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

Amira Zaky, Carlos Busso, Tadahide Izumi, Ranajoy Chattopadhyay, Ahmad Bassiouny, Sankar Mitra, Kishor K Bhakat

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1555-1566
Number of pages12
JournalNucleic Acids Research
Volume36
Issue number5
DOIs
StatePublished - Mar 1 2008

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DNA Damage
Down-Regulation
DNA-(Apurinic or Apyrimidinic Site) Lyase
Topoisomerase I Inhibitors
Apoptosis
Camptothecin
Null Lymphocytes
Chromatin Immunoprecipitation
Luciferases
Genetic Promoter Regions
DNA Repair
Colorectal Neoplasms
Neoplasms
Proteins
Messenger RNA
Pharmaceutical Preparations
human APEX1 protein
Ectopic Gene Expression

ASJC Scopus subject areas

  • Genetics

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Regulation of the human AP-endonuclease (APE1/Ref-1) expression by the tumor suppressor p53 in response to DNA damage. / Zaky, Amira; Busso, Carlos; Izumi, Tadahide; Chattopadhyay, Ranajoy; Bassiouny, Ahmad; Mitra, Sankar; Bhakat, Kishor K.

In: Nucleic Acids Research, Vol. 36, No. 5, 01.03.2008, p. 1555-1566.

Research output: Contribution to journalArticle

Zaky, Amira ; Busso, Carlos ; Izumi, Tadahide ; Chattopadhyay, Ranajoy ; Bassiouny, Ahmad ; Mitra, Sankar ; Bhakat, Kishor K. / Regulation of the human AP-endonuclease (APE1/Ref-1) expression by the tumor suppressor p53 in response to DNA damage. In: Nucleic Acids Research. 2008 ; Vol. 36, No. 5. pp. 1555-1566.
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