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.