Tuberin regulates the DNA repair enzyme OGG1

Samy L. Habib, Daniel J. Riley, Lenin Mahimainathan, Basant Bhandari, Goutam Ghosh Choudhury, Hanna E. Abboud

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Abstract

The tuberous sclerosis complex (TSC) is caused by defects in one of two tumor suppressor genes, TSC-1 or TSC-2. The TSC-2 gene encodes tuberin, a protein involved in the pathogenesis of kidney tumors, both angiomyolipomas and renal cell carcinomas. We investigated a potential role for tuberin in regulating a key DNA repair pathway. Downregulation of tuberin in human renal epithelial cells using siRNA resulted in a marked decrease in the abundance of the 8-oxoG-DNA glycosylase (OGG1). Mouse embryonic fibroblasts deficient in tuberin (TSC2-/- and TSC2-/-) also had markedly decreased OGG1 mRNA and protein expression, as well as undetectable OGG1 activity accompanied by accumulation of 8-oxodG. Gel shift analyses and chromatin immunoprecipatation identified the transcription factor NF-YA as a regulator of OGG1 activity. The binding of NF-YA to the OGG1 promoter was significantly reduced in TSC2-/- compared with TSC2-/- cells. Introduction of TSC2 cDNA into the tuberin-deficient cells restored NF-YA and OGG1 expression. Transcriptional activity of the OGG1 promoter was also decreased in tuberin-null cells. In addition, mutation of both CAAT boxes, the sites to which NF-YA binds, completely inhibits OGG1 promoter activity. These data provide the first evidence that tuberin regulates a specific DNA repair enzyme, OGG1. This regulation may be important in the pathogenesis of kidney tumors in patients with TSC.

Original languageEnglish (US)
Pages (from-to)F281-F290
JournalAmerican Journal of Physiology - Renal Physiology
Volume294
Issue number1
DOIs
StatePublished - Jan 1 2008

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ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Habib, S. L., Riley, D. J., Mahimainathan, L., Bhandari, B., Choudhury, G. G., & Abboud, H. E. (2008). Tuberin regulates the DNA repair enzyme OGG1. American Journal of Physiology - Renal Physiology, 294(1), F281-F290. https://doi.org/10.1152/ajprenal.00370.2007