Tuberous sclerosis complex and DNA repair

Abstract

Abstract Tubero us sclerosis complex (TSC) is an autosomal dominant disorder in humans characterized by the development of hamartomas in several organs, including renal angiomyolipomas, cardiac rhabdomyomas and subependymal giant cell astrocytomas. TSC causes disabling neurologic disorders, including epilepsy, mental retardation and autism. Brain lesions, including subependymal and subcortical hamartomas, have also been reported in TSC patients. TSC is associated with hamartomas and renal cell carcinoma (RCC) as well as sporadic tumors in TSC patient. Renal angiomyolipomas associated with TSC tend to be larger, bilateral, rnultifocal and present at a younger age compared with sporadic forms. Tuberous sclerosis complex of2 genes, TSC2 encodes a protein called tuberin that normally exists in an active state and forms a heterodimeric complex with hamartin, the protein encoded by the TSCl. Deficiency ofTSC2 in Eker rat is associated with the development oftumors in several organs including kidney. The majority of renal cell tumors observed in the Eker rat originates from renal proximal tubules and are histologically similar to renal cell carcinoma in humans. On the other hand, mutations in DNA repair enzyme 8-oxoG-DNA glycosylase (OGGl) are associated with cancer. OGG1 gene is found somatically mutated in some cancer cells and is highly polymorphic among human cancers . Moreover, knockout mice in OGG1 developed spontaneously adenoma and carcinoma. We recently show that the constitutive expression of OGG1 in heterozygous (TSC2+1- ) Eker rat and in angiomyolipomas kidney tissue from human is 2-3fold less than in kidney from wild -type rats and control human subjects. In addition, we show that loss of TSC2 in kidney tumor of Eker rat is associated with loss ofOGG1 and accumulation significant levels ofoxidative DNA damage 8-oxo-deoxyguanine suggesting that TSC2 and OGG1 playa major role in renal tumorigenesis. © 2010 Landes Bioscience and Springer Science+Business Media.