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Am J Physiol Renal Physiol 294: F281-F290, 2008. First published November 7, 2007; doi:10.1152/ajprenal.00370.2007
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Tuberin regulates the DNA repair enzyme OGG1

Samy L. Habib,1,2 Daniel J. Riley,1,2 Lenin Mahimainathan,1 Basant Bhandari,1 Goutam Ghosh Choudhury,1,2 and Hanna E. Abboud1,2

1George O'Brien Kidney Research Center, Department of Medicine, University of Texas Health Science Center, and 2South Texas Veterans Healthcare System, Geriatric Research, Education, and Clinical Center, San Antonio, Texas

Submitted 7 August 2007 ; accepted in final form 7 November 2007

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.


Address for reprint requests and other correspondence: S. L. Habib, Dept. of Medicine-MSC 7882, The Univ. of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229 (e-mail: habib{at}uthscsa.edu)




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L. Mahimainathan, N. Ghosh-Choudhury, B. Venkatesan, F. Das, C. C. Mandal, N. Dey, S. L. Habib, B. S. Kasinath, H. E. Abboud, and G. Ghosh Choudhury
TSC2 Deficiency Increases PTEN via HIF1{alpha}
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[Abstract] [Full Text] [PDF]


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