Tuberin regulates the DNA repair enzyme OGG1.
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.
Habib
Samy L
SL
George O'Brien Kidney Research Center, Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA. habib@uthscsa.edu
Riley
Daniel J
DJ
Mahimainathan
Lenin
L
Bhandari
Basant
B
Choudhury
Goutam Ghosh
GG
Abboud
Hanna E
HE
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001483:Base Sequence; D023081:CCAAT-Binding Factor / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D023081:CCAAT-Binding Factor; C492061:NFYA protein, human; C492060:Nfya protein, mouse; D012333:RNA, Messenger; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C479058:oxoguanine glycosylase 1, human; D045643:DNA Repair Enzymes; D003849:Deoxyguanosine