007. Accepted December 20, 2007.

The human AP-endonuclease (APE1/Ref-1), an essential multifunctional protein, plays a central role in the repair of oxidative base damage via the DNA base excision repair (BER) pathway. The mammalian AP-endonuclease (APE1) overexpression is often observed in tumor cells, and confers resistance to various anticancer drugs; its downregulation sensitizes tumor cells to those agents via induction of apoptosis. Here we show that wild type (WT) but not mutant p53 negatively regulates APE1 expression. Time-dependent decrease was observed in APE1 mRNA and protein levels in the human colorectal cancer line HCT116 p53(+/+), but not in the isogenic p53 null mutant after treatment with camptothecin, a DNA topoisomerase I inhibitor. Furthermore, ectopic expression of WTp53 in the p53 null cells significantly reduced both endogenous APE1 and APE1 promoter-dependent luciferase expression in a dose-dependent fashion. Chromatin immunoprecipitation assays revealed that endogenous p53 is bound to the APE1 promoter region that includes a Sp1 site. We show here that WTp53 interferes with Sp1 binding to the APE1 promoter, which provides a mechanism for the downregulation of APE1. Taken together, our results demonstrate that WTp53 is a negative regulator of APE1 expression, so that repression of APE1 by p53 could provide an additional pathway for p53-dependent induction of apoptosis in response to DNA damage.


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