Novel mechanism of regulation of the DNA repair enzyme OGG1 in tuberin-deficient cells

Samy L Habib, Besant K. Bhandari, Nahed Sadek, Sherry L. Abboud-Werner, Hanna E. Abboud

Research output: Contribution to journalArticle

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Abstract

Tuberin (protein encodes by tuberous sclerosis complex 2, Tsc2) deficiency is associated with the decrease in the DNA repair enzyme 8-oxoG-DNA glycosylase (OGG1) in tumour kidney of tuberous sclerosis complex (TSC) patients. The purpose of this study was to elucidate the mechanisms by which tuberin regulates OGG1. The partial deficiency in tuberin expression that occurs in the renal proximal tubular cells and kidney cortex of the Eker rat is associated with decreased activator protein 4 (AP4) and OGG1 expression. A complete deficiency in tuberin is associated with loss of AP4 and OGG1 expression in kidney tumour from Eker rats and the accumulation of significant levels of 8-oxodeoxyguanosine. Knockdown of tuberin expression in human renal epithelial cells (HEK293) with small interfering RNA (siRNA) also resulted in a marked decrease in the expression of AP4 and OGG1. In contrast, overexpression of tuberin in HEK293 cells increased the expression of AP4 and OGG1 proteins. Downregulation of AP4 expression using siRNA resulted in a significant decrease in the protein expression of OGG1. Immunoprecipitation studies show that AP4 is associated with tuberin in cells. Gel shift analysis and chromatin immunoprecipitation identified the transcription factor AP4 as a positive regulator of the OGG1 promoter. AP4 DNA-binding activity is significantly reduced in Tsc2-/- as compared with Tsc2+/+ cells. Transcriptional activity of the OGG1 promoter is also decreased in tuberin-null cells compared with wild-type cells. These data indicate a novel role for tuberin in the regulation of OGG1 through the transcription factor AP4. This regulation may be important in the pathogenesis of kidney tumours in patients with TSC disease.

Original languageEnglish (US)
Pages (from-to)2022-2030
Number of pages9
JournalCarcinogenesis
Volume31
Issue number11
DOIs
StatePublished - Nov 2010

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DNA Repair Enzymes
Tuberous Sclerosis
Kidney
Small Interfering RNA
Transcription Factors
tuberous sclerosis complex 2 protein
DNA Glycosylases
enhancer-binding protein AP-4
Kidney Cortex
Null Lymphocytes
Neoplasms
Chromatin Immunoprecipitation
HEK293 Cells
Electrophoretic Mobility Shift Assay
Immunoprecipitation
Proteins
Down-Regulation
Epithelial Cells

ASJC Scopus subject areas

  • Cancer Research

Cite this

Habib, S. L., Bhandari, B. K., Sadek, N., Abboud-Werner, S. L., & Abboud, H. E. (2010). Novel mechanism of regulation of the DNA repair enzyme OGG1 in tuberin-deficient cells. Carcinogenesis, 31(11), 2022-2030. https://doi.org/10.1093/carcin/bgq189

Novel mechanism of regulation of the DNA repair enzyme OGG1 in tuberin-deficient cells. / Habib, Samy L; Bhandari, Besant K.; Sadek, Nahed; Abboud-Werner, Sherry L.; Abboud, Hanna E.

In: Carcinogenesis, Vol. 31, No. 11, 11.2010, p. 2022-2030.

Research output: Contribution to journalArticle

Habib, SL, Bhandari, BK, Sadek, N, Abboud-Werner, SL & Abboud, HE 2010, 'Novel mechanism of regulation of the DNA repair enzyme OGG1 in tuberin-deficient cells', Carcinogenesis, vol. 31, no. 11, pp. 2022-2030. https://doi.org/10.1093/carcin/bgq189
Habib SL, Bhandari BK, Sadek N, Abboud-Werner SL, Abboud HE. Novel mechanism of regulation of the DNA repair enzyme OGG1 in tuberin-deficient cells. Carcinogenesis. 2010 Nov;31(11):2022-2030. https://doi.org/10.1093/carcin/bgq189
Habib, Samy L ; Bhandari, Besant K. ; Sadek, Nahed ; Abboud-Werner, Sherry L. ; Abboud, Hanna E. / Novel mechanism of regulation of the DNA repair enzyme OGG1 in tuberin-deficient cells. In: Carcinogenesis. 2010 ; Vol. 31, No. 11. pp. 2022-2030.
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